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TITLE
Exploration of New Reactivities ofAzetidinols and Alkynylborates(Dissertation_全文 )
Shimamoto Yasuhiro
Shimamoto Yasuhiro Exploration of New Reactivities of Azetidinols and Alkynylborates京都大学 2014 博士(工学)
2014-03-24
httpsdoiorg1014989doctork18301
Exploration of New Reactivities of Azetidinols and Alkynylborates
Yasuhiro Shimamoto
2014
Preface
The studies presented in this thesis have been carried out under the direction of
Professor Masahiro Murakami at Kyoto University during 2008-2014 The studies
concerned with the development of the new synthetic reactions using azetidinols and
alkynyl borates
The author would like to express his sincerest gratitude to Professor Masahiro
Murakami for his kind guidance powerful encouragement stimulating discussions
throughout this study The author learned a lot of things from Professor Murakami They
are not only chemistry but also important things to live
The author is grateful to Assistant Professor Naoki Ishida for his support and teaching
chemical techniques and discussions The author is also grateful to Associate Professor
Tomoya Miura and Assistant Professor Akira Yada for their discussion and suggestion
The author was fortunate to have had a lot of assistance of Dr David Neĉas Ms
Hanako Sunaba and Mr Takaaki Yano The author acknowledge to them for their
patience earnest and collaborations
The author wishes to express his gratitude to Dr Peter Bruumlchner Dr Akiko Okamoto
Dr Lantao Liu Dr Changkun Li Dr Scott G Stewart Dr Hiroshi Shimizu Dr
Masanori Shigeno Dr Motoshi Yamauchi Dr Takeharu Toyoshima Mr Yoshiteru Ito
Ms Mizuna Narumi Mr Yoshiyuki Yamaguchi Mr Keita Ueda Mr Taisaku Moriya
Mr Tomohiro Igarashi Mr Masao Morimoto Mr Taiga Yamamoto Mr Osamu
Kozawa Ms Paula de Mendoza Bonmati Mr Shota Sawano Mr Wataru Ikemoto Mr
Yusuke Mikano Mr Akira Kosaka Mr Tsuneaki Biyajima Mr Yuuta Nakanishi Mr
Tatsuya Yuhki Mr Kentaro Hiraga Ms Yui Nishida Mr Yusuke Masuda Mr
Takamasa Tanaka Mr Yuuta Funakoshi Mr Tetsuji Fujii Mr Shintaro Okumura Mr
Shoichiro Fujita Mr Yuuki Yamanaka Mr Takayuki Nakamuro Mr Andreas Fetzer
Mr Norikazu Ishikawa Mr Shoki Nishi Mr Kohei Matsumoto Ms Yuki Sakai and all
other members of Murakami Laboratory for their enthusiasm and kind consideration
The author is grateful to Mr Daishi Fujino Mr Kenichiro Nakai Mr Momotaro
Takeda Mr Yosuke Tani and all other friends for stimulating conversation with them
The author thanks Mr Haruo Fujita Mr Tadashi Yamaoka Ms Keiko Kuwata Ms
Midori Yamamura Ms Sakiko Goto Ms Eriko Kusaka Ms Karin Nishimura for the
measurement of NMR spectra and Mass spectra
The author is grateful for Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists
Finally the author expresses his deep appreciation to his family especially his parents
Mr Takashi Shimamoto Ms Akiyo Shimamoto for their constant assistant and
encouragement
Yasuhiro Shimamoto
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of engineering
Kyoto University
Contents
General Introduction 1
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino Ketones 9
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams 29
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters Stereochemistry
Reversed by Ligand in the Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides 67
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units 89
Chapter 5
Regioselective Construction of Indene Skeltons by Palladium-Catalyzed Annulation of
Alkynylborates with o-Iodophenyl Ketones 105
List of Publications 127
General Introduction
1
General Introduction
Organic synthesis has contributed to our lives For example various chemical
industries pharmaceutical chemistry material chemistry and others make our lives
more comfortable and convenient
In this thesis the author would like to describe new synthetic reactions which are
directed towards following issues
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into benzo-
sultams
(3) Palladium catalyzed reaction of alkynylborates with aryl halides
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
The utilization of solar energy is an attractive subject in organic synthesis because
solar energy is one of the most sustainable energy in the world1 On the other hand the
utilization of carbon dioxides as the C1 source is still significant challenge because of
its stability2 In chapter 1 the author describs solar-driven incorporation of carbon
dioxide into -amino ketones In first step photoreaction promoted by solar light
produces azetidinols3 This transformation is endergonic thus harvesting the solar
energy as the chemical energy in the form of structural strain In second step carbon
dioxides is incorporated into the azetidinls to afford cyclic carbonates The relief of the
structural strain serves as driving force for the CO2 incorporation reaction This two
phase reaction system demonstrates a simple model of chemical utilization of solar
energy for CO2 incorporation
sun
CO2energy charge
Ph
O
NTs
Me
N
Ts
OHPh
OO
O
Ph
NHTs
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 2
Exploration of New Reactivities of Azetidinols and Alkynylborates
Yasuhiro Shimamoto
2014
Preface
The studies presented in this thesis have been carried out under the direction of
Professor Masahiro Murakami at Kyoto University during 2008-2014 The studies
concerned with the development of the new synthetic reactions using azetidinols and
alkynyl borates
The author would like to express his sincerest gratitude to Professor Masahiro
Murakami for his kind guidance powerful encouragement stimulating discussions
throughout this study The author learned a lot of things from Professor Murakami They
are not only chemistry but also important things to live
The author is grateful to Assistant Professor Naoki Ishida for his support and teaching
chemical techniques and discussions The author is also grateful to Associate Professor
Tomoya Miura and Assistant Professor Akira Yada for their discussion and suggestion
The author was fortunate to have had a lot of assistance of Dr David Neĉas Ms
Hanako Sunaba and Mr Takaaki Yano The author acknowledge to them for their
patience earnest and collaborations
The author wishes to express his gratitude to Dr Peter Bruumlchner Dr Akiko Okamoto
Dr Lantao Liu Dr Changkun Li Dr Scott G Stewart Dr Hiroshi Shimizu Dr
Masanori Shigeno Dr Motoshi Yamauchi Dr Takeharu Toyoshima Mr Yoshiteru Ito
Ms Mizuna Narumi Mr Yoshiyuki Yamaguchi Mr Keita Ueda Mr Taisaku Moriya
Mr Tomohiro Igarashi Mr Masao Morimoto Mr Taiga Yamamoto Mr Osamu
Kozawa Ms Paula de Mendoza Bonmati Mr Shota Sawano Mr Wataru Ikemoto Mr
Yusuke Mikano Mr Akira Kosaka Mr Tsuneaki Biyajima Mr Yuuta Nakanishi Mr
Tatsuya Yuhki Mr Kentaro Hiraga Ms Yui Nishida Mr Yusuke Masuda Mr
Takamasa Tanaka Mr Yuuta Funakoshi Mr Tetsuji Fujii Mr Shintaro Okumura Mr
Shoichiro Fujita Mr Yuuki Yamanaka Mr Takayuki Nakamuro Mr Andreas Fetzer
Mr Norikazu Ishikawa Mr Shoki Nishi Mr Kohei Matsumoto Ms Yuki Sakai and all
other members of Murakami Laboratory for their enthusiasm and kind consideration
The author is grateful to Mr Daishi Fujino Mr Kenichiro Nakai Mr Momotaro
Takeda Mr Yosuke Tani and all other friends for stimulating conversation with them
The author thanks Mr Haruo Fujita Mr Tadashi Yamaoka Ms Keiko Kuwata Ms
Midori Yamamura Ms Sakiko Goto Ms Eriko Kusaka Ms Karin Nishimura for the
measurement of NMR spectra and Mass spectra
The author is grateful for Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists
Finally the author expresses his deep appreciation to his family especially his parents
Mr Takashi Shimamoto Ms Akiyo Shimamoto for their constant assistant and
encouragement
Yasuhiro Shimamoto
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of engineering
Kyoto University
Contents
General Introduction 1
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino Ketones 9
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams 29
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters Stereochemistry
Reversed by Ligand in the Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides 67
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units 89
Chapter 5
Regioselective Construction of Indene Skeltons by Palladium-Catalyzed Annulation of
Alkynylborates with o-Iodophenyl Ketones 105
List of Publications 127
General Introduction
1
General Introduction
Organic synthesis has contributed to our lives For example various chemical
industries pharmaceutical chemistry material chemistry and others make our lives
more comfortable and convenient
In this thesis the author would like to describe new synthetic reactions which are
directed towards following issues
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into benzo-
sultams
(3) Palladium catalyzed reaction of alkynylborates with aryl halides
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
The utilization of solar energy is an attractive subject in organic synthesis because
solar energy is one of the most sustainable energy in the world1 On the other hand the
utilization of carbon dioxides as the C1 source is still significant challenge because of
its stability2 In chapter 1 the author describs solar-driven incorporation of carbon
dioxide into -amino ketones In first step photoreaction promoted by solar light
produces azetidinols3 This transformation is endergonic thus harvesting the solar
energy as the chemical energy in the form of structural strain In second step carbon
dioxides is incorporated into the azetidinls to afford cyclic carbonates The relief of the
structural strain serves as driving force for the CO2 incorporation reaction This two
phase reaction system demonstrates a simple model of chemical utilization of solar
energy for CO2 incorporation
sun
CO2energy charge
Ph
O
NTs
Me
N
Ts
OHPh
OO
O
Ph
NHTs
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 3
Preface
The studies presented in this thesis have been carried out under the direction of
Professor Masahiro Murakami at Kyoto University during 2008-2014 The studies
concerned with the development of the new synthetic reactions using azetidinols and
alkynyl borates
The author would like to express his sincerest gratitude to Professor Masahiro
Murakami for his kind guidance powerful encouragement stimulating discussions
throughout this study The author learned a lot of things from Professor Murakami They
are not only chemistry but also important things to live
The author is grateful to Assistant Professor Naoki Ishida for his support and teaching
chemical techniques and discussions The author is also grateful to Associate Professor
Tomoya Miura and Assistant Professor Akira Yada for their discussion and suggestion
The author was fortunate to have had a lot of assistance of Dr David Neĉas Ms
Hanako Sunaba and Mr Takaaki Yano The author acknowledge to them for their
patience earnest and collaborations
The author wishes to express his gratitude to Dr Peter Bruumlchner Dr Akiko Okamoto
Dr Lantao Liu Dr Changkun Li Dr Scott G Stewart Dr Hiroshi Shimizu Dr
Masanori Shigeno Dr Motoshi Yamauchi Dr Takeharu Toyoshima Mr Yoshiteru Ito
Ms Mizuna Narumi Mr Yoshiyuki Yamaguchi Mr Keita Ueda Mr Taisaku Moriya
Mr Tomohiro Igarashi Mr Masao Morimoto Mr Taiga Yamamoto Mr Osamu
Kozawa Ms Paula de Mendoza Bonmati Mr Shota Sawano Mr Wataru Ikemoto Mr
Yusuke Mikano Mr Akira Kosaka Mr Tsuneaki Biyajima Mr Yuuta Nakanishi Mr
Tatsuya Yuhki Mr Kentaro Hiraga Ms Yui Nishida Mr Yusuke Masuda Mr
Takamasa Tanaka Mr Yuuta Funakoshi Mr Tetsuji Fujii Mr Shintaro Okumura Mr
Shoichiro Fujita Mr Yuuki Yamanaka Mr Takayuki Nakamuro Mr Andreas Fetzer
Mr Norikazu Ishikawa Mr Shoki Nishi Mr Kohei Matsumoto Ms Yuki Sakai and all
other members of Murakami Laboratory for their enthusiasm and kind consideration
The author is grateful to Mr Daishi Fujino Mr Kenichiro Nakai Mr Momotaro
Takeda Mr Yosuke Tani and all other friends for stimulating conversation with them
The author thanks Mr Haruo Fujita Mr Tadashi Yamaoka Ms Keiko Kuwata Ms
Midori Yamamura Ms Sakiko Goto Ms Eriko Kusaka Ms Karin Nishimura for the
measurement of NMR spectra and Mass spectra
The author is grateful for Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists
Finally the author expresses his deep appreciation to his family especially his parents
Mr Takashi Shimamoto Ms Akiyo Shimamoto for their constant assistant and
encouragement
Yasuhiro Shimamoto
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of engineering
Kyoto University
Contents
General Introduction 1
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino Ketones 9
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams 29
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters Stereochemistry
Reversed by Ligand in the Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides 67
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units 89
Chapter 5
Regioselective Construction of Indene Skeltons by Palladium-Catalyzed Annulation of
Alkynylborates with o-Iodophenyl Ketones 105
List of Publications 127
General Introduction
1
General Introduction
Organic synthesis has contributed to our lives For example various chemical
industries pharmaceutical chemistry material chemistry and others make our lives
more comfortable and convenient
In this thesis the author would like to describe new synthetic reactions which are
directed towards following issues
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into benzo-
sultams
(3) Palladium catalyzed reaction of alkynylborates with aryl halides
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
The utilization of solar energy is an attractive subject in organic synthesis because
solar energy is one of the most sustainable energy in the world1 On the other hand the
utilization of carbon dioxides as the C1 source is still significant challenge because of
its stability2 In chapter 1 the author describs solar-driven incorporation of carbon
dioxide into -amino ketones In first step photoreaction promoted by solar light
produces azetidinols3 This transformation is endergonic thus harvesting the solar
energy as the chemical energy in the form of structural strain In second step carbon
dioxides is incorporated into the azetidinls to afford cyclic carbonates The relief of the
structural strain serves as driving force for the CO2 incorporation reaction This two
phase reaction system demonstrates a simple model of chemical utilization of solar
energy for CO2 incorporation
sun
CO2energy charge
Ph
O
NTs
Me
N
Ts
OHPh
OO
O
Ph
NHTs
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 4
Midori Yamamura Ms Sakiko Goto Ms Eriko Kusaka Ms Karin Nishimura for the
measurement of NMR spectra and Mass spectra
The author is grateful for Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists
Finally the author expresses his deep appreciation to his family especially his parents
Mr Takashi Shimamoto Ms Akiyo Shimamoto for their constant assistant and
encouragement
Yasuhiro Shimamoto
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of engineering
Kyoto University
Contents
General Introduction 1
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino Ketones 9
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams 29
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters Stereochemistry
Reversed by Ligand in the Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides 67
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units 89
Chapter 5
Regioselective Construction of Indene Skeltons by Palladium-Catalyzed Annulation of
Alkynylborates with o-Iodophenyl Ketones 105
List of Publications 127
General Introduction
1
General Introduction
Organic synthesis has contributed to our lives For example various chemical
industries pharmaceutical chemistry material chemistry and others make our lives
more comfortable and convenient
In this thesis the author would like to describe new synthetic reactions which are
directed towards following issues
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into benzo-
sultams
(3) Palladium catalyzed reaction of alkynylborates with aryl halides
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
The utilization of solar energy is an attractive subject in organic synthesis because
solar energy is one of the most sustainable energy in the world1 On the other hand the
utilization of carbon dioxides as the C1 source is still significant challenge because of
its stability2 In chapter 1 the author describs solar-driven incorporation of carbon
dioxide into -amino ketones In first step photoreaction promoted by solar light
produces azetidinols3 This transformation is endergonic thus harvesting the solar
energy as the chemical energy in the form of structural strain In second step carbon
dioxides is incorporated into the azetidinls to afford cyclic carbonates The relief of the
structural strain serves as driving force for the CO2 incorporation reaction This two
phase reaction system demonstrates a simple model of chemical utilization of solar
energy for CO2 incorporation
sun
CO2energy charge
Ph
O
NTs
Me
N
Ts
OHPh
OO
O
Ph
NHTs
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 5
Contents
General Introduction 1
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino Ketones 9
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams 29
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters Stereochemistry
Reversed by Ligand in the Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides 67
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units 89
Chapter 5
Regioselective Construction of Indene Skeltons by Palladium-Catalyzed Annulation of
Alkynylborates with o-Iodophenyl Ketones 105
List of Publications 127
General Introduction
1
General Introduction
Organic synthesis has contributed to our lives For example various chemical
industries pharmaceutical chemistry material chemistry and others make our lives
more comfortable and convenient
In this thesis the author would like to describe new synthetic reactions which are
directed towards following issues
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into benzo-
sultams
(3) Palladium catalyzed reaction of alkynylborates with aryl halides
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
The utilization of solar energy is an attractive subject in organic synthesis because
solar energy is one of the most sustainable energy in the world1 On the other hand the
utilization of carbon dioxides as the C1 source is still significant challenge because of
its stability2 In chapter 1 the author describs solar-driven incorporation of carbon
dioxide into -amino ketones In first step photoreaction promoted by solar light
produces azetidinols3 This transformation is endergonic thus harvesting the solar
energy as the chemical energy in the form of structural strain In second step carbon
dioxides is incorporated into the azetidinls to afford cyclic carbonates The relief of the
structural strain serves as driving force for the CO2 incorporation reaction This two
phase reaction system demonstrates a simple model of chemical utilization of solar
energy for CO2 incorporation
sun
CO2energy charge
Ph
O
NTs
Me
N
Ts
OHPh
OO
O
Ph
NHTs
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 6
General Introduction
1
General Introduction
Organic synthesis has contributed to our lives For example various chemical
industries pharmaceutical chemistry material chemistry and others make our lives
more comfortable and convenient
In this thesis the author would like to describe new synthetic reactions which are
directed towards following issues
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into benzo-
sultams
(3) Palladium catalyzed reaction of alkynylborates with aryl halides
(1) Solar-driven incorporation of carbon dioxides into -amino ketones
The utilization of solar energy is an attractive subject in organic synthesis because
solar energy is one of the most sustainable energy in the world1 On the other hand the
utilization of carbon dioxides as the C1 source is still significant challenge because of
its stability2 In chapter 1 the author describs solar-driven incorporation of carbon
dioxide into -amino ketones In first step photoreaction promoted by solar light
produces azetidinols3 This transformation is endergonic thus harvesting the solar
energy as the chemical energy in the form of structural strain In second step carbon
dioxides is incorporated into the azetidinls to afford cyclic carbonates The relief of the
structural strain serves as driving force for the CO2 incorporation reaction This two
phase reaction system demonstrates a simple model of chemical utilization of solar
energy for CO2 incorporation
sun
CO2energy charge
Ph
O
NTs
Me
N
Ts
OHPh
OO
O
Ph
NHTs
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 7
General Introduction
2
(2) 15-Rhodium shift in rearrangement of N-arenesulfonylazetidinols into
benzosultams
1n-metal shift is an attractive process which enables unique metal catalyzed reactions
Therefore many reactions have been developed via a 1n-metal shift Especially a lot of
rhodium and palladium catalyzed reactions involving 14-metal shift have been
developed456
However there are much less examples of 15-metal shift than 14-metal
shift7
MH14-metal shift
1
2 3
4
HM
1
2 3
4
H M1
23
4
5
M H1
23
4
515-metal shift
In chapter 2 the author describes rhodium catalyzed rearrangement of
N-arenesulfonylazetidinols into benzosultams via 15-rhodium shift Various
benzosultams were obtained in quantitative yield In addition chiral azetidinols which
are easily available by modified Seebachrsquos procedure8 afford the enatio- and
diastereopure benzosultams quantitatively
N
Ts
Ph OHMe
SN
MeO O
Ph OH
cat Rh
(3) Palladium catalyzed reaction of alkynylborates with aryl halide
Organoboron compounds are versatile synthetic reagents for carbon-carbon bond
formation reactions because they are easily handled and have the well known
reactivities9 In addition their utilizations are increasing in the field of pharmaceutical
chemistry10
and material science11
Therefore it is the important for organic chemists to
develop the new efficient methods to synthesis the organoboron compounds precisely
Alkynylborates react with electrophiles on the -position of boron to afford the
alkenylboranes which are difficult to synthesize by other conventional methods12
We
have focused such reactivities and developed a palladium catalyzed reaction of
alkynylborates13
R1 B
R2
R2
R2
+ R3 Br
R3
R1 R2
B
R2
R2
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 8
General Introduction
3
In chapter 3 the author describes the palladium catalyzed reaction of alkynylborates
with aryl halides which provids the trisubstituted alkenylboranes regio- and
stereoselectively The stereochemistry of the alkenylboranes is dependent upon the
ligand employed Using Xantphos as the ligand (Z)-alkenylboranes were obtained
stereoselectively On the other hand in the case of (o-tol)3P (E)-alkenylboranes were
obtained
Et
Ph
Ph
B O+
PhBr LPd(-allyl)Cl
L = XANTPhos
LPd(-allyl)Cl
L = P(o-tol)3 Ph
Et
Ph
B O
B
Et
Ph
Et
Ph
B
Ph
Ph
Et
B
Ph
Me3NO
Me3NO
[Me4N]
Oligo(arylenevinylene)s are important compounds in the field of material science14
Though a wide variety of oligo(arylenevinylene)s have been synthesized
oligo(arylenevinylene)s with tetrasubstituted olefin units have not been synthesized In
chapter 4 the author describes an iterative approach to this class of molecules Various
oligo(arylenevinylene)s are synthesized stereoselectively starting from bromo (iodo)
benzenes and alkynylborates
MeO
Br
I
Br
NaOH
R Ph
MeO Br
B
R
Ph
RB
Ph
OMe
[Me4N]
R Ph
MeOR Ph
Br
R =OMOM
n
B
R
Ph
[Me4N] I
Br
NaOH
R Ph
MeOR Ph
Br
n = 2~4
Pd-XANTPhos
Pd-XANTPhos
Indene skeleton is an important substructure in the field of pharmaceutical chemistry
and material science An annulation reaction of o-halobenzoyl compounds with alkyne
provides an efficient way to synthesize indenols however it is difficult to control the
regioselectivity In chapter 5 the author describs a palladuium-catalyzed reaction of
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 9
General Introduction
4
alkynylborates with o-iodophenyl ketones which provides 23-disubstituted indenols
regioselectively
I
Me
O+
MeOH
R2
R1Pd-XANTPhosB
R2
R1
[Me4N]
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 10
General Introduction
5
Reference
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(3) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H J
Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi M
M Hill J J Chem Soc Perkin Trans 1 1980 1671
(4) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi F
Larock R Top Curr Chem 2010 292 123-164
(5) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S J
Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127 739-742
(c) Campo M A Larock R C J Am Chem Soc 2002 124 14326-14327 (d)
Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed 2003 42 5736-5740
(e) Masselot D Charmant J P H Gallagher T J Am Chem Soc 2005 128
694-695 (f) Barder T E Walker S D Martinelli J R Buchwald S L J Am
Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D Campo M A Larock R
C J Am Chem Soc 2007 129 5288-5295 and references cited therein
(6) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d) Shintani
R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873 (e) Yamabe
H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005 127 3248-3249
(f) Matsuda T Shigeno M Murakami M J Am Chem Soc 2007 129
12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth Catal 2008 350
2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem Int Ed 2009 48
6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem Eur J 2009 15
12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed 2010 49
10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A B
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076
Page 11
General Introduction
6
Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi A
Chem Commun 2012 48 2988-2990 and references cited therein
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439 (d) So C M Kume S Hayashi T J Am Chem Soc 2013 135
10990
(8) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280 (c)
(9) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(10) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis S
A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b) Zhu
Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai L Gao
Q Z J Med Chem 2009 52 4192
(11) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem Rev
2006 250 1107
(12) (a) Negishi E J Org Chem 1976 108 281 (b) Pelter A Bentley T W
Harrison C R Subrahmanyam C Laub R J J Chem Soc Perkin Trans 1 1976
2419
(13) (a) Ishida N Miura T Murakami M Chem Commun 2006 4381 (b) Ishida
N Narumi M Murakami M Org Lett 2008 10 1279 (c) Ishida N Shinmoto
T Sawano S Miura T Murakami M Bull Chem Soc Jpn 2010 11 1380 (d)
Ishida N Ikemoto W Narumi M Murakami M Org Lett 2011 13 3008 (e)
Ishida N Narumi M Murakami M Helv Chim Acta 2012 95 2474
(14) (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E Diederich F Angew
Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr Chem 1999 201 163
(15) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R Greengrass
P M Casy A F Mercer A D Br J Pharmacol 1991 104 270ndash276 (c)
Huffman J W Padgett L W Curr Med Chem 2005 12 1395ndash1411
General Introduction
7
(16) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
General Introduction
8
Chapter 1
9
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into -Amino
Ketones
Abstract
-Amino ketones react with carbon dioxides to give cyclic carbonates via
photocyclization promoted by solar light This reaction demonstrates a model of
chemical utilization of solar energy for CO2 incorporation
Reproduced with permission from Angew Chem Int Ed 2012 51 11750-11752
Copyright 2012 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 1
10
Introduction
The recent manifestation of the potential risk inherent to nuclear technologies has
incited a strong demand for exploration of innovative means to exploit energy from
natural sources thus increasing the need for research on sustainable energy in many
scientific fields Chemists can contribute by developing chemical systems to utilize
solar light which is undoubtedly the best source of sustainable energy available on the
planet1 Another imperative issue is the establishment of carbon-neutral systems
2 One
synthetic approach to this issue is the incorporation of CO2 into organic compounds as a
chemical feedstock3 High-energy compounds suit energetically low CO2 as the reaction
partner Under these circumstances it presents a significant challenge to simultaneously
tackle the two issues mentioned above Thus we tried to develop a reaction that is
promoted by solar light and utilizes CO2 as a chemical feedstock (Figure 1)
Figure 1 Solar Driven Incorporation of Carbon Dioxide
starting substances
Incorporated products
CO2
sun
CO2energy charge
high energy
intermediates
Results and Discussion
We report herein a solar-driven process that incorporates CO2 into -methylamino
ketones The resulting aminosubstituted cyclic carbonates are expected to be useful
building blocks of pharmaceuticals and fuel additives4 Our attention was initially
directed to a photochemical cyclization reaction observed with a-methylamino ketones5
Of note was that this photoreaction proceeded in an energetically uphill direction A
high-energy four-membered ring6 was constructed through the insertion of a
photo-excited carbonyl group into the carbonndashhydrogen bond of a pendant methyl group
on a nitrogen atom In a formal sense the intrinsically inert carbonndashhydrogen bond was
cleaved7 and added across the carbonndashoxygen double bond in a 4-exo-trig mode
8
Although the reaction was originally reported to require irradiation with a mercury lamp
which used electricity5b
we discovered that natural solar light successfully effected this
energetically uphill reaction -amino ketone 1a cyclized at a reasonable rate upon
exposure to solar light (Scheme 1)
Chapter 1
11
Scheme 1 Solar Light Promoted Cyclization of 1a
Ph
O
NTs
Mesolar light
N
Ph OH
Ts
2a 91
1aDMA
Furthermore ordinary Pyrex glass not quartz was suitable for the reaction vessel
light of wavelengths below 400 nm was required for the photoreaction and Pyrex glass
transmitted a sufficient amount of operative light even on a cloudy day Thus simply
setting a Pyrex tube containing a solution of 1a in NN-dimethylacetamide (DMA) on a
balcony or rooftop brought about the cyclization The conversion was dependent upon
the amount of solar radiation We defined it as ldquosunnyrdquo when an hourly solar radiation
over 04 kWm-2
was observed and as ldquocloudyrdquo when it ranged from 01 to 04 kWm-2
Typically the total amount of solar radiation amounted to 55 kWhm-2
in eight hours on
a sunny day to cause full conversion of 1a on a 01 mmol scale (010 mmolL-1
Figure
2A) The reaction mixture was subsequently applied to conventional column
chromatography on silica gel and analytically pure azetidinol 2a was isolated in 91
yield In contrast an analogous experiment on a cloudy day produced 2a in 54yield
after eight hours (Figure 2B) when the total amount of solar radiation reached 09
kWhm-2
Thus it turned out to be possible to transfer 1a into the product9 by using solar
energy even on a cloudy day
Chapter 1
12
Figure 2 Solar-Light Promoted Cyclization of 1a
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8
0
20
40
60
80
100
0 1 2 3 4 5 6
(A) Residual ratio of 1a () and yield of 2a () during solar
radiation (B) Yield of 2a over time on sunny () and cloudy day ()
We next attempted to incorporate CO2 into azetidinol 2a in which energy has been
stored by reacting it with CO2 and a remarkably simple way was found CO2 was
successfully incorporated upon exposure of a solution of 2a in DMA to gaseous CO2 in
the presence of a base For example stirring a heterogeneous mixture of 2a and Cs2CO3
(40 equiv) in DMA under an atmosphere of CO2 (1 atm) at 60degC for ten hours led to the
quantitative production of the cyclic carbonate 3a which was isolated in 93 yield after
purification by chromatography (Scheme 2) Organic bases such as
18-diazabicyclo[540]undec-7-ene (DBU) also afforded 3a albeit in a lower yield
(56)
Chapter 1
13
Scheme 2 Incorporation of Carbon Dioxide
40 equiv Cs2CO3
1 atm CO2
DMA 60 degC
OO
O
Ph
NHTs
3a 93
N
Ph OH
Ts
2a
The formation of 3a is explained by assuming the pathway depicted in Scheme 34
Azetidinol 2a is initially deprotonated by Cs2CO3 to produce alkoxide anion A which
subsequently adds to CO2 to afford carbonate anion B The following nucleophilic
attack of the anionic oxygen onto the 2-carbon atom prompts displacement of the
tosylamide anion through a 5-exo-tet process8 Thus the four-membered ring is opened
thereby releasing the energy originating from sun Finally protonation of C affords 3a
Scheme 3 Plausible Mechanism
N
Ph O
Ts
A
N
Ph O
Ts
B
O
O
OO
O
Ph
NTs
CO2
H
C
Cs2CO3
CsHCO 3
Cs
Cs
Cs
2
1
N
Ph OH
Ts
2a
OO
O
Ph
NHTs
3a
For comparison pyrrolidinol 4 was subjected to the identical reaction
conditions Unlike the four-membered counterpart 2a the five-membered
compound 4 failed to react and was recovered unchanged The contrasting
results observed with 2a and 4 lend support to the explanation that the major
driving force for the CO2-capturing reaction is the release of the energy
stored in the form of the strained four-membered ring
The experimental procedures for both the photochemical cyclization reaction and the
CO2-capturing reaction are so simple that it is possible to carry them out in a single
flask (Scheme 4) Initially a DMA solution of 1a in an atmosphere of CO2 (1 atm) was
irradiated with solar light outside After completion of the photoreaction Cs2CO3 was
simply added to the reaction mixture which was then heated at 60degC for ten hours in a
N
Ts
OHPh
4
Chapter 1
14
fume hood Isolation by chromatography afforded the analytically pure cyclic carbonate
3a in 83 yield based on 1a
Scheme 4 Solar Driven Incorporation of Carbon Dioxide into -Amino Ketone 1a
solar light
CO2Cs2CO3
60degCDMAPh
O
NTs
Me
1a
OO
O
Ph
NHTs
3a 83
The broad generality of this consecutive process was verified by application to
various acetophenone derivatives (Scheme 5) Both an electron-donating methoxy
group and an electron-withdrawing trifluoromethyl group were allowed at the
para-position of the benzoyl group and the corresponding products 3b and 3c were
isolated in reasonable total yields The presence of possibly photoactive bromo and
chloro groups10
had essentially no effect on the reaction (3d and 3e) Sulfonyl groups
other than a p-toluenesulfonyl group were also suitable as the substituent on the
nitrogen atom (3fndashh)
Table 1 Scope of Solar Driven CO2 Incorporation into -Amino Ketone
Ar
O
NR
Me OO
O
Ar
NHR3
1
OO
O
NHTs3b 80
MeO
OO
O
NHTs3c 57
F3C
OO
O
NHTs3d 73
Cl
OO
O
NHTs3e 85
Br
OO
O
Ph
NH
3f 87
O2S OMe
OO
O
Ph
NH
3g 85
O2S CF3
OO
O
Ph
NH
3h 87
O2S
N
solar lightCO2
Cs2CO3
60degCDMA
Overall yields of isolated products are given Reactions were conducted on a 02 mmol
scale with the following reagents and conditions 1 (020 mmol) DMA (10 mL) solar
light ambient temperature CO2 (1 atm) then Cs2CO3 (080 mmol) 60 degC
Chapter 1
15
Conclusions
In summary we have developed the unique solar-driven transformation of -amino
ketones CO2 is incorporated to afford amino-substituted cyclic carbonates which are
potentially useful ingredients in industry
Although photosynthesis is a complex assembly of a number of elementary reactions
it can be divided into two major reactions the light reaction and the dark reaction In the
former reaction solar energy is captured to promote an energetically uphill process with
production of high-energy molecules (adenosine triphosphate (ATP) and nicotinamide
adenine dinucleotide phosphate (NADPH) The dark reaction is an energetically
downhill process that does not require light ATP and NADPH which have chemically
stored solar energy during the former reaction assist in the fixation of CO2 which is
intrinsically low in energy Photosynthesis as a whole reduces CO2 into carbohydrates
Although the present consecutive process does not involve CO2 reduction its
mechanistic profile of energy resembles that of photosynthesis and presents a simple
model of the chemical utilization of solar energy for CO2 incorporation
Chapter 1
16
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and 13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and 13C at
10069 MHz) spectrometer NMR data were obtained in CDCl3 Proton chemical shifts
were referenced to the residual proton signal of CHCl3 at 726 ppm Carbon chemical
shifts were referenced to the carbon signal of CDCl3 at 770 ppm High-resolution mass
spectra were recorded on a Thermo Scientific Exactive (ESI) spectrometer Flash
column chromatography was performed with silica gel 60N (Kanto) Preparative
thin-layer chromatography (PTLC) was performed on silica gel plates with PF254
indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers (2-Pyridyl)sulfonyl chloride1 was prepared
according to the reported procedure
Preparation of α-Amino Ketone 1a A Typical Procedure for the Preparation of
α-Amino Ketone 1a-1h
Ph
O
NTs
MeTsClMeNH2 +
Et2OTsNHMe
CH3CN
K2CO3
To an Et2O solution (40 mL) of p-toluenesulfonyl chloride (38 g 20 mmol) was added
an aqueous solution of methylamine (40 wt 40 mL) After being stirred for 6 h at
room temperature water was added to the reaction mixture The organic layer was
separated and the remaining aqueous layer was extracted with AcOEt (3 times) The
combined organic layer was washed with brine (once) dried over MgSO4 and
concentrated The residue was subsequently dissolved in acetonitrile
2-Bromoacetophenone (40 g 20 mmol) and potassium carbonate (28 g 20 mmol)
were added therein After being stirred overnight water was added to the reaction
mixture The aqueous layer was extracted with AcOEt (3 times) washed with brine
(once) dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 51) to afford the α-amino ketone
Chapter 1
17
1a (51 g 17 mmol 84 yield)
Ph
O
NTs
Me
1a 1H NMR δ = 244 (s 3H) 283 (s 3H) 457 (s 2H) 733 (dd J = 88 04 Hz 2H)
745-751 (m 2H) 760 (tt J = 76 12 Hz 1H) 771-775 (m 2H) 795-799 (m 2H)
13C NMR δ = 215 356 560 1275 1282 1288 1297 1338 1347 1348 1436
1937 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040994 IR
(ATR) 1693 1339 1227 1157 743 cm-1
O
NTs
Me
1bMeO
1H NMR δ = 244 (s 3H) 280 (s 3H) 388 (s 3H) 447 (s 2H) 693-697 (m 2H)
733 (d J = 80 Hz 2H) 770-774 (m 2H) 796-802 (m 2H) 13
C NMR δ = 215
355 555 558 1139 1275 1277 1296 1307 1346 1436 1640 1921 HRMS
(ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz 3341101 IR (ATR) 1688
1601 1329 1180 1159 cm-1
O
NTs
Me
1cF3C
1H NMR δ = 245 (s 3H) 280 (s 3H) 453 (s 2H) 735 (d J = 88 Hz 2H) 772 (d J
= 84 Hz 2H) 776 (d J = 84 Hz 2H) 812 (d J = 84 Hz 2H) 13
C NMR δ = 215
357 564 1234 (q JC-F = 2711 Hz) 1259 (q JC-F = 37 Hz) 1276 1288 1298
1344 1350 (q JC-F = 327 Hz) 1373 1439 1932 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720865 IR (ATR) 1697 1325 1161
1121 1109 cm-1
Chapter 1
18
O
NTs
Me
1dCl
1H NMR δ = 245 (s 3H) 279 (s 3H) 448 (s 2H) 734 (d J = 80 Hz 2H) 744-748
(m 2H) 771 (d J = 80 Hz 2H) 792-796 (m 2H) 13
C NMR δ = 216 356 561
1276 1292 1297 1298 1330 1344 1404 1438 1928 HRMS (ESI+) Calcd for
C16H17ClNO3S M+H+ 3380612 Found mz 3380600 IR (ATR) 1692 1339 1225
1159 1088 cm-1
O
NTs
Me
1eBr
1H NMR δ = 244 (s 3H) 279 (s 3H) 447 (s 2H) 733 (d J = 80 Hz 2H) 762 (d J
= 84 Hz 2H) 771 (d J = 84 Hz 2H) 786 (d J = 84 Hz 2H) 13
C NMR δ = 215
356 561 1275 1291 1297 1298 1321 1334 1344 1438 1930 HRMS (ESI+)
Calcd for C16H17BrNO3S M+H+ 3820107 Found mz 3820094 IR (ATR) 1697 1325
1223 1155 810cm-1
Ph
O
NS
Me
1f
OMe
OO
1H NMR δ = 282 (s 3H) 389 (s 3H) 456 (s 2H) 698-703 (m 2H) 746-751 (m
2H) 761 (tt J = 72 12 Hz 1H)776-781 (m 2H) 796-800 (m 2H) 13
C NMR δ =
356 556 561 1142 1283 1288 1294 1297 1338 1348 1630 1938 HRMS
(ESI+) Calcd for C16H18NO4S M+H
+ 3200951 Found mz 3200943 IR (ATR) 1692
1342 1259 1155 741 cm-1
Chapter 1
19
Ph
O
NS
Me
1g
CF3
OO
1H NMR δ = 294 (s 3H) 474 (s 2H) 747-752 (m 2H) 762 (tt J = 76 12 Hz 1H)
780 (d J = 84 Hz 2H) 790-794 (m 2H) 798 (d J = 80 Hz 2H) 13
C NMR δ =
356 558 1233 (q JC-F = 2711 Hz) 1261 (q JC-F = 36 Hz) 12796 12799 1289
1340 1343 (q JC-F = 327 Hz) 1345 1421 1931 HRMS (ESI+) Calcd for
C16H15F3NO3S M+H+ 3580719 Found mz 3580707 IR (ATR) 1699 1319 1128
1059 748 cm-1
Ph
O
NS
Me
1h
N
OO
1H NMR δ = 302 (s 3H) 486 (s 2H) 744-753 (m 3H) 757-762 (m 1H)
788-798 (m 4H) 870 (ddd J = 48 16 08 Hz 1H)13
C NMR δ = 363 569 1224
1266 1281 1288 1338 1347 1379 1499 1570 1936 HRMS (ESI+) Calcd for
C14H15N2O3S M+H+ 2910798 Found mz 2910785 IR (ATR) 1695 1337 1175 945
752 cm-1
Photoreaction of α-Amino Ketone 1a upon Irradiation with Solar Light
Ph
O
NTs
Mesolar light
N
Ph OH
TsDMA rt
1a
2a
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After 10 h water was added to the reaction mixture and the aqueous layer was
extracted with Et2O (3 times) washed with water (3 times) brine (once) dried over
MgSO4 and concentrated The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 21) to afford the azetidinol 2a
Chapter 1
20
(253 mg 0091 mmol 91 yield)
N
Ph OH
Ts
2a 1H NMR δ = 229 (s 1H) 248 (s 3H) 397 (d J = 96 Hz 2H) 415 (d J = 96 Hz
2H) 728-737 (m 5H) 740 (d J = 80 Hz 2H) 779 (d J = 80 Hz 2H) 13
C NMR δ
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 Anal Calcd for
C16H17NO3S C 6334 H 565 N 462 O 1582 S 1057 Found C 6317 H 555
N 458 O 1555 S 1058 IR (ATR) 3477 1333 1184 1148 671 cm-1
Reaction of Azetidinol 2a with Carbon Dioxide
N
Ph OH
Ts
2a
40 equiv Cs2CO3
1 atm CO2
DMA 60 C
OO
O
Ph
NHTs
3a
Under an atmospheric pressure of CO2 an NN-dimethylacetamide solution (10 mL)
containing azetidinol 2a (303 mg 010 mmol) and cesium carbonate (130 mg 040
mmol) were stirred at 60 degC for 10 h The reaction mixture then treated with HCl aq (20
M) and the aqueous layer was extracted with Et2O (3 times) The combined organic
layer was washed with water (3 times) brine (once) dried over MgSO4 and
concentrated The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the cyclic carbonate 3a (322 mg 0093
mmol 93 yield)
Chapter 1
21
One-Pot Reaction of α-Amino Ketone 1a with Carbon Dioxide
A Typical Procedure for the CO2-Capturing Reaction of α-Amino Ketones
40 equiv Cs2CO3
60 CPh
O
NR
Me OO
O
Ph
NHR3a
1a
solar light
DMA rt
1 atm CO2
α-Amino ketone 1a (303 mg 010 mmol) was placed in a Pyrex flask which was
subsequently filled with an atmospheric pressure of CO2 by vacuum-refill cycles The
flask was added NN-dimethylacetamide (10 mL) and exposed to solar light outside
After completion of the photochemical reaction Cs2CO3 (130 mg 040 mmol) was
added to the reaction mixture which was then stirred at 60 degC for 10 h in a room The
reaction mixture was treated with HCl aq (20 M) and the aqueous layer was extracted
with Et2O (3 times) The combined organic layer was washed with water (3 times)
brine (once) dried over MgSO4 and concentrated The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 31) to
afford the cyclic carbonate 3a (288 mg 0083 mmol 83 yield)
OO
O
Ph
NHTs
3a 1H NMR δ = 240 (s 3H) 330 (dd J = 144 56 Hz 1H) 340 (dd J = 144 88 Hz
1H) 454 (d J = 84 Hz 1H) 508 (d J = 84 Hz 1H) 570 (dd J = 84 Hz 56 Hz 1H)
726-732 (m 4H) 734-743 (m 3H) 769-773 (m 2H) 13
C NMR δ = 215 503
724 850 1242 1269 1292 1299 1365 1381 1439 1542 HRMS (ESI+) Calcd
for C17H18NO5S M+H+
3480900 Found mz 3480892 Anal Calcd for C17H18NO5S
C 5878 H 493 N 403 O 2303 S 923 Found C 5871 H 496 N 389 O
2284 S 932 IR (ATR) 3261 1773 1435 1319 1045 cm-1
Chapter 1
22
OO
O
NHTs
3b
MeO
1H NMR δ = 240 (s 3H) 327 (dd J = 144 56 Hz 1H) 335 (dd J = 144 88 Hz
1H) 380 (s 3H) 452 (d J = 84 Hz 1H) 504 (d J = 88 Hz 1H) 564 (dd J = 84
56 Hz 1H) 688-693 (m 2H) 719-724 (m 2H) 728 (d J = 80 Hz 2H) 770 (d J =
84 Hz 2H) 13
C NMR δ = 215 503 554 724 848 1145 1256 1269 1298
1299 1365 1440 1541 1601 HRMS (ESI+) Calcd for C18H20NO6S M+H
+
3781006 Found mz 3780996 IR (ATR) 3238 1794 1518 1329 1057 723 cm-1
OO
O
NHTs
3c
F3C
1H NMR δ = 240 (s 3H) 331 (dd J = 144 56 Hz 1H) 342 (dd J = 148 84 Hz
1H) 453 (d J = 88 Hz 1H) 513 (d J = 84 Hz 1H) 565 (dd J = 84 60 Hz 1H)
729 (d J = 84 Hz 2H) 746 (d J = 84 Hz 2H) 765-771 (m 4H) 13
C NMR δ =
215 501 722 846 1235 (q JC-F = 2704 Hz) 1249 1263 (q JC-F = 37 Hz) 1268
1300 1315 (q JC-F = 327 Hz) 1363 1418 1442 1537 HRMS (EI) Calcd for
C18H16F3NO5S M 4150701 Found mz 4150701 IR (ATR) 3244 1801 1323 1157
1067 cm-1
OO
O
NHTs
3d
Cl
1H NMR δ = 240 (s 3H) 328 (dd J = 144 60 Hz 1H) 337 (dd J = 144 84 Hz
1H) 450 (d J = 84 Hz 1H) 507 (d J = 88 Hz 1H) 572 (dd J = 84 60 Hz 1H)
722-727 (m 2H) 728 (d J = 84 Hz 2H) 735-739 (m 2H) 769 (d J = 84 Hz 2H)
13C NMR δ = 215 502 723 847 1257 1268 1294 1300 1353 1364 1365
1441 1539 HRMS (ESI+) Calcd for C17H17ClNO5S M+H
+ 3820510 Found mz
Chapter 1
23
3820506 IR (ATR) 3250 1800 1325 1155 1069 cm-1
OO
O
NHTs
3e
Br
1H NMR δ = 241 (s 3H) 328 (dd J = 144 56 Hz 1H) 337 (dd J = 144 84 Hz
1H) 449 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 574 (dd J = 84 60 Hz 1H)
716-720 (m 2H) 728 (d J = 80 Hz 2H) 750-755 (m 2H) 766-770 (m 2H) 13
C
NMR δ = 215 501 723 847 1235 1260 1268 1300 1323 1364 1370 1441
1538 HRMS (ESI+) Calcd for C17H17BrNO5S M+H
+ 4260005 Found mz 4260003
IR (ATR) 3252 1800 1331 1175 1057 cm-1
OO
O
Ph
NH
SO
O
OMe
3f 1H NMR δ = 330 (dd J = 144 60 Hz 1H) 339 (dd J = 144 88 Hz 1H) 384 (s
3H) 454 (d J = 84 Hz 1H) 506 (d J = 84 Hz 1H) 555 (dd J = 88 60 Hz 1H)
693-698 (m 2H) 727-732 (m 2H) 734-744 (m 3H) 773-778 (m 2H) 13
C NMR
δ = 503 556 724 849 1145 1242 1291 1292 1310 1381 1541 1632 HRMS
(ESI+) Calcd for C17H18NO6S M+H
+ 3640849 Found mz 3640836 IR (ATR) 3246
1801 1325 1155 1067 cm-1
OO
O
Ph
NH
SO
O
CF3
3g
Chapter 1
24
1H NMR δ = 336 (dd J = 144 52 Hz 1H) 347 (dd J = 144 88 Hz 1H) 459 (d J
= 84 Hz 1H) 510 (d J = 84 Hz 1H) 628 (dd J = 84 52 Hz 1H) 727-731 (m
2H) 735-744 (m 3H) 775 (d J = 88 Hz 2H) 796 (d J = 84 Hz 2H) 13
C NMR δ
= 505 725 851 1231 (q JC-F = 2711 Hz) 1241 1265 (q JC-F = 37 Hz) 1274
1293 1294 1347 (q JC-F = 337 Hz) 1377 1432 1542 HRMS (ESI+) Calcd for
C17H15F3NO5S M+H+ 4020618 Found mz 4020609 IR (ATR) 3335 1784 1337
1161 1105 cm-1
OO
O
Ph
NH
SO
O
N
3h 1H NMR δ = 357 (dd J = 148 60 Hz 1H) 365 (dd J = 148 84 Hz 1H) 456 (d J
= 84 Hz 1H) 514 (d J = 84 Hz 1H) 597 (dd J = 80 60 Hz 1H) 729-734 (m
2H) 735-745 (m 3H) 751 (ddd J = 72 48 12 Hz 1H) 792 (dt J = 80 16 Hz
1H) 798 (d J = 76 Hz 1H) 866 (d J = 44 Hz 1H) 13
C NMR δ = 510 723 849
1219 1242 1271 1292 1380 1383 1501 1539 1572 HRMS (ESI+) Calcd for
C15H15N2O5S M+H+ 3350696 Found mz 3350686 IR (ATR) 3258 1801 1337
1175 1063 cm-1
Synthesis of N-Tosyl-3-phenyl-3-pyrrolidinol 4 from N-Tosyl-3-pyrrolidinone
N
Ts
OHPh
N
Ts
O CeCl 3
PhLi
THF -78 C to rt
4
CeCl3 (570 mg 15 mmol) was dried under vacuum at 140 degC for 5 h After cooling the
flask to ambient temperature the vessel was filled with argon THF (50 mL) was added
therein The resulting suspension was cooled to -78 degC and PhLi (10 M in Et2O 15 ml
15 mmol) was added After being stirred for 30 min N-tosyl-3-pyrrolidinone (240 mg
10 mmol) was added The cooling bath was removed to allow the mixture to reach
Chapter 1
25
room temperature The reaction was quenched by adding NH4Cl aq and the aqueous
layer was extracted with AcOEt (3 times) The combined organic layer was washed with
brine (once) dried over MgSO4 and concentrated The residue was purified by flash
column chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-tosyl-3-phenyl-3-pyrrolidinol 4 (270 mg 085 mmol 85 yield)
N
Ts
OHPh
4 1H NMR δ = 199 (br s 1H) 209-215 (m 1H) 218-227 (m 1H) 243 (s 3H)
351-364 (m 4H) 726-738 (m 7H) 773-777 (m 2H) 13
C NMR δ = 215 396
469 608 804 1250 1276 1280 1286 1297 1339 1418 1435 HRMS (ESI+)
Calcd for C17H23N2O3S M+NH4+ 3351424 Found mz 3351412 IR (ATR) 3491
1325 1159 1101 770 cm-1
Chapter 1
26
References and Notes
(1) Armaroli N Balzani V Energy for a Sustainable World From the Oil Age to a
Sun-Powered Future Wiley-VCH Weinheim 2011
(2) (a) Arakawa H Aresta M Armor J N Barteau M A Beckman E J Bell A
T Bercaw J E Creutz C Dinjus E Dixon D A Domen K DuBois D L
Eckert J Fujita E Gibson D H Goddard W A Goodman D W Keller J
Kubas G J Kung H H Lyons J E Manzer L E Marks T J Morokuma K
Nicholas K M Periana R Que L Rostrup-Nielson J Sachtler W M H
Schmidt L D Sen A Somorjai G A Stair P C Stults B R Tumas W Chem
Rev 2001 101 953 (b) Olah G A Prakash G K S Goeppert A J Am Chem
Soc 2011 133 12881
(3) (a) DellrsquoAmico D B Calderazzo F Labella L Marchetti F Pampaloni G
Chem Rev 2003 103 3857 (b) Sakakura T Choi J-C Yasuda H Chem Rev
2007 107 2365 (c) Darensbourg D J Chem Rev 2007 107 2388 (d) Carbon
Dioxide as hemical Feedstock (Ed M Aresta) Wiley-VCH Weinheim 2010 (e)
Riduan S N Zhang Y Dalton Trans 2010 39 3347 (f) Behr A Henze G
Green Chem 2011 13 25 (g) Cokoja M Bruckmeier C Rieger B Herrmann
W A Kuumlhn F E Angew Chem 2011 123 8662 Angew Chem Int Ed 2011 50
8510 (h) Omae I Coord Chem Rev 2012 256 1384
(4) For selected examples of carbonate formation using CO2 see (a) Dimroth P
Pasedach H Ger 1098953 1961 (b) Fujinami T Suzuki T Kamiya M
Fukuzawa S Sakai S Chem Lett 1985 199 (c) Trost B M Angle S R J Am
Chem Soc 1985 107 6123 (d) Iritani K Yanagihara N Uchimoto K J Org
Chem 1986 51 5499 (e) Inoue Y Ishikawa J Taniguchi M Hashimoto H
Bull Chem Soc Jpn 1987 60 1204 (f) Myers A G Widdowson K L
Tetrahedron Lett 1988 29 6389 (g) Fournier J Bruneau C Dixneuf P H
Tetrahedron Lett 1989 30 3981 (h) Kayaki Y Yamamoto M Ikariya T Angew
Chem 2009 121 4258 Angew Chem Int Ed 2009 48 4194 (i) Minakata S
Sasaki I Ide T Angew Chem 2010 122 1331 Angew Chem Int Ed 2010 49
1309 (j) Yoshida S Fukui K Kikuchi S Yamada T J Am Chem Soc 2010
132 4072 For a review Sakakura T Kohno K Chem Commun 2009 1312
(5) (a) Yang N C Yang D-D H J Am Chem Soc 1958 80 2913 (b) Gold E H
J Am Chem Soc 1971 93 2793 (c) Allworth K L El-Hamamy A A Hesabi
M M Hill J J Chem Soc Perkin Trans 1 1980 1671
(6) Winberg K B Angew Chem 1986 98 312 Angew Chem Int Ed Engl 1986
25 312
Chapter 1
27
(7) (a) Activation of Unreactive Bonds and Organic Synthesis (Ed S Murai)
Springer Berlin 1999 (b) Handbook of C-H Transformations (Ed G Dyker)
Wiley-VCH Weinheim 2005 (c) For a special issue on selective functionalization
of C-H bonds see Chem Rev 2010 110 575 (Ed R H Crabtree)
(8) Baldwin J E J Chem Soc Chem Commun 1976 734
(9) Jones II G Chiang S-H Xuan P T J Photochem 1979 10 1
(10) Wagner P J Seldon J H Gudmundsdottir A J Am Chem Soc 1996 118 746
Chapter 1
28
Chapter 2
29
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-
3-ols into Benzosultams
Abstract
Benzosultams are synthesized in an enantiopure form starting from -amino acids
through a rhodium-catalyzed rearrangement reaction of N-arenesulfonylazetidin-3-ols
Mechanistically it involves C-C bond cleavage by -carbon elimination and C-H bond
cleavage by 15-rhodium shift
Reproduced with permission from J Am Chem Soc 2013 135 19103-19106
Copyright 2013 American Chemical Society
Chapter 2
30
Introduction
Carbonndashcarbon (CndashC) and carbonndashhydrogen (CndashH) bonds constitute the major
frameworks of organic molecules Such nonpolar -bonds are kinetically inert and
thermodynamically stable in general and therefore remain intact under most
conventional reaction conditions The past few decades however have seen the rise of
methods to selectively transform such intrinsically unreactive bonds with the use of
transition metal catalysts12
A 14-metal shift is defined as an intramolecular metal-hydrogen exchange process
occurring between 1- and 4-positions This process provides a convenient way to
activate a specific CndashH bond and a number of unique reactions involving a 14-metal
shift have been reported3-6
For example Catellani and coworkers have reported a
palladium-catalyzed reaction of bromobenzenes with norbornenes in which multiple
CndashC bonds are introduced on the benzene ring through a 14-palladium shift4a
A
14-rhodium shift has been also successfully exploited5 Phenylboronic acid is multiply
alkylated with norbornene through repetition of a 14-rhodium shift5a
Indanones are
synthesized through rearrangement of 1-arylpropargyl alcohols5cd
A rearrangement
reaction of cyclobutanols affords indanols in an enantio- and diastereoselective way5hi
On the other hand there are significantly less precedents reported for a 15-metal shift7
Herein we report a rearrangement reaction of N-arenesulfonylazetidin-3-ols into
benzosultams8 which involves a 15-rhodium shift as the key mechanistic element It
provides a stereoselective synthetic pathway starting from natural-amino acids
leading to enantiopure benzosultams which are substructures of potent pharmaceuticals
like Piroxicam and Meloxicam9
Results and Discussion
Initially N-p-toluenesulfonylazetidinol 1a was prepared from commercially available
azetidin-3-ol in 3 steps10
Then the reaction of 1a was examined in the presence of
[Rh(OH)(cod)]2 (2 mol ) and various phosphine ligands (Rh P = 1 25)10
Whereas
almost no reaction occurred when ligands like PPh3 DPPB DPPF were employed the
use of rac-BINAP prompted a rearrangement reaction to give 2a in 46 yield
Rac-DM-BINAP which possessed 35-xylyl groups in place of phenyl groups on
phosphorus exhibited a considerably higher activity to promote quantitative transfor
mation of 1a Simple elution of the reaction mixture through a pad of silica gel afforded
2a in 96 isolated yield (Scheme 1)
Chapter 2
31
Scheme 1 Rhodium-Catalyzed Rearrangement of 1a to 2a
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
S NS Me
HO PhMe
1a2a 96
Me
O
OO O
A stepwise mechanism involving a 15-rhodium shift from C(sp3) to C(sp
2) is
proposed to explain the formation of 2a from 1a (Scheme 2) Initially the hydroxy
group of 1a is exchanged onto the rhodium hydroxide to generate rhodium alkoxide A
Subsequently -carbon elimination follows to cleave the carbonndashcarbon bond of the
symmetrical azetidine ring thereby relieving the ring strain11
The generated
alkylrhodium B then undergoes a 15-rhodium shift to furnish arylrhodium species C
An intramolecular 6-exo addition to the carbonyl group12
occurs with C to reconstruct
the six-membered ring structure of a benzosultam skeleton Finally the rhodium
alkoxide D is exchanged with the hydroxy group of another azetidinol 1a to release the
benzosultam 2a with regeneration of intermediate A
Scheme 2 Proposed Mechanism for the Rearrangement of 1a to 2a
N
S O
O
O[Rh]
Ph
SN
[Rh]O Ph
O OMe
[Rh] OH
N
S O
O
O Ph
H
[Rh]
H
N
[Rh]O Ph
S O
O
Me Me
Me
Me
1a
H2O
2a
A B
CD
1a
A
We next carried out the reaction of 1a-d whose p-tolyl group was fully deuterated
(Scheme 3) One of the deuterium atoms on the ortho positions of the p-tolyl moiety
was transferred onto the N-methyl group of 2a-d being consistent with the proposed
Chapter 2
32
mechanism The HD ratio of the N-methyl group and the 8-position were 1911 and
0109 respectively The slightly lower and higher HD ratios at the N-methyl and 8-
positions respectively than expected may suggest the microscopic reversibility between
the intermediary arylrhodium C and the alkylrhodium B
Scheme 3 Rhodium-Catalyzed Reaction of 1a-d to 2a-d
[Rh(OH)(cod)] 2 (2 mol )rac -DM-BINAP (5 mol )K2CO3 (20 equiv)
toluene 60 ordmC 12 h
N
HO Ph
SN
S CH19D11
HO Ph
D3C
1a-d2a-d 96
D3C
O
O
O O
D
D
D
D
D
D
H01D09
8
Next optically active diphosphine ligands were examined to induce
enantioselectivity at the step of intramolecular carbonyl addition ie from C leading to
D12
Although (R)-DM-BINAP exhibited the best reactivity among the chiral ligands
examined to give 2a in 94 yield the enantiomeric ratio (er) was low (6238)
(R)-DIFLUORPHOS afforded the best selectivity of 928 er (91 yield)10
Application
of this reaction conditions to various azetidinols 1 furnished benzosultams 2 in the range
of 919 to 937 er (Table 1)
Table 1 Enantioselective Rearrangement of 1 to 2ab
1
2
SN
HO Ar
O OMe
N
HO Ar
S O
O
[Rh(OH)(cod)] 2 (5 mol )(R)-DIFLUORPHOS (12 mol )
K2CO 3 (20 equiv)
toluene 60 ordmC 12 h
NS Me
HO PhMe
2a
91 er = 928
O O
NS Me
HO Ph
2b
95 er = 937
O O
S
NS Me
HOMe
2c
90 er = 937
O O
OMe
NS Me
HOMe
2c
92 er = 919
O O
CF3
a Reaction conditions [Rh(OH)(cod)]2 (5 mol ) (R)-DIFLUORPHOS (12
mol ) toluene 60 degC 12 h b Isolated yield
Chapter 2
33
Asymmetrical azetidinol 1e was prepared in an enantiopure form from (L)-alanine
according to the modified Seebachrsquos method (Scheme 4)13
Initially (L)-alanine (3) was
treated with p-toluenesulfonyl chloride to afford N-tosylate 4 Subsequent treatment
with oxalyl chloride followed by coupling with diazomethane gave diazo ketone 5
Copper-catalyzed denitrogenative cyclization of 5 afforded azetidinone 6 Addition of
phenylmagnesium bromide to 6 occurred selectively from the face opposite to the
methyl group to furnish azetidinol 1e in an enantiopure form
Scheme 4 Synthesis of Enantiopure Azetidinol 1e
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6 84
5 56
1) (COCl) 2 DMF2) CH2N2
Cu(OAc)2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2Ort 10 h 4 90
PhMgBr
THF rt 1 h N
HO
Ts
Me
1e 93
er gt 991 dr = 201
Ph
3
The azetidinol 1e was heated at 60 degC in toluene for 8 h in the presence of
[Rh(OH)(cod)]2 (2 mol ) and rac-DM-BINAP (5 mol ) (Scheme 5) The
rearrangement reaction proceeded efficiently to furnish the benzosultam 2e in a
quantitative yield stereoselectively with the enantiopurity retained The stereochemistry
was confirmed by X-ray crystallography10
Scheme 5 Rearrangement of 1e to 2e
SN
HO PhMe
O OMe
MeN
HO Ph
S O
O
Me
Me
1e
er gt 991 dr = 201
2e 99
er gt 991 dr gt 201
[Rh(OH)(cod)] 2 (2 mol )rac-DM-BINAP (5 mol )
toluene 60 ordmC 8 h
The exclusive formation of 2e demonstrates that the -carbon elimination occurs
site-selectively at the methylene side rather than at the methyne side probably due to
Chapter 2
34
steric reasons In addition intramolecular carbonyl addition takes place in a
diastereoselective fashion We assume that the six-membered ring transition state takes
a boat-like conformation in which the CndashRh linkage can align with the C=O bond for
the maximum orbital interaction as shown in Scheme 8 With the conformer E the
methyl group at the -position takes a pseudoequatorial position whereas the -methyl
group of the conformer Ersquo takes a pseudoaxial position Thus the conformer E is
favored over the conformer Ersquo to produce the adduct F diastereoselectively
Scheme 6 Models for Diastereoselective 6-exo-dig Cyclization
SN
PhRhOMe
O OMe
Me
SN
PhRhOMe
O OMe
Me
favored
disfavored
F
F
NSRh
Ph
Me
O
O
MeO
H
Me
E
E
NSRh
Ph
Me
O
O
MeO
Me
H
Various benzosultams were synthesized in an enantio- and diasteropure form (Table
2) The reaction of N-p-toluenesulfonylazetidinol 1f the diastereomer of 1e also
furnished the same stereoisomer 2e exclusively being consistent with the proposed
mechanism the stereochemistry of the alcohol moiety once disappears upon -carbon
elimination to produce the same intermediate C Azetidinols 1g-1j having various aryl
groups on the sulfonyl moiety gave the corresponding products 2g-2j (entries 2-5) The
reaction of N-m-toluenesulfonylazetidinol 1i gave product 2i with complete
regioselectivity (entry 4) suggesting that rhodium preferred the sterically less hindered
position as the destination of its 15-shift Substituted aryl groups were allowed at the
C3-position (entries 6 7)14
Benzosultam 2m was obtained from azetidinol 1m which
was prepared from valine (entry 8) The reaction of methionine-derived 1n successfully
furnished 2n demonstrating the compatibility of a sulfide functionality (entry 9)
Chapter 2
35
Table 2 Rhodium-Catalyzed Rearrangement of 1 to 2a
1
er gt 991 dr gt 201
2
er gt 991 dr gt 201
SN
HO ArR
O OMe
N
HO Ar
S O
O
R [Rh(OH)(cod)] 2 (2 mol )
rac -DM-BINAP (5 mol )
toluene 60 ordmC 8 h
entry 1 2b entry 1 2b
1 N
HO Ph
S O
O
Me
Me
1f
SN
HO PhMe
O OMe
Me
2e 99
6 N
HO
S O
O
Me
1k
OMe
SN
HOMe
O OMe
2k 97
OMe
2
N
HO Ph
S O
O
MeO
Me
1g
SN
HO PhMe
O OMe
MeO
2g 98
7 N
HO
S O
O
Me
Me
1l
CF3
SN
HOMe
O OMe
Me
2l 97
CF3
3 N
HO Ph
S O
O
F3C
Me
1h
SN
HO PhMe
O OMe
F3C
2h 99
8 N
HO Ph
S O
O
Me
i-Pr
1m
SN
HO Phi-Pr
O OMe
Me
2m 97
4
N
HO Ph
S O
O
Me
1iMe
SN
HO PhMe
O OMeMe
2i 99
9 N
HO Ph
S O
O
Me
SMe
SN
HO Ph
O OMe
Me
2n 97
SMe
5 N
HO Ph
S O
O
Me
S
1j
SN
HO PhMe
O OMeS
2j 99
a Reaction conditions [Rh(OH)(cod)]2 (2 mol ) rac-DM-BINAP (5 mol ) toluene
60 degC 8 h b Isolated yield
Chapter 2
36
Conclusions
In summary we have described the rhodium-catalyzed rearrangement reaction of
N-arenesulfonylazetidinols into benzosultams The unique transformation
mechanistically involves reorganization of nonpolar -bonds via 15-rhodium shift and
provides a method to synthesize enantio- and diastereopure benzosultams starting from
natural -amino acids
Chapter 2
37
Experimental Section
General All reactions were carried out with standard Schlenk techniques IR
measurements were performed on a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter 1H and
13C NMR
spectra were recorded on a Varian Mercury-vx400 (1H at 40044 MHz and
13C at 10069
MHz) and JEOL JNM-ECA600 (1H at 60017 MHz) spectrometer NMR data were
obtained in CDCl3 and C6D6 Proton chemical shifts were referenced to the residual
proton signal of the solvent at 726 ppm (CHCl3) and 716 ppm (C6D6) Carbon
chemical shifts were referenced to the carbon signal of the solvent at 770 ppm (CDCl3)
High-resolution mass spectra were recorded on a Thermo Scientific Exactive (ESI)
spectrometer Flash column chromatography was performed with silica gel 60N (Kanto)
Preparative thin-layer chromatography (PTLC) was performed on silica gel plates with
PF254 indicator (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers
Preparation of N-Toluenesulfonylazetidinol 1a and 1a-d
N
OHNEt3
DCM rt 12 h
1) Dess-Martin ReagentDCM rt 12 h
2) PhMgBrTHF rt 3 h
N
HO Ph
1a
TsCl
N
OH
8a
H HCl
Ts Ts
To a dichloromethane solution (20 mL) of 3-hydroxyazetidine hydrochloride (12 g 11
mmol) and triethylamine (31 mL 22 mmol) was added p-toluenesulfonyl chloride (19
g 10 mmol) After being stirred at room temperature for 12 h HCl aq (2N) was added
to the reaction mixture The organic layer was separated and the remaining aqueous
layer was extracted with dichloromethane (3 times) The combined organic layer was
washed with brine (once) dried over MgSO4 and concentrated under reduced pressure
The residue was purified by Flash column chromatography on silica gel (hexaneethyl
acetate = 11) to afford the N-toluenesulfonylazetidinol 8a (15 g 66 mmol 66 yield)
Chapter 2
38
N
S
Me
O
O
OH
8a 1H NMR = 213 (bs 1H) 245 (s 3H) 350-361 (m 2H) 394-404 (m 2H)
442-452 (m 1H) 737 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR =
216 602 605 1284 1298 1313 1443 HRMS (ESI+) Calcd for C10H14NO3S
M+H+ 2280689 Found mz 2280686 IR (ATR) 3501 1331 1144 1049 665 cm
-1
N
S
D3C
O
O
OH
8a-d
D
D
D
D
1H NMR = 283 (bs 1H) 349-355 (m 2H) 389-396 (m 2H) 435-444 (m 1H)
13C NMR = 195-202 (m) 601 602 1279 (t JC-D = 247 Hz) 1294 (t J = 247 Hz)
1308 1441 HRMS (ESI+) Calcd for C10H7D7NO3S M+H
+ 2351128 Found mz
2351125 IR (ATR) 3503 1333 1142 1059 638 cm-1
N
S O
O
OH
8b
S
1H NMR = 277 (bs 1H) 357-364 (m 2H) 400-407 (m 2H) 441-450 (m 1H)
721 (dd J = 48 40 Hz 1H) 762 (dd J = 36 12 Hz 1H) 771 (dd J = 52 12 Hz
1H) 13
C NMR = 600 606 1279 1332 1335 1338 HRMS (ESI+) Calcd for
C7H10D7NO3S2 M+H+ 2200097 Found mz 2200094 IR (ATR) 3476 1325 1148
1038 737 cm-1
Chapter 2
39
To a dichloromethane solution (20 mL) of N-toluenesulfonylazetidinol 8 (780 mg 34
mmol) was added Dess-Martin reagent (15 g 35 mmol) After being stirred for 12 h at
room temperature saturated Na2CO3 aq was added to the reaction mixture The organic
layer was separated and the remaining aqueous layer was extracted with
dichloromethane (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated
The residue was dissolved in THF (20 mL) PhMgBr (10 M in THF 5 mL 5 mmol)
was added therein at -78 degC and the reaction mixture was then allowed to be at room
temperature After being stirred for 3 h HCl (2N) was added to the reaction mixture at
0 degC The aqueous layer was extracted with AcOEt (3 times) washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 31) to afford the
N-toluenesulfonylazetidinol 1a (600 mg 20 mmol 59 yield)
N
HO Ph
S
1a
Me
O
O
1H NMR = 162 (s 1H) 247 (s 3H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz
2H) 728-737 (m 5H) 739 (d J = 84 Hz 2H) 778 (d J = 80 Hz 2H) 13
C NMR
= 216 652 703 1244 1281 1284 1286 1299 1312 1420 1444 HRMS
(ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040995 IR (ATR) 3477
1333 1184 1148 671 cm-1
The spectral characteristics of 1a were in agreement with the previously reported data15
N
HO Ph
S
1a-d
D3C
O
O
D
D
D
D
1H NMR = 250 (bs 1H) 397 (d J = 92 Hz 2H) 413 (d J = 92 Hz 2H) 727-736
(m 5H) 13
C NMR = 203-211 (m) 652 703 1244 1281 (t JC-D = 247 Hz)
1281 1286 1294 (t JC-D = 247 Hz) 1311 1420 1441 HRMS (ESI+) Calcd for
Chapter 2
40
C16H11D7NO3S M+H+ 3111441 Found mz 3111434 IR (ATR) 3481 1335 1142
702 648 cm-1
N
HO Ph
S
S
O
O
1b 1H NMR = 232 (bs 1H) 400-408 (m 2H) 416-424 (m 2H) 724 (dd J = 48 36
Hz 1H) 730-737 (m 5H) 768 (dd J = 40 16 Hz 1H) 773 (dd J = 48 12 Hz
1H) 13
C NMR = 656 702 1244 1280 1283 1288 1331 13387 13392 1417
HRMS (ESI+) Calcd for C13H14NO3S2 M+H
+ 2960410 Found mz 2960404 IR
(ATR) 3524 1333 1161 1148 748 cm-1
N
HO
S
Me
O
O
OMe
1c
1H NMR = 246 (s 3H) 257 (bs 1H) 379 (s 3H) 393 (d J = 84 Hz 2H) 408 (d
J = 88 Hz 2H) 683 (d J = 84 Hz 2H) 723 (d J = 88 Hz 2H) 738 (d J = 80 Hz
2H) 775 (d J = 80 Hz 2H) 13
C NMR =216 553 652 702 1139 1259 1285
1298 1312 1340 1443 1593 HRMS (ESI+) Calcd for C17H20NO4S M+H
+
3341108 Found mz 3341097 IR (ATR) 3460 1518 1331 1250 1146 cm-1
N
HO
S
Me
O
O
CF3
1d 1H NMR = 247 (s 3H) 318 (bs 1H) 396-410 (m 4H) 739 (d J = 80 Hz 2H)
746 (d J = 80 Hz 2H) 754 (d J = 84 Hz 2H) 774 (d J = 80 Hz 2H) 13
C NMR
Chapter 2
41
=216 654 697 1239 (q JC-F = 2704 Hz) 1249 1255 (q JC-F = 37 Hz) 1284
1300 1302 (q JC-F = 320 Hz) 1310 1448 1460 HRMS (ESI+) Calcd for
C17H17F3NO3S M+H+ 3720876 Found mz 3720866 IR (ATR) 3450 1329 1151
1109 1076 cm-1
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure of 1e and
1l-1n
HO2C Me
NHTs
Me
NHTs
O
N2
N
O
Ts
Me
6a
5a
1) (COCl) 2 DMF2) CH 2N2
Cu(OAc) 2H2O (5 mol )
benzene 90 C 1 min
HO2C Me
NH2
TsCl NEt3
acetone H2O
rt 10 h 4a
PhMgBr
THF rt 1 h N
OH
Ts
Me
1e
Ph
3a
Preparation of -Diazo Ketone 5a A Typical Procedure for Preparation of 5a-5c
N-toluenesulfonylalanine 4a (24 g 10 mmol) was prepared according to the reported
procedure16
The resulting 4a was dissolved in dichloromethane (50 mL) The mixture
was cooled to 0 degC under argon atmosphere and oxalyl chloride (13 mL 15 mmol) and
one-drop of NN-dimethylformamide were added After being stirred at room
temperature for 12 h solvent was removed under reduced pressure
The residue was dissolved in THF under argon atmosphere Diazomethane (which was
freshly prepared by diazald and KOH 25 mmol) in Et2O was added to the solution at
0 degC After being stirred for 3 h at room temperature water was added to the reaction
mixture The organic layer was separated and the remaining aqueous layer was extracted
with ethyl acetate (3 times) The combined organic layer was washed with brine (once)
dried over MgSO4 and concentrated The residue was purified by Flash column
chromatography on silica gel (hexaneethyl acetate = 21 to 11) to afford the -diazo
ketone 5a (15 g 56 mmol 56 yield)
Me
NHTs
O
N2
5a 1H NMR = 126 (d J = 72 Hz 3H) 242 (s 3H) 378-390 (m 1H) 537-552 (m
Chapter 2
42
2H) 730 (d J = 84 Hz 2H) 772 (d J = 84 Hz 2H) 13
C NMR = 194 215 539
554 1271 1297 1368 1438 1928 HRMS (ESI+) Calcd for C11H14N3O3S M+H
+
2680750 Found mz 2680747 IR (ATR) 2112 1639 1337 1319 1161 cm-1
[]27
D = -1184 (c = 079 in CHCl3)
The spectral characteristics of 5a were in agreement with the previously reported data17
i-Pr
NHTs
O
N2
5b 1H NMR = 081 (d J = 68 Hz 3H) 090 (d J = 64 Hz 3H) 190-202 (m 1H) 240
(s 3H) 352-368 (m 1H) 527 (s 1H) 551 (d J = 84 Hz 1H) 727 (d J = 80 Hz
2H) 769 (d J = 84 Hz 2H) 13
C NMR =169 193 215 315 548 647 1273
1296 1367 1436 1922 HRMS (ESI+) Calcd for C13H18N3O3S M+H
+ 2961063
Found mz 2961060 IR (ATR) 2129 1622 1362 1329 1161 cm-1
[]28
D = -730 (c = 071 in CHCl3)
NHTs
O
N2
5c
SMe
1H NMR = 174-196 (m 2H) 204 (s 3H) 242 (s 3H) 244-252 (m 2H)
390-400 (m 1H) 541 (s 1H) 560-572 (m 1H) 730 (d J = 84 Hz 2H) 772 (d J =
84 Hz 2H) 13
C NMR = 153 215 297 323 545 585 1272 1297 1366 1439
1918 HRMS (ESI+) Calcd for C13H18N3O3S2 M+H
+ 3280784 Found mz 3280779
IR (ATR) 2129 1618 1375 1339 1163 cm-1
[]29
D = -506 (c = 063 in CHCl3)
The spectral characteristics of 5c were in agreement with the previously reported data17
Preparation of N-Toluenesulfonylazetidinone 6a A Typical Procedure for
Preparation of 6a-6c
Cu(OAc)2H2O (80 mg 04 mmol) was added to a benzene solution (70 mL) of -diazo
ketone 5a (12 g 45 mmol) at 90 degC After being stirred for 1 min the reaction mixture
was allowed to be at room temperature Solvent was removed under reduced pressure
The residue was purified by column chromatography on silica gel (HexaneAcOEt =
31) to afford N-toluenesulfonylazetidinone 6a (090 g 38 mmol 84 yield)
Chapter 2
43
N
O
Ts
Me
6a
1H NMR = 145 (d J = 68 Hz 3H) 246 (s 3H) 443-454 (m 2H) 473-480 (m
1H) 736-742 (m 2H) 776-781 (m 2H) 13
C NMR = 157 216 696 810 1284
1300 1315 1450 1967 HRMS (ESI+) Calcd for C11H14NO3S M+H
+ 2400689
Found mz 2400688 IR (ATR) 1825 1339 1155 669 cm-1
[]28
D = 614 (c = 081 in CHCl3)
The spectral characteristics of 6a were in agreement with the previously reported data17
N
O
Ts
i-Pr
6b
1H NMR = 099-111 (m 6H) 206-218 (m 1H) 246 (s 3H) 441 (dd J = 164 36
Hz 1H) 450 (d J = 164 Hz 1H) 461 (dd J = 52 36 Hz 1H) 738 (d J = 84 Hz
2H) 777 (d J = 80 Hz 2H) 13
C NMR = 174 181 216 304 703 903 1284
1300 1320 1449 1973 HRMS (ESI+) Calcd for C13H18NO3S M+H
+ 2681002
Found mz 2680998 IR (ATR) 1815 1340 1155 1007 671 cm-1
[]29
D = 567 (c = 095 in CHCl3)
N
O
Ts
6c
SMe
1H NMR = 204 (s 3H) 209-218 (m 2H) 247 (s 3H) 265-279 (m 2H) 446 (d
J = 156 Hz 1H) 460 (dd J = 156 36 Hz 1H) 482-488 (m 1H) 740 (d J = 84 Hz
2H) 780 (d J = 80 Hz 2H) 13
C NMR = 147 216 291 293 705 832 1286
1301 1311 1451 1963 HRMS (ESI+) Calcd for C13H18NO3S2 M+H
+ 3000723
Found mz 3000718 IR (ATR) 1813 1342 1308 1157 667 cm-1
[]29
D = 1183 (c = 036 in CHCl3)
The spectral characteristics of 6c were in agreement with the previously reported data17
Chapter 2
44
Preparation of N-Toluenesulfonylazetidinol 1e A Typical Procedure for
Preparation of 1e and 1l-1n
To a THF solution (20 mL) of N-toluenesulfonylazetidinone 6a (12 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then allowed to be at room temperature After being stirred for 3 h HCl aq (2N)
was added to the reaction mixture at 0 degC The aqueous layer was extracted with AcOEt
(3 times) washed with brine (once) dried over MgSO4 and concentrated The residue
was purified by Flash column chromatography on silica gel (hexaneethyl acetate = 31)
to afford the N-toluenesulfonylazetidinol 1e (15 mg 47 mmol 93 yield)
N
HO
S O
O
Me
Me
1e
H
NOE
NOE
1H NMR =142 (d J = 68 Hz 3H) 162 (bs 1H) 248 (s 3H) 388 (dd J = 92 08
Hz 1H) 399 (d J = 92 Hz 1H) 419 (q J = 64 Hz 1H) 694-698 (m 2H) 720-722
(m 3H) 739 (d J = 84 Hz 2H) 777 (d J = 84 Hz 2H) 13
C NMR = 144 216
628 702 731 1247 1279 1284 1285 1298 1319 1415 1443 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3470 1335
1155 1092 667 cm-1
[]25
D = 364 (c = 106 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 251 min (minor) t2 = 287 min (major) er gt 991
Chapter 2
45
N
HO
S O
O
Me
1l
H
NOE
NOE
CF3
Me
1H NMR = 142 (d J = 64 Hz 3H) 251 (s 3H) 295 (bs 1H) 392 (d J = 92 Hz
1H) 398 (d J = 96 Hz 1H) 416 (q J = 64 Hz 1H) 708 (d J = 84 Hz 2H)
739-747 (m 4H) 777 (d J = 84 Hz 2H) 13
C NMR = 143 216 630 706 727
1238 (JC-F = 2704 Hz) 1253 1254 (JC-F = 36 Hz) 1285 1299 1301 (JC-F = 324
Hz) 1316 1446 1454 HRMS (ESI+) Calcd for C18H19F3NO3S M+H
+ 3861032
Found mz 3861025 IR (ATR) 3422 1327 1151 1109 839 cm-1
[]28
D = 404 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 111 min (minor) t2 = 123 min (major) er gt 991
N
HO
S O
O
Me
iPr
1m
H
NOE
NOE
1H NMR = 087 (d J = 68 Hz 3H) 114 (d J = 68 Hz 3H) 161 (bs 1H) 226-240
(m 1H) 245 (s 3H) 386 (d J = 92 Hz 1H) 393 (dd J = 96 08 Hz 1H) 410 (d J
= 100 Hz 1H) 690-696 (m 2H) 712-720 (m 3H) 732 (d J = 80 Hz 2H) 773 (d
J = 80 Hz 2H) 13
C NMR = 190 193 215 291 641 729 801 1247 1275
1284 1285 1297 1324 1428 1441 HRMS (ESI+) Calcd for C19H24NO3S M+H
+
3461471 Found mz 3461466 IR (ATR) 3454 1331 1163 739 669 cm-1
[]27
D = 611 (c = 118 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
Chapter 2
46
= 387 min (minor) t2 = 409 min (major) er gt 991
N
HO Ph
S O
O
1n
Me
SMe
1H NMR = 202 (s 3H) 218-258 (m 8H) 388-394 (m 2H) 427 (dd J = 84 48
Hz 1H) 688-693 (m 2H) 714-721 (m 3H) 740 (d J = 80 Hz 2H) 779 (d J = 80
Hz 2H) 13
C NMR = 154 216 290 297 634 725 733 1246 1277 1284
1286 1299 1318 1424 1443 HRMS (ESI+) Calcd for C19H24NO3S2 M+H
+
3781192 Found mz 3781188 IR (ATR) 3481 1339 1157 702 669 cm-1
[]28
D = 719 (c = 090 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 182 min (minor) t2 = 193 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1f
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol2 mol ) and (S)-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 1 h the reaction
mixture was passed through a pad of florisil The solvent was removed under reduced
pressure The crude residue was purified by preparative thin-layer chromatography on
silica gel (dichloromethaneethyl acetate = 51) and GPC to afford the
N-toluenesulfonylazetidinol 1f (62 mg 0020 mmol 20 yield)
N
HO
S O
O
Me
Me
1f
H
NOE
NOE
1H NMR = 089 (d J = 64 Hz 3H) 224 (bs 1H) 247 (s 3H) 366 (d J = 84 Hz
1H) 398 (q J = 64 Hz 1H) 424 (dd J = 84 08 Hz 1H) 732-744 (m 5H)
750-755 (m 2H) 774-778 (m 2H) 13
C NMR = 165 216 627 718 739 1257
Chapter 2
47
1282 1285 1286 1298 1310 1390 1443 HRMS (ESI+) Calcd for C17H20NO3S
M+H+ 3181158 Found mz 3181154 IR (ATR) 3425 1325 1175 1146 694 cm
-1
[]25
D = 68 (c = 030 in CHCl3) Enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1 =
128 min (minor) t2 = 153 min (major) er gt 991
Preparation of N-Toluenesulfonylazetidinol 1g A Typical Procedure for
Preparation of 1g-1k
HO2C Me
NHCbz
Me
NHCbz
O
N2N
O
Cbz
Me
6d5d
1) (COCl) 2 DMF
2) CH2N2 Rh2(OAc)4 (05 mol )
DCM rt 12 h4d
PhMgBr
THF rt 1 h
N
OH
Cbz
Me
7a
Ph
N
OH
H
Me
PhPd C (5 mol )
H2 (1atm)
MeOH rt 12 h
MeO SO2Cl
NEt3
DCM rt 12 h
N
HO Ph
S O
O
MeO
Me
1g
Preparation of -Diazo Ketone 5d
The N-benzyloxycarbonylalanine 4d (67 g 30 mmol) was dissolved in THF (150 mL)
Triethylamine (6 mL) and ethyl chlorocarbonate were added therein at ndash15 degC
Diazomethane in Et2O (which was freshly prepared by diazald and KOH 70 mmol) was
added The mixture was stirred at room temperature for 3 h and then water was added
The mixture was extracted with AcOEt washed with water and brine dried over
MgSO4 and concentrated The residue was washed with Et2O to afford the -diazo
ketone (59 g 24 mmol 80 yield)
Me
NHCbz
O
N2
5d 1H NMR = 134 (d J = 68 Hz 3H) 420-436 (m 1H) 504-516 (m 2H) 534-564
(m 2H) 728-736 (m 5H) 13
C NMR = 184 535 (2C) 669 1280 1282 1285
1361 1556 1938 HRMS (ESI+) Calcd for C12H14N3O3 M+H
+ 2481030 Found mz
2481028 IR (ATR) 2116 1717 1636 1533 1252 cm-1
[]28
D = -434 (c = 085 in CHCl3)
The spectral characteristics of 5d were in agreement with the previously reported data18
Chapter 2
48
Preparation of N-Benzyloxycarbonylazetidinone 6d
To a dichloromethane solution (50 mL) of -diazo ketone 5d (25 g 10 mmol) at 0 degC
was added Rh2(OAc)4 (20 mg 005 mmol 05 mol ) The reaction mixture was then
warmed to room temperature After being stirred for 12 h solvent was removed under
reduced pressure The residue was purified by GPC to afford
N-benzyloxycarbonylazetidinone 6d (12 g 56 mmol 56 yield)
N
O
Cbz
Me
6d
1H NMR = 149 (d J = 72 Hz 3H) 466 (dd J = 164 40 Hz 1H) 477 (d J = 164
Hz 1H) 498-505 (m 1H) 513-521 (m 2H) 731-739 (m 5H) 13
C NMR = 153
674 687 790 1281 1283 1286 1361 1563 1998 HRMS (ESI+) Calcd for
C12H14NO3 M+H+ 2200968 Found mz 2200966 IR (ATR) 1811 1690 1410 1342
696 cm-1
[]29
D = 390 (c = 068 in CHCl3)
Preparation of N-Benzyloxycarbonylazetidinol 7a and 7b
To a THF solution (20 mL) of N-benzyloxycarbonylazetidinone 6d (11 g 50 mmol) at
-78 degC was added PhMgBr (10 M in THF 55 mL 55 mmol) The reaction mixture
was then warmed to room temperature After being stirred for 3 h HCl aq (2N) was
added at 0 degC The mixture was separated and the aqueous layer was extracted with
AcOEt (3 times) The combined organic phase was washed with brine (once) dried over
MgSO4 and concentrated The residue was purified by Flash column chromatography on
silica gel (hexaneethyl acetate = 11) to afford the N-benzyloxycarbonyl azetidinol 7a
(14 g 48 mmol 96 yield)
N
OH
Cbz
Me
7a
Ph
1H NMR = 150 (d J = 64 Hz 3H) 251 (bs 1H) 411 (d J = 96 Hz 1H) 434 (d J
= 96 Hz 1H) 458 (q J = 64 Hz 1H) 507-518 (m 2H) 729-746 (m 10H) 13
C
NMR = 142 623 667 689 730 1246 1278 1279 1280 1285 1287 1366
Chapter 2
49
1434 1565 HRMS (ESI+) Calcd for C18H20NO3 M+H
+ 2981438 Found mz
2981433 IR (ATR) 1670 1423 1248 1016 702 cm-1
[]29
D = 46 (c = 089 in CHCl3)
N
OH
Cbz
Me
7b
MeO
1H NMR = 149 (d J = 64 Hz 3H) 226 (bs 1H) 381 (s 3H) 409 (d J = 96 Hz
1H) 432 (d J = 96 Hz 1H) 452-461 (m 1H) 506-518 (m 2H) 687-694 (m 2H)
726-739 (m 7H) 13
C NMR = 143 553 622 666 687 729 1140 1260 1278
1280 1285 1355 1366 1566 1593 HRMS (ESI+) Calcd for C19H22NO4 M+H
+
3281543 Found mz 3281539 IR (ATR) 1682 1418 1352 1024 696 cm-1
[]29
D = 02 (c = 085 in CHCl3)
Preparation of N-Toluenesulfonylazetidinol 1g A Typical procedure for
Preparation of 1g-1k
PdC (100 mg) was placed in a flask A methanol (20 mL) solution of
N-benzyloxycarbonylazetidinol 7a (5 mmol 15 mmol) was added therein and the flask
was purged with hydrogen After being stirred at room temperature for 12 h the reaction
mixture was passed through a pad of celitereg
The solvent was removed under reduced
pressure
The residue was dissolved in dichloromethane (20 mL) and p-methoxyphenylsulfonyl
chloride (10 g 50 mmol) and NEt3 (700 mL 5 mmol) were added The reaction
mixture was stirred for 12 h and then water was added The aqueous layer was extracted
with dichloromethane (3 times) washed with brine (once) dried over MgSO4 and
concentrated The residue was purified by flash column chromatography on silica gel
(hexaneethyl acetate = 31) to afford the p-methoxyphenylazetidinol 1g (960 mg 29
mmol 58 yield)
Chapter 2
50
N
HO
S O
O
MeO
Me
1g
H
NOE
NOE
1H NMR = 141 (d J = 64 Hz 3H) 259 (bs 1H) 387 (dd J = 92 08 Hz 1H)
390 (s 3H) 399 (d J = 92 Hz 1H) 419 (q J = 60 Hz 1H) 698-707 (m 4H)
720-727 (m 3H) 779-785 (m 2H) 13
C NMR = 143 557 627 701 731 1144
1247 1265 1280 1285 1306 1416 1635 HRMS (ESI+) Calcd for C17H20NO4S
M+H+ 3341108 Found mz 3341102 IR (ATR) 3470 1595 1333 1153 671 cm
-1
[]28
D = 384 (c = 089 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 309 min (minor) t2 = 359 min (major) er gt 991
N
HO
S O
O
F3C
Me
1h
H
NOE
NOE
1H NMR = 147 (d J = 64 Hz 3H) 255 (bs 1H) 395 (dd J = 88 08 Hz 1H)
406 (d J = 92 Hz 1H) 430 (qd J = 64 08 Hz 1H) 694-699 (m 2H) 721-727
(m 3H) 784 (d J = 80 Hz 2H) 801 (d J = 84 Hz 2H) 13
C NMR = 145 629
706 729 1232 (JC-F = 2711 Hz) 1245 1263 (JC-F = 37 Hz) 1283 12868 12871
1350 (JC-F = 327 Hz) 1392 1414 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+
3720876 Found mz 3720870 IR (ATR) 3503 1348 1323 1165 646 cm-1
[]28
D = 340 (c = 077 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 120 min (minor) t2 = 130 min (major) er gt 991
Chapter 2
51
N
HO
S O
O
Me
1i
H
NOE
NOE
Me 1H NMR = 144 (d J = 64 Hz 3H) 217 (bs 1H) 245 (s 3H) 389 (d J = 92 Hz
1H) 401 (d J = 88 Hz 1H) 422 (q J = 64 Hz 1H) 694-698 (m 2H) 720-724 (m
3H) 746-750 (m 2H) 767-772 (m 2H) 13
C NMR = 144 214 630 704 730
1247 1256 1279 1285 1286 1291 1341 1347 1395 1416 HRMS (ESI+)
Calcd for C17H20NO3S M+H+ 3181158 Found mz 3181154 IR (ATR) 3487 1325
1151 714 700 cm-1
[]29
D = 380 (c = 105 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 204 min (minor) t2 = 218 min (major) er gt 991
N
HO
S O
O
Me
1j
H
NOE
NOE
S
1H NMR = 148 (d J = 64 Hz 3H) 259 (bs 1H) 396-401 (m 1H) 406 (d J = 92
Hz 1H) 425 (q J = 64 Hz 1H) 696-701 (m 2H) 720-728 (m 4H) 764-767 (m
1H) 769-772 (m 1H) 13
C NMR = 144 632 709 730 1246 1279 1281 1286
1329 1337 1346 1414 HRMS (ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566
Found mz 3100559 IR (ATR) 3508 1340 1151 756 669 cm-1
[]29
D = 342 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 183 min (minor) t2 = 220 min (major) er gt 991
Chapter 2
52
N
HO
S O
O
Me
1k
H
NOE
NOE
OMe
1H NMR = 142 (d J = 64 Hz 3H) 261 (bs 1H) 375 (s 3H) 387 (d J = 92 Hz
1H) 394 (d J = 88 Hz 1H) 416 (q J = 64 Hz 1H) 670-675 (m 2H) 684-689 (m
2H) 756-762 (m 2H) 765-770 (m 1H) 786-790 (m 2H) 13
C NMR = 143 553
630 704 729 1138 1259 1283 1292 1332 1337 1348 1592 HRMS (ESI+)
Calcd for C17H20NO4S M+H+ 3341108 Found mz 3341102 IR (ATR) 3466 1508
1327 1155 606 cm-1
[]29
D = 360 (c = 113 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 417 min (minor) t2 = 499 min (major) er gt 991
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Ligand
Screening
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP
(37 mg 5 mol 5 mol ) in toluene (10 mL) was heated at 60 degC After being stirred
for 12 h the reaction mixture was passed through a pad of florisil The solvent was
removed and the residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a (291 mg 0093
mmol 93 yield)
Chapter 2
53
Table S1 Screening of Achiral Ligands
rac -DM-BINAP
rac-BINAP
dppf
dppb
PPh3
dppe
46
trace
trace
yield
PCy3
Ligand
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
entry
1
2
3
4
5
6
7
8
nd
nd
nd
93
none nd
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Table S2 Screening of Chiral Ligands
entry Ligand yield
1
2
3
4
(R)-BINAP
(R)-DM-BINAP
(R)-SEGPHOS
(R)-DIFLUORPHOS
er
94
46
48
43
5
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS trace -
3862
91
7
8
(R)-MeO-BIPHEP
(R)-MeO-DM-BIPHEP
64
91
892
3169
1288
1486
2476
2575
2 mol [Rh(OH)cod]2
Ligand (10mol P)
toluene 60 C 12 h
20 eq K2CO3
NS Me
HO PhMe
2a
O O
N
HO Ph
Ts
1a
Rhodium-Catalyzed Reaction of Azetidinol 1a A Typical Procedure for Reactions
of Azetidinols 1a-1d
A mixture containing N-toluenesulfonylazetidinol 1a (303 mg 010 mmol) K2CO3
(276 mg 020 mmol) [Rh(OH)(cod)]2 (23 mg 5 mol 5 mol ) and
(R)-DIFLUORPHOS (82 mg 12 mol 12 mol ) in toluene (10 mL) was heated at
60 degC After being stirred for 12 h the reaction mixture was passed through a pad of
florisil The solvent was removed and the residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2a
(275 mg 0091 mmol 91 yield)
Chapter 2
54
NS Me
HO PhMe
2a
O O
1H NMR = 228 (s 3H) 277 (bs 1H) 304 (s 3H) 347 (d J = 148 Hz 1H) 429 (d
J = 148 Hz 1H) 683 (s 1H) 727-744 (m 6H) 781 (d J = 84 Hz 1H) 13
C NMR
= 216 361 626 732 1238 1263 1280 1284 1299 1301 1330 1412 1431
1438 HRMS (ESI+) Calcd for C16H18NO3S M+H
+ 3041002 Found mz 3040998 IR
(ATR) 3472 1325 1161 1142 735 cm-1
[]29
D = 339 (c = 028 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 175 min (minor) t2 = 194 min (major) er = 928
NS CH2D
HO Ph
D3C
2a-d
O O
D
D
D
1H NMR = 293 (bs 1H) 300 (t J = 20 Hz 3H) 347 (d J = 148 Hz 1H) 426 (d
J = 148 Hz 1H) 728-743 (m 5H) 13
C NMR = 201-210 (m) 358 (t JC-D = 212
Hz) 625 731 1234 (t JC-D = 249 Hz) 1262 1279 1283 1291-1300 (m 2C)
1327 1411 1432 1434 HRMS (ESI+) Calcd for C16H11D7NO3S M+H
+ 3111441
Found mz 3111436 IR (ATR) 3524 1318 1290 1150 721 cm-1
NS Me
HO Ph
O O
S
2b
1H NMR = 263 (bs 1H) 310 (s 3H) 359 (d J = 152 Hz 1H) 428 (d J = 156 Hz
1H) 668 (d J = 52 z 1H) 730-738 (m 5H) 750 (d J = 52 Hz 1H) 13
C NMR =
378 630 722 1257 1264 1282 1286 1299 1338 1427 1467 HRMS (ESI+)
Calcd for C13H14NO3S2 M+H+ 2960410 Found mz 2960403 IR (ATR) 3437 1323
1150 1063 748 cm-1
[]29
D = 313 (c = 100 in CHCl3) Enantiomeric excess was determined by HPLC with
Chapter 2
55
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 266 min (major) t2 = 306 min (minor) er = 937
NS Me
HOMe
O O
OMe
2c
1H NMR = 227 (s 3H) 290-326 (m 4H) 345 (d J = 148 Hz 1H) 381 (s 3H)
422 (d J = 148 Hz 1H) 684-690 (m 3H) 724-733 (m 3H) 774-779 (m 1H) 13
C
NMR = 216 360 553 626 729 1137 1237 1275 1299 1230 1328 1351
1413 1437 1592 HRMS (ESI+) Calcd for C17H20NO4S M+H
+ 3341108 Found mz
3341098 IR (ATR) 3441 1508 1250 1144 735 cm-1
[]29
D = 166 (c = 033 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 244 min (minor) t2 = 261 min (major) er = 937
NS Me
HOMe
O O
CF3
2d 1H NMR = 229 (s 3H) 304 (s 3H) 347 (d J = 148 Hz 1H) 425 (d J = 148 Hz
1H) 677 (s 1H) 732 (d J = 84 Hz 1H) 756 (d J = 84 Hz 2H) 763 (d J = 84 Hz
2H) 782 (d J = 80 Hz 1H) 13
C NMR = 216 360 625 731 12392 (q JC-F =
2708) 12395 1254 (q JC-F = 36 Hz) 1268 1298 1303 (q JC-F = 352) 1329
1404 1441 1471 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720869 IR (ATR) 3481 1323 1121 1067 733 cm-1
[]29
D = 162 (c = 026 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 167 min (minor) t2 = 192 min (major) er = 919
Chapter 2
56
Rhodium-Catalyzed Reaction of Azetidinol 1e A Typical Procedure for Reactions
of Azetidinols 1e-1n
A mixture containing N-toluenesulfonylazetidinol 1e (317 mg 010 mmol)
[Rh(OH)(cod)]2 (09 mg 2 mol 2 mol ) and rac-DM-BINAP (37 mg 5 mol 5
mol ) in toluene (10 mL) was heated at 60 degC After being stirred for 12 h the
reaction mixture was passed through a pad of florisil The solvent was removed under
reduced pressure The crude residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 31) to afford the benzosultam 2e
(313 mg 0099 mmol 99 yield)
SN
HO
Me
O OMe
Me
2e
H
NOE
NOE
1H NMR = 120 (d J = 64 Hz 3H) 224 (s 3H) 226 (s 1H) 297 (s 3H) 468 (q J
= 68 Hz 1H) 675 (s 1H) 723-738 (m 6H) 777 (d J = 84 Hz 1H) 13
C NMR =
119 215 314 608 750 1242 1262 1275 1282 1298 1301 1316 1427
1436 1440 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3481 1315 1163 1146 683 cm-1
[]28
D = -640 (c = 093 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 324 min (minor) t2 = 385 min (major) er gt 991
SN
HO
Me
O OMe
MeO
2g
H
NOE
NOE
Chapter 2
57
1H NMR = 119 (d J = 68 Hz 3H) 239 (s 1H) 296 (s 3H) 367 (s 3H) 467 (q J
= 68 Hz 1H) 641 (d J = 24 Hz 1H) 694 (dd J = 88 28 Hz 1H) 724-736 (m
5H) 782 (d J = 88 Hz 1H) 13
C NMR = 120 314 555 609 752 1144 1151
1261 1262 1268 1276 1282 1439 1450 1626 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341103 IR (ATR) 3487 1327 1161 1142
735 cm-1
[]29
D = -373 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 176 min (minor) t2 = 196 min (major) er gt 991
SN
HO
Me
O OMe
F3C
2h
H
NOE
NOE
1H NMR = 124 (d J = 68 Hz 3H) 253 (bs 1H) 300 (s 3H) 473 (q J = 68 Hz
1H) 724 (s 1H) 730-740 (m 5H) 770 (dd J = 84 12 Hz 1H) 802 (d J = 84 Hz
1H) 13
C NMR = 118 314 608 750 1228 (q JC-F = 2711 Hz) 1251 1258 (q
JC-F = 37 Hz) 1260 1274 (q JC-F = 37 Hz) 1281 1286 1346 (q JC-F = 327 Hz)
1377 1428 1437 HRMS (ESI+) Calcd for C17H17F3NO3S M+H
+ 3720876 Found
mz 3720872 IR (ATR) 3461 1325 1161 1142 739 cm-1
[]29
D = -640 (c = 063 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 132 min (minor) t2 = 143 min (major) er gt 991
SN
HO
Me
O OMe
2i
H
NOE
NOE
Me
Chapter 2
58
1H NMR = 121 (d J = 68 Hz 3H) 218 (bs 1H) 238 (s 3H) 300 (s 3H) 468 (q
J = 68 Hz 1H) 684 (d J = 80 Hz 1H) 718-736 (m 6H) 770 (s 1H) 13
C NMR
=119 211 314 607 748 1242 1262 1275 1282 1299 1338 1341 1395
1399 1441 HRMS (ESI+) Calcd for C17H20NO3S M+H
+ 3181158 Found mz
3181155 IR (ATR) 3489 1448 1319 1148 735 cm-1
[]29
D = -962 (c = 062 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260 nm) t1
= 124 min (minor) t2 = 141 min (major) er gt 991
SN
HO
Me
O OMe
2j
H
NOE
NOES
1H NMR = 124 (d J = 68 Hz 3H) 224 (bs 1H) 301 (s 3H) 461 (q J = 68 Hz
1H) 656 (d J = 52 Hz 1H) 726-736 (m 5H) 743 (d J = 48 Hz 1H) 13
C NMR
= 114 319 619 742 1256 1266 1278 1284 1297 1334 1429 1480 HRMS
(ESI+) Calcd for C14H16NO3S2 M+H
+ 3100566 Found mz 3100561 IR (ATR) 3524
1329 1151 1020 729 cm-1
[]29
D = -803 (c = 053 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 253 min (major) t2 = 273 min (minor) er gt 991
SN
HO
Me
O OMe
2k
H
NOE
NOE
OMe
1H NMR = 121 (d J = 68 Hz 3H) 226 (bs 1H) 298 (s 3H) 379 (s 3H) 466 (q
J = 68 Hz 1H) 685 (d J = 88 Hz 2H) 698-703 (m 1H) 722-730 (m 2H)
738-748 (m 2H) 785-790 (m 1H) 13
C NMR = 119 314 553 608 747 1136
Chapter 2
59
1241 1274 1289 1300 1328 1344 1359 1429 1589 HRMS (ESI+) Calcd for
C17H20NO4S M+H+ 3341108 Found mz 3341101 IR (ATR) 3479 1508 1313 1157
760 cm-1
[]26
D = -1007 (c = 087 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 112 min (minor) t2 = 125 min (major) er gt 991
SN
HO
Me
O OMe
2l
H
NOE
NOE
CF3
Me
1H NMR = 120 (d J = 68 Hz 3H) 226 (s 3H) 235 (s 1H) 296 (s 3H) 465 (q J
= 68 Hz 1H) 670 (s 1H) 729 (d J = 80 Hz 1H) 750 (d J = 80 Hz 2H) 760 (d J
= 84 Hz 2H) 778 (d J = 80 Hz 1H) 13
C NMR = 119 215 313 607 749
1239 (JC-F = 2704 Hz) 1244 1252 (JC-F = 43 Hz) 1268 1299 (JC-F = 316 Hz)
1300 1303 1316 1419 1439 1482 HRMS (ESI+) Calcd for C18H19F3NO3S
M+H+ 3861032 Found mz 3861026 IR (ATR) 3481 1323 1159 1118 731 cm
-1
[]26
D = -517 (c = 060 in CHCl3) Enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IC hexanei-PrOH = 9010 flow rate = 06 mLmin = 260 nm) t1
= 169 min (minor) t2 = 195 min (major) er gt 991
SN
HO
iPr
O OMe
2m
H
NOE
NOE
Me
1H NMR = 056 (d J = 68 Hz 3H) 110 (d J = 64 Hz 3H) 222 (s 3H) 230-241
(m 1H) 264 (s 1H) 285 (s 3H) 441 (d J = 100 Hz 1H) 685 (s 1H) 714-735 (m
4H) 748 (d J = 76 Hz 2H) 772 (d J = 80 Hz 1H) 13
C NMR = 211 214 217
278 330 718 742 1244 1256 1270 1283 1292 1295 1300 1435 1442
1464 HRMS (ESI+) Calcd for C19H24NO3S M+H
+ 3461471 Found mz 3461466 IR
Chapter 2
60
(ATR) 3412 1315 1165 1146 683 cm-1
[]29
D = -1528 (c = 059 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 127 min (major) t2 = 139 min (minor) er gt 991
SN
HO
O OMe
2n
H
Me
NOE
SMe
1H NMR = 160-170 (m 1H) 184 (s 3H) 212-226 (m 4H) 230-242 (m 2H)
254-263 (m 1H) 294 (s 3H) 471 (dd J = 108 28 Hz 1H) 675 (s 1H) 722-738
(m 6H) 776 (d J = 80 Hz 1H) 13
C NMR = 150 215 242 301 321 643 748
1245 1262 1276 1283 12986 12993 1312 1429 1437 1441 HRMS (ESI+)
Calcd for C19H24NO3S2 M+H+ 3781192 Found mz 3781186 IR (ATR) 3483 1319
1165 1134 748 cm-1
[]28
D = -1240 (c = 047 in CHCl3) Enantiomeric excess was determined by HPLC
with a Daicel Chiralpak IC hexanei-PrOH = 7030 flow rate = 06 mLmin = 260
nm) t1 = 166 min (minor) t2 = 230 min (major) er gt 991
Details for X-ray Crystallography
Single crystal of 2e was obtained from hexanedichloromethane solution and mounted
on a grass capillary The data was collected on a Rigaku R-AXIS imaging plate area
detector with graphite-monochromated Mo K radiation operating at 50 kV and 40 mA
at minus173 degC All the following procedure for analysis Yadokari-XG19
was used as a
graphical interface The structure was solved by direct methods with SIR-9720
and
refined by full-matrix least-squares techniques against F2 (SHELXL-97)
21 All
non-hydrogen atoms were refined anisotropically The positions of hydrogen atoms
were calculated and their contributions in structural factor calculations were included
Chapter 2
61
Figure S1 ORTEP diagram of 2e
Table S3 Crystallographic data and structure refinement details for 2e
2e
formula C17H19NO3S
fw 31739
T (K) 100(2)
cryst syst monoclinic
space group P21c
a (Aring) 105967(5)
b (Aring) 134725(7) c (Aring) 110152(5) (deg) 9000 (deg) 1047740(15) (deg) 9000 V (Aring
3) 152058(13)
Z 4 Dcalc (gcm
3) 1386
(mm-1
) 0225 F(000) 672
cryst size (mm) 120times060times030
radiation (Aring) 071075 reflns collected 14659 indep reflnsRint
348500135
params 203 GOF on F
2 1069
R1 wR2 [Igt2(I)]
00322 00868
R1 wR2 (all data)
00335 00878
Chapter 2
62
References and Notes
(1) For reviews on CndashH activation (a) Crabtree R H Chem Rev 1985 85 245-269
(b) Halpern J Inorg Chim Acta 1985 100 41-48 (c) Shilov A E Shulrsquopin G B
Chem Rev 1997 97 2879-2932 (d) Jones W D Top Organomet Chem 1999
9-46 (e) Kakiuchi F Murai S Top Organomet Chem 1999 47-79 (f) Dyker G
Angew Chem Int Ed 1999 38 1698-1712 (g) Jia C Kitamura T Fujiwara Y
Acc Chem Res 2001 34 633-639 (h) Handbook of CndashH Transformations Dyker
G Ed Wiley-VCH Weinheim Germany 2005 (i) Daugulis O Do H-Q
Shabashov D Acc Chem Res 2009 42 1074-1086 (j) Giri R Shi B-F Engle
K M Maugel N Yu J-Q Chem Soc Rev 2009 38 3242-3272 (k) Colby D
A Bergman R G Ellman J A Chem Rev 2010 110 624-655 (l) Mkhalid I A
I Barnard J H Marder T B Murphy J M Hartwig J F Chem Rev 2010
110 890-931 (m) Lyons T W Sanford M S Chem Rev 2010 110 1147-1169
(n) Ackermann L Chem Commun 2010 46 4866-4877 (o) Newhouse T Baran
P S Angew Chem Int Ed 2011 50 3362-3374 (p) McMurray L OrsquoHara F
Gaunt M J Chem Soc Rev 2011 40 1885-1898 (q) Yeung C S Dong V M
Chem Rev 2011 111 1215-1292 (r) Sun C-L Li B-J Shi Z-J Chem Rev
2011 111 1293-1314 (s) Cho S H Kim J Y Kwak J Chang S Chem Soc
Rev 2011 40 5068-5083 (t) Kuhl N Hopkinson M N Wencel-Delord J
Glorius F Angew Chem Int Ed 2012 51 10236-10254 (u) Yamaguchi J
Yamaguchi A D Itami K Angew Chem Int Ed 2012 51 8960-9009 (v)
Arockiam P B Bruneau C Dixneuf P H Chem Rev 2012 112 5879-5918L
Sun C Liang S Shirazian Y Zhou T Miller J Cui J Y Fukuda J-Y Chu A
Nematalla X Wang H Chen A Sistla T C Luu F Tang J Wei C Tang J
Med Chem 2003 46 1116
(2) For reviews on CndashC activation (a) Rybtchinski B Milstein D Angew Chem Int
Ed 1999 38 870-883 (b) Murakami M Ito Y Top Organomet Chem 1999
97-129 (c) Takahashi T Kotora M Hara R Xi Z Bull Chem Soc Jpn 1999
72 2591-2602 (d) Perthuisot C Edelbach B L Zubris D L Simhai N
Iverson C N Muumlller C Satoh T Jones W D J Mol Cat A 2002 189
157-168 (e) Nishimura T Uemura S Synlett 2004 201-216 (f) Jun C-H Chem
Soc Rev 2004 33 610-618 (g) Miura M Satoh T Top Organomet Chem
Chapter 2
63
2005 14 1-20 (h) Kondo T Mitsudo T Chem Lett 2005 34 1462-1466 (i)
Nečas D Kotora M Curr Org Chem 2007 11 1566-1591 (j) Tobisu M
Chatani N Chem Soc Rev 2008 37 300-307 (k) Nakao Y Hiyama T Pure
Appl Chem 2008 80 1097-1107 (l) Yorimitsu H Oshima K Bull Chem Soc
Jpn 2009 82 778-792 (m) Seiser T Cramer N Org Biomol Chem 2009 7
2835-2840 (n) Bonesi S M Fagnoni M Chem Eur J 2010 16 13572-13589
(o) Murakami M Matsuda T Chem Commun 2011 47 1100-1105 (p) Aїssa C
Synthesis 2011 3389-3407 (q) Ruhland K Eur J Org Chem 2012 2683-2706
(r) Dong G Synlett 2013 24 1-5
(3) Reviews (a) Ma S Gu Z Angew Chem Int Ed 2005 44 7512-7517 (b) Shi
F Larock R Top Curr Chem 2010 292 123-164
(4) For a 14-palladium shift (a) Bocelli G Catellani M Chiusoli G P Larocca S
J Organomet Chem 1984 26 C9-C11 (b) Dyker G Chem Ber 1994 127
739-742 (c) Campo M A Larock R C J Am Chem Soc 2002 124
14326-14327 (d) Baudoin O Herrbach A Gueacuteritte F Angew Chem Int Ed
2003 42 5736-5740 (e) Masselot D Charmant J P H Gallagher T J Am
Chem Soc 2005 128 694-695 (f) Barder T E Walker S D Martinelli J R
Buchwald S L J Am Chem Soc 2005 127 4685-4696 (g) Zhao J Yue D
Campo M A Larock R C J Am Chem Soc 2007 129 5288-5295 and
references cited therein
(5) For a 14-rhodium shift (a) Oguma K Miura M Satoh T Nomura M J Am
Chem Soc 2000 122 10464-10465 (b) Hayashi T Inoue K Taniguchi N
Ogasawara M J Am Chem Soc 2001 123 9918-9919 (c) Miura T Sasaki T
Nakazawa H Murakami M J Am Chem Soc 2005 127 1390-1391 (d)
Shintani R Okamoto K Hayashi T J Am Chem Soc 2005 127 2872-2873
(e) Yamabe H Mizuno A Kusama H Iwasawa N J Am Chem Soc 2005
127 3248-3249 (f) Matsuda T Shigeno M Murakami M J Am Chem Soc
2007 129 12086-12087 (g) Panteleev J Menard F Lautens M Adv Synth
Catal 2008 350 2893-2902 (h) Seiser T Roth O A Cramer N Angew Chem
Int Ed 2009 48 6320-6323 (i) Shigeno M Yamamoto T Murakami M Chem
Eur J 2009 15 12929-12931 (j) Seiser T Cramer N Angew Chem Int Ed
2010 49 10163-10167 (k) Sasaki K Nishimura T Shintani R Kantchev E A
Chapter 2
64
B Hayashi T Chem Sci 2012 3 1278-1283 (l) Matsuda T Suda Y Takahashi
A Chem Commun 2012 48 2988-2990 and references cited therein
(6) For a 14-cobalt shift Tan B-H Dong J Yoshikai N Angew Chem Int Ed
2012 51 9160
(7) (a) Bour C Suffert J Org Lett 2005 7 653-656 (b) Mota A J Dedieu A
Bour C Suffert J J Am Chem Soc 2005 127 7171-7182 (c) Shintani R
Otomo H Ota K Hayashi T J Am Chem Soc 2012 134 7305-7306 (d)
Tobisu M Hasegawa J Kita Y Kinuta H Chatani N Chem Commun 2012
11437-11439
(8) For recent reports on synthesis of benzosultams (a) Zeng W Chemler S R J
Am Chem Soc 2007 129 12948-12949 (b) Miura T Yamauchi M Kosaka
A Murakami M Angew Chem Int Ed 2010 49 4955-4957 (c) Majumdar K
C Mondal S Chem Rev 2011 111 7749-7773 (d) Pham M V Ye B Cramer
N Angew Chem Int Ed 2012 51 10610-10614 (e) Dong W Wang L
Parthasarathy K Pan F Bolm C Angew Chem Int Ed 2013 52 11573-11576
and references cited therein
(9) (a) Lombardino J G Wiseman E H Mclamore W J Med Chem 1971 14
1171ndash1175 (b) Lazer E S Miao C K Cywin C L Sorcek R Wong H-C
Meng Z Potocki I Hoermann M Snow R J Tschantz M A Kelly T A
McNeil D W Coutts S J Churchill L Graham A G David E Grob P M
Engel W Meier H Trummlitz G J Med Chem 1997 40 980ndash989 (c) Wells
G J Tao M Josef K A Bihovsky R J Med Chem 2001 44 3488ndash3503 (d)
Zia-ur-Rehman M Choudary J A Ahmad S Siddiqui H L Chem Pharm
Bull 2006 54 1175-1178 and references cited therein
(10) See Supporting Information for details
(11) For transition metal-catalyzed reactions of cyclobutanolscyclobutenols involving
-carbon elimination (a) Nishimura T Ohe K Uemura S J Am Chem Soc
1999 121 2645-2646 (b) Nishimura T Uemura S J Am Chem Soc 1999 121
11010-11011 (c) Matsuda T Makino M Murakami M Org Lett 2004 6
1257-1259 (d) Seiser T Cramer N Angew Chem Int Ed 2008 47 9294-9297
(e) Seiser T Cramer N J Am Chem Soc 2010 132 5340-5341 (f)
Chtchemelinine A Rosa D Orellana A J Org Chem 2011 76 9157-9162 (g)
Chapter 2
65
Ziadi A Martin R Org Lett 2012 14 1266-1269 (h) Ishida N Sawano S
Masuda Y Murakami M J Am Chem Soc 2012 134 17502-17504 (i)
Matsuda T Miura N Org Biomol Chem 2013 11 3424-3427 (j) Ishida N
Nakanishi Y Murakami M Angew Chem Int Ed in press [DOI
101002anie201306343] and references cited therein
(12) For 6-exo cyclization of arylmetal intermediates having a pendant ketone see (a)
Liu G X Lu X Y J Am Chem Soc 2006 128 16504-16505 (b) Yin L
Kanai M Shibasaki M Angew Chem Int Ed 2011 50 7620-7623 (c)
Sarpong R Gallego G L Chem Sci 2012 3 1338-1342 (d) Low D W
Pattison G Wieczysty M D Churchill G H Lam H W Org Lett 2012 14
2548-2551
(13) (a) Podlech J Seebach D Helv Chim Acta 1995 78 1238-1246 (b) Wang J
Hou Y Wu P J Chem Soc Perkin Trans 1 1999 2277-2280
(14) In case the 3-substituent was a methyl group a 15-rhodium shift occurred onto the
methyl group rather than onto the aryl group to form the rhodium enolate which
was subsequently protonated to give a simple ring-opened product
(15) Ishida N Shimamoto Y Murakami M Angew Chem Int Ed 2012 51
11750
(16) Ghosh D Sahu D Saravanan S Abdi S H R Ganguly B Khan N-u H
Kureshy R I Bajaj H C Org Biomol Chem 2013 11 3451
(17) Wang J Hou Y J Chem Soc Perkin Trans 1 1998 1919
(18) Bures F Kulhanek J Tetrahedron Asymmetry 2005 16 1347
(19) (a) Wakita K Yadokari-XG Software for Crystal Structure Analyses 2001 (b)
Kabuto C Akine S Kwon E J Cryst Soc Jpn 2009 51 218
(20) Altomare A Burla M C Camalli M Cascarano G L Giacovazzo C
Guagliardi A Moliterni A G G Polidori G Spagna R J Appl Cryst 1999
32 115
(21) Sheldrick G M SHELX-97 Programs for Crystal Structure Analysis University
of Goumlttingen Germany 1997
Chapter 2
66
Chapter 3
67
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic
Esters Stereochemistry Reversed by Ligand in the
Palladium-Catalyzed Reaction of Alkynylborates with Aryl
Halides
Abstract
The palladium-catalyzed reaction of alkynylborates with aryl halides stereoselectively
gave (E)-(trisubstituted alkenyl)-9-BBNs in which two different aryl groups were
installed trans to each other
Reproduced with permission from Org Lett 2009 11 5434-5437
Copyright 2009 American Chemical Society
Chapter 3
68
Introduction
Organoboron compounds are stable and easily handled organometallics with well
understood reactivities rendering them indispensable synthetic reagents for
carbonndashcarbon bond formation1 In addition organoboron compounds have found
increasing applications in the fields of pharmaceutical chemistry2 and materials
science3 Therefore the development of efficient methods to prepare them is of even
higher demand than ever
Well established preparative methods exist for the synthesis of (monosubstituted
alkenyl)(diorganyl)boranes such that these compounds have been widely applied for the
synthesis of unsaturated organic compounds like allylic alcohols4 However the
selective preparation of both stereoisomers of (trisubstituted alkenyl)(diorganyl)boranes
remains a significant challenge56
We have reported that alkynyl(triaryl)borates (aryl =
Ar1) react with aryl halides (Ar
2ndashX) in the presence of a palladium catalyst to afford a
(trisubstituted alkenyl)(diaryl)boranes in which the two aryl groups (Ar1 and Ar
2) are
incorporated cis to each other across the resulting carbonndashcarbon double bond7
Considering the potential utility of these compounds we embarked on the development
of a complementary synthetic method for the (E)-isomers In this communication we
describe the stereoselective synthesis of (E)-(trisubstituted alkenyl)-9-BBNs by a
palladium-catalyzed reaction of alkynylborates with aryl halides in which the two
different aryl groups are installed trans to each other
Results and Discussion
Alkynylborate 1a was readily prepared by the reaction of Ph-9-BBN with
but-1-ynyllithium in THF8 and subsequent cation exchange with tetramethylammonium
chloride in methanol (Scheme 1) Borate 1a obtained is a white precipitate of high
purity stable to air and moisture and therefore storable without any decomposition for
several months
Scheme 1 Preparation of Alkynyl Borate 1aa
Et LiB
Ph
+B
Ph
Et
1a 74
(a)(b)[Me4N]
a Reagents and conditions (a) THF - 78 degC to rt 1 h (b) Me4NCl MeOH rt 5 min
Chapter 3
69
Alkynylborate 1a thus derived from Ph-9-BBN is preferred over the corresponding
alkynyltriarylborate as the starting substance from a synthetic point of view It was
subjected to the palladium-catalyzed reaction with 4-bromoanisole in the presence of
various phosphine ligands (Table 1) When tri(o-tolyl)phosphine was employed as the
ligand the phenyl group on boron underwent 13-migration onto the palladium in
preference to the bridgehead sp3 carbons of the 9-BBN moiety and the (Z)-isomer was
stereoselectively formed as with the case of the corresponding triphenylborate7a
Although we attempted to isolate the produced triorganoborane 3a it failed because 3a
was prone to decompose in air Instead 3a was immediately hydrolyzed with acetic
acid9 to give the alkene (Z)-4a (EZ = 397 entry 1) The EZ ratio changed in favor of
the (E)-isomer as the steric bulkiness of the monodentate phosphine increased (entries
2-4) Surprisingly the stereochemical preference was reversed for the (E)-isomer (EZ =
928) when bidentate ligand DPEPhos having a large bite angle was used (entry 5)
Finally it was found that XANTPhos possessing an even larger bite angle exclusively
gave (E)-4a in 73 yield (entry 6)
Table 1 Ligand Screeninga
OMe
BrB
Ph
Et
OMe
3a
Ph
Et
OMe
H
4a
Pd-ligand AcOH
2a
+B
Ph
Et
1a
[Me4N]
entry ligand yield of 4a b
EZ of 4ab
1 P(o-tol)3 69 397
2 P(t-Bu)3 47 1783
3 1-[(t-Bu)2P](biphenyl) 18 2872
4 2-[(t-Bu)2P](11-binaphthyl) 21 6733
5 DPEPhos 24 928
6 XANTPhos 73 gt199 a reaction conditions 10 equiv of 1a 105 equiv of 2a 25 mol of [Pd(-allyl)Cl]2 6
mol of Ligand toluene 70 degC 30 min then AcOH rt 3 h b Dtermined by GC
analysis
Thus the stereochemistry of the product depended strongly on the phosphine ligand
employed A proposed mechanism for the trans-addition reaction is shown in Scheme 2
Chapter 3
70
(i) oxidative addition of 4-bromoanisole (2a) to palladium(0) gives arylpalladium
bromide A (ii) arylpalladium species A is coordinated by alkynylborate 1a to form
intermediate B (iii) carbopalladation across the carbonndashcarbon triple bond occurs in a
cis fashion to provide alkenylpalladium C (iv) a phenyl group on boron migrates to the
-carbon with inversion of stereochemistry1011
resulting in the formation of
trans-addition product 3a with regeneration of the palladium(0)12
Scheme 2 Proposed Mechanism
Pd(0)
Pd
MeO
B
PdEt
OMe
Ph
B
Ph
Et
2a
BC
Pd
MeO
Br
A
1a
3a
The ligand-dependent reaction pathway of the phenyl migration is explained as
follows Tri(o-tolyl)phosphine is relatively less stereo-demanding and when located
around the palladium center provides enough space for the phenyl group on boron to
undergo 13-migration to palladium (Scheme 4) On the other hand a bulky bidentate
ligand XANTPhos likely disfavors the 13-phenyl migration from boron to palladium
Instead the direct 12-migration of the phenyl group from boron onto the -carbon
dominates10
giving trans-addition product Tri(t-butyl)phosphine and Buchwald type
ligands which are intermediates between tri(o-tolyl)phosphine and XANTPhos in
sterics may permit both of these pathways resulting in a mixture of EZ isomers
Next we tried to isolate the addition product in a form of an alkenylborane which
was applicable to subsequent synthetic transformations rather than loosing a carbon-
ndashboron linkage by hydrolysis When the reaction mixture was directly subjected to a
migrative oxidation reaction with trimethylamine-N-oxide (trisubstituted
alkenyl)borinic ester 5a in which the bridgehead sp3 carbon migrated onto oxygen was
obtained stereoselectively13
The resulting borinic ester (E)-5a was stable enough to be
isolated by column chromatography on silica gel and could be stored without any
decomposition for a longer period of time than 1 month Most importantly this reagent
could be employed for subsequent carbonndashcarbon bond forming reactions (vide infra)
A wide variety of borinic esters were synthesized using the palladiumXANTPhos
system followed by migrative oxidation with trimethylamine-N-oxide (Scheme 3) Aryl
Chapter 3
71
halides having either an electron-donating or an electron-withdrawing substituent gave
the corresponding borinic esters in good yields (5a and 5b) Phthalimide (5c) chloro (5f
5j and 5l) and ester (5i) groups remained intact under the reaction conditions A
sterically demanding aryl iodide was also reactive (5d) In addition to the substituted
phenyl groups 2- and 3-bromothiophene afforded the desired product in good yield (5e
and 5h) Primary alkyl (5a to 5g 5l and 5m) secondary alkyl (5h to 5k) and aryl (5n)
groups can be used as the substituent of the alkynyl moiety The scope of the aryl group
on boron was also broad electron-rich (5g and 5n) and -deficient (5f) phenyl and
thienyl (5l) groups successfully participated in the migration reaction
Chapter 3
72
Table 2 Synthesis of Borinic Esters
BO
Ph
Et
OMe
5a 83
BO
Ph
Et
CF3
5b 85
BO
Ph
Et
NPhth
5c 82
BO
Ph
Et
5d 72b
BO
Ph
Et
5e 85
S
BO
n-Pr
Me
Cl
5f 74
BO
n-Pr
Ph
OMe
5g 82
BO
Ph
S
5h 83
BO
Ph
CO2Et
5i 81
BO
Ph
5j 82
Cl
BO
Ph
CF3
TBSO
BO
Cl
S
Ph
BO
Ph
Me
OMe
5n 71b
5m 925l 82
BO
Ph
5k 76
Me
+B
Ar
R
1
[Me4N]
2
Ar-Xcat XANTPhos-Pd Me3NO
BO
Ar
R
Ar
5
a Reaction conditions 10 equiv of alkynylborate 1 105 equiv of aryl halide 2 1 mol
of (xantphos)PdCl(-allyl) toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt
2 h Isolated yields were shown The major isomers shown in the table were observed
gt955 ratio by NMR analysis b Aryl iodide was used
Finally we applied this reaction to the synthesis of both isomers of Tamoxifen
(Scheme 5) which has been in clinical use for cancer treatment1415
The reaction of 1a
with bromobenzene with the palladiumtri(o-tolyl)phospine catalyst followed by
oxidation with trimethylamine-N-oxide gave borinic ester (Z)-5o (71 yield EZ =
793) On the other hand the corresponding (E)-isomer was stereoselectively obtained
in 83 yield (EZ = gt955) when the reaction of 1a with bromobenzene was carried out
with the palladiumXANTPhos calatyst the loading of which could be decreased even
Chapter 3
73
to 01 mol The Suzuki-Miyaura coupling reaction of each stereoisomer of 5o with
1-bromo-4-[2-(NN-dimethylamino)ethoxy]benzene (2b) afforded Tamoxifen (6) with
retention of the each stereochemistry Thus the present study made it possible to
synthesize either stereoisomer of tetrasubstituted olefins16
starting from the same
substances by choice of the appropriate ligand
Scheme 3 Synthesis of Tamoxifensa
(E)-5o83 EZ = gt955
BO
Ph
Et
Ph
Ph
Et
PhO
NMe2
(Z)-685 EZ = lt595
Ph
Ph
EtO
NMe 2
(E)-675 EZ = 928
1a
(Z)-5o71 EZ = 793
+ PhBr
BO
Ph
Ph
Et
(a)
(c) (c)
(b)
a Reagents and conditions (a) 1 mol of (o-tol)3PPdCl(-allyl) toluene 70 degC 30
min then 15 equiv of Me3NO DCM rt 2 h (b) 01 mol of (xantphos)PdCl(-allyl)
toluene 70 degC 30 min then 15 equiv of Me3NO DCM rt 2 h (c) 105 equiv of
4-BrC6H4[O(CH2)2NMe2] (2b) 25 mol of Pd(OAc)2 5 mol of SPhos K3PO4
THF 60 degC 12 h for (E)-5o 24 h for (Z)-5o
Conclusions
In summary we have developed a new catalyst system for the palladium-catalyzed
reaction of alkynylborates with aryl halides which produces (E)-(trisubstituted
alkenyl)boranes stereoselectively With both stereoisomers being available the
reinforced palladium-catalyzed reaction of alkynylborates serves as an authentic method
for the synthesis of (trisubstituted alkenyl)boron compounds
Chapter 3
74
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) or Varian Mercury-400 (
1H at 400 MHz and
11B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
are recorded in ppm referenced to a residual CDCl3 (= 726 for 1H 770 for
13C)
CD3CN ( = 194 for 1H =132 for
13C) and BF3OEt2 ( = 000 for
11B)
High-resolution mass spectra were recorded on JEOL JMS-SX102A spectrometer
Infrared spectra were recorded on SHIMADZU FT-IR 8100 Column chromatography
was performed with silica gel 60 N (Kanto) Preparative thin-layer chromatography was
performed with Silica gel 60 PF254 (Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl AcOH was degassed by N2 bubbling
(XANTPhos)Pd(-allyl)Cl17
and Ph-9-BBN18
were prepared according to the reported
procedures
Preparation of alkynylborates 1a
Et LiB
Ph
+B
Ph
Et
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
To a stirred solution of 1-butyne (1 ml) in THF (80 ml) at -78 ˚C was added n-BuLi
(16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature Ph-9-BBN
(990 mg 50 mmol) was added and the cooling bath was then removed After being
stirred for 1 h at room temperature the reaction was quenched by adding a small
amount of methanol Then volatile materials were removed under reduced pressure
The residue was dissolved in methanol and tetramethylammonium chloride (600 mg
55 mmol) was added with stirring at -78 ˚C resulting in white solid It was collected by
filtration and washed with cold methanol to give alkynylborate 1a (12 g 37 mmol
74 yield)
Chapter 3
75
B
Ph
Et
1a
[Me4N]
1H NMR (CD3CN) = 092 (bs 2H) 097 (t J = 78 Hz 3H) 111-120 (m 1H)
136-207 (m 11H) 236-250 (m 2H) 303 (s 12 H) 679-686 (m 1H) 700-707 (m
2H) 735 (d J = 72 Hz 2H) 13
C NMR (CD3CN) = 149 166 266 (q JC-B = 379
Hz) 271 275 324 349 561 948 1221 1269 1339 11
B NMR = -133 HRMS
(FAB) Calcd for C18H24B [M-(NMe4)] 2511971 Found 2511975
Preparation of alkynylborates 1b A typical procedure for the preparation of
alkynylborates 1b-1h
n-Pr LiB
Ar
+1) THF -78 degC to rt
2) Me4NCl MeOH B
n-Pr
1b
Cl
[Me4N]
To a stirred solution of 1-pentyne (375 mg 55 mmol) in THF (80 ml) at -78 ˚C was
added n-BuLi (16 M in hexane 34 ml 55 mmol) After 30 minutes at this temperature
4-ClC6H4-9-BBN (116 g 50 mmol) was added and the cooling bath was removed
After being stirred for 1 h at room temperature the reaction was quenched by adding a
small amount of methanol Then volatile materials were removed under reduced
pressure The residue was dissolved in methanol and tetramethylammonium chloride
(600 mg 55 mmol) was added with stirring at -78 ˚C resulting in white solid It was
collected by filtration and was washed with cold methanol to give alkynylborate 1b
(105g 28 mmol 56 yield)
Chapter 3
76
B
n-Pr
1b
Cl
[Me4N]
1H NMR (CD3CN) = 084-096 (m 5H) 111-121 (m 1H) 126-200 (m 13H)
235-250 (m 2H) 304 (s 12H) 700-705 (m 2H) 733 (d J = 84 Hz 2H) 13
C NMR
(CD3CN) = 139 234 249 266 (q JC-B = 393 Hz) 270 273 323 348 561
933 1265 1272 1355 11
B NMR = -133 HRMS (FAB) Calcd for C19H25BCl
[M-(NMe4)] 2991738 Found 2991730
B
n-Pr
1c
OMe
[Me4N]
1H NMR (CD3CN) = 087 (bs 2H) 093 (t J = 72 Hz 3H) 110-120 (m 1H)
128-201 (m 13H) 237-252 (m 2H) 303 (s 12H) 371 (s 3H) 663-668 (m 2H)
723 (d J = 81 Hz 2H) 13
C NMR (CD3CN) = 140 235 250 268 (q JC-B = 393
Hz) 272 275 324 349 554 561 929 1128 1344 1561 11
B NMR = -135
HRMS (FAB) Calcd for C20H28BO [M-(NMe4)] 2952233 Found 2952231
B
Ph
1d
[Me4N]
1H NMR (CD3CN) = 020-028 (m 2H) 045-053 (m 2H) 089 (bs 2H) 098-119
(m 2H) 134-196 (m 9H) 230-244 (m 2H) 304 (s 12H) 679-686 (m 1H)
699-706 (m 2H) 733 (d J = 72 Hz 2H) 13
C NMR (CD3CN) =23 87 266 (q
JC-B = 393 Hz) 271 274 323 349 562 1222 1269 1338 11
B NMR = -134
HRMS (FAB) Calcd for C19H24B [M-(NMe4)] 2631971 Found 2631976
Chapter 3
77
B
Ph
1e
[Me4N]
1H NMR (CD3CN) = 090 (bs 2H) 110-120 (m 1H) 130-196 (m 17H) 236-254
(m 3H) 302 (s 12H) 679-686 (m 1H) 699-706 (m 2H) 734 (d J = 66 Hz 2H) 13
C NMR (CD3CN) = 253 268 (q JC-B = 379 Hz) 271 275 324 333 349 361
561 980 1221 1269 1339 11
B NMR = -133 HRMS (FAB) Calcd for C21H28B
[M-(NMe4)] 2912284 Found 2912278
B
1f
S
Ph
[Me4N]
1H NMR (CD3CN) = 077 (bs 2H) 117-128 (m 1H) 138-160 (m 5H) 168- 197
(m 4H) 231 (t J = 75 Hz 2H) 234-237 (m 2H) 268 (t J = 75 Hz 2H) 301 (s
12H) 673 (dd J = 30 06 Hz 1H) 689 (dd J = 48 30 Hz 1H) 707 (dd J = 45
09 Hz 1H) 712-730 (m 5H) 13
C NMR (CD3CN) = 240 268-290 (m) 325 347
380 562 928 1225 1261 1265 1271 1289 1297 1434 11
B NMR = -135
HRMS (FAB) Calcd for C22H26BS [M-(NMe4)] 3331848 Found 3331852
B
Ph
1g
TBSO
[Me4N]
1H NMR (CD3CN) = 005 (s 6H) 084-096 (m 11H) 110-120 (m 1H) 134-197
(m 9H) 216-233 (t J = 72 Hz 2H) 235-250 (m 2H) 301 (s 12H) 356 (t J = 78
Hz 2H) 680-687 (m 1H) 700-708 (m 2H) 735 (d J = 66 Hz 2H) 13
C NMR
(CD3CN) = -50 189 254-277 (m) 323 348 561 649 889 1222 1269
1339 11
B NMR = -133 HRMS (FAB) Calcd for C24H38BOSi [M-(NMe4)] 3812785
Found 3812789
Chapter 3
78
B
Ph
1h
OMe
[Me4N]
1H NMR (CD3CN) = 104 (bs 2H) 116-126 (m 1H) 140-203 (m 9H) 240-254
(m 2H) 298 (s 12H) 373 (s 3H) 668-674 (m 2H) 701-718 (m 5H) 732 (d J =
87 Hz 2H) 13
C NMR (CD3CN) = 255-277 (m) 322 350 554 561 961 1129
1251 1287 1302 1312 1345 1564 11
B NMR = -131 HRMS (FAB) Calcd for
C23H26BO [M-(NMe4)] 3292077 Found 3292081
Palladium-Catalyzed Reaction of Alkynylborate 1a with 4-Bromoanisole Typical
Procedure for the Ligand Screening
Br
+
MeO
25 mol [PdCl(-allyl)]2
6 mol Ligand
toluene 70 degC 30 min
2a
B
Ph
Et
OMe
(E)-3a
AcOH
Ph
Et
OMe
H
Ph
B
Et
OMe
+
+
(Z)-3a
(E)-4a
H
Et
OMe
Ph
(Z)-4a
B
Ph
Et
1a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) [Pd(-allyl)Cl]2 (18 mg 5 mol) P(o-tol)3 (37 mg 12 mol) and
4-bromoanisole 2a (393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the
reaction mixture was added AcOH at room temperature After being stirred for 3 h the
resulting mixture was neutralized with saturated Na2CO3 solution The aqueous layer
was extracted with AcOEt (3 times) washed with water (once) brine (once) dried over
MgSO4 and concentrated A portion of the sample was taken in a GC tube and diluted
with Et2O to determine the GC yields
Chapter 3
79
PalladiumXANTPhos-Catalyzed Reaction of Alkynylborate 1a with 4-Bromo-
anisole A Typical Procedure for the PalladiumXANTPhos-Catalyzed Reaction of
Alkynylborates with Arylhalides
B
Ph
Et
+
1 mol (xantphos)PdCl(-allyl)
toluene 70 degC
Me3NO
Br
MeO
BO
Ph
Et
OMe
5a
1a
2a
[Me4N]
Under an argon atmosphere a toluene solution (10 ml) of alkynylborate 1a (651 mg
020 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 mol) and 4-bromoanisole 2a
(393 mg 021 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were
added Me3NO (225 mg 030 mmol) and CH2Cl2 (10 ml) at room temperature After
being stirred for 2 h the resulting mixture was passed through a pad of Florisil and
eluted with ethyl acetate The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted
alkenyl)borinic ester 5a (619 mg 017 mmol 83 yield EZ = gt955)
BO
Ph
Et
OMe
5a 1H NMR = 080 (t J = 78 Hz 3H) 102-171 (m 13H) 227 (q J = 78 Hz 2H)
383 (s 3H) 438-444 (m 1H) 685-691 (m 2H) 714-736 (m 7H) 13
C NMR =
138 221 267 273 (br) 277 312 553 736 1132 1251 1278 1283 1298
1366 1436 1494 1586 11
B NMR = 500 HRMS (EI) Calcd for C25H31BO2 (M+)
3742417 Found 3742410
Chapter 3
80
BO
Ph
Et
CF3
5b
1H NMR = 081 (t J = 75 Hz 3H) 097-170 (m 13H) 231 (q J = 75 Hz 2H)
437-443 (m 1H) 718-726 (m 3H) 734-739 (m 2H) 745-748 (m 2H) 760-763
(m 2H) 13
C NMR = 135 220 266 271 (br) 276 312 738 12429 (q JC-F =
2701 Hz) 1247 (q JC-F = 36 Hz) 1280 1281 1289 (q JC-F = 320 Hz) 1291 1425
1476 1480 11
B NMR = 505 HRMS (EI) Calcd for C25H28BF3O (M+) 4122185
Found 4122186
BO
Ph
Et
NPhth
5c
1H NMR = 088 (t J = 78 Hz 3H) 105-176 (m 13H) 234 (q J = 75 Hz 2H)
440-450 (m 1H) 720-727 (m 3H) 734-739 (m 2H) 743-751 (m 4H) 777-783
(m 2H) 794-800 (m 2H) 13
C NMR = 137 221 266 274 (br) 275 312 738
1235 1254 1258 1279 1282 1294 1304 1317 1342 1429 1440 1482
1671 11
B NMR = 502 IR (KBr) = 2928 1742 1509 1381 714 cm-1
HRMS (EI)
Calcd for C32H32BNO3 (M+) 4892475 Found 4892473
BO
Ph
Et
5d
1H NMR = 021-034 (m 1H) 068-100 (m 8H) 120-150 (m 7H) 224-238 (m
1H) 244-258 (m 1H) 424-431 (m 1H) 722-754 (m 9H) 778 (d J = 78 Hz 1H)
783-788 (m 1H) 809-816 (m 1H) 13
C NMR = 137 216 219 259 262 264
(br) 282 309 314 734 1249 12537 12539 1255 1264 1270 1273 12795
Chapter 3
81
12799 1283 1321 1335 1413 1427 1467 11
B NMR = 497 HRMS (EI) Calcd
for C28H31BO (M+) 3942468 Found 3942476
BO
Ph
Et
5e
S
1H NMR = 092 (t J = 78 Hz 3H) 118-182 (m 13H) 228 (q J = 78 Hz 2H)
448-456 (m 1H) 702 (dd J = 51 36 Hz 1H) 708 (dd J = 36 12 Hz 1H)
715-730 (m 4H) 732-738 (m 2H) 13
C NMR =141 221 271 289 312 739
1250 1255 1266 1269 1279 1281 1416 1427 1468 11
B NMR = 496
HRMS (EI) Calcd for C22H27BOS (M+) 3501876 Found 3501880
BO
n-Pr
Me
Cl
5f
1H NMR = 070 (t J = 75 Hz 3H) 096-133 (m 9H) 142-172 (m 6H) 220-228
(m 2H) 237 (s 3H) 439-446 (m 1H) 708-735 (m 8H) 13
C NMR = 140 212
219 221 267 274 (br) 313 363 737 1279 12846 12855 1298 1309 1365
1411 1420 1488 11
B NMR = 506 HRMS (EI) Calcd for C26H32BClO (M+)
4062235 Found 4062237
BO
n-Pr
Ph
OMe
5g
Chapter 3
82
1H NMR = 073 (t J = 72 Hz 3H) 095-170 (m 15H) 229 (t J = 78 Hz 2H) 384
(s 3H) 435-450 (m 1H) 690 (d J = 81 Hz 2H) 711 (d J = 81 Hz 2H) 720-740
(m 5H) 13
C NMR = 140 219 221 267 274 (br) 312 362 551 736 1133
1267 1278 1287 1294 1354 1446 1475 1573 11
B NMR = 507 HRMS (EI)
Calcd for C26H33BO2 (M+) 3882754 Found 3882572 The stereochemistry was
assigned by NOE analysis
BO
Ph
S
5h
1H NMR = 027-032 (m 2H) 046-052 (m 2H) 098-130 (m 6H) 140-170 (m
8H) 430-445 (m 1H) 696-700 (m 1H) 704-707 (m 1H) 715-726 (m 2H)
729-738 (m 4H) 13
C NMR = 60 150 222 263 272 (br) 313 736 1241
1243 1253 1278 1290 1295 1410 1425 1431 11
B NMR = 498 HRMS (EI)
Calcd for C23H27BOS (M+) 3621876 Found 3621881
BO
Ph
CO2Et
5i
1H NMR = 017-023 (m 2H) 045-053 (m 2H) 090-119 (m 6H) 132-173 (m
11H) 427-433 (m 1H) 438 (q J = 75 Hz 2H) 718-738 (m 7H) 798 (dt J = 78
15 Hz 2H) 13
C NMR = 56 144 151 220 263 269 (br) 312 609 735 1255
1279 1284 1287 1289 1303 1423 1453 1469 1665 11
B NMR = 496 IR
(KBr) = 2928 1717 1287 1100 cm-1
HRMS (EI) Calcd for C28H33BO3 (M+) 4282523
Found 4282526
BO
Ph
5j
Cl
Chapter 3
83
1H NMR = 023-029 (m 2H) 048-055 (m 2H) 094-123 (m 6H) 134-171 (m
8H) 432-439 (m 1H) 706-714 (m 1H) 718-726 (m 4H) 728-738 (m 4H) 13
C
NMR = 57 150 220 263 271 (br) 312 736 1255 1267 1279 1283 1284
1289 1304 1332 1423 1424 1461 11
B NMR = 496 HRMS (EI) Calcd for
C25H28BClO (M+) 3901922 Found 3901923
BO
Ph
5k
Me
1H NMR = 082-113 (m 6H) 126-164 (m 15H) 237 (s 3H) 268-280 (m 1H)
434-441 (m 1H) 704-709 (m 3H) 717-725 (m 4H) 730-737 (m 2H) 13
C NMR
= 215 219 248 263 273 (br) 312 315 433 735 1252 12689 12693 1275
1278 1283 1316 1365 1418 1424 1481 11
B NMR = 498 HRMS (EI) Calcd
for C28H35BO (M+) 3982781 Found 3982780
BO
Cl
S
Ph
5l
1H NMR = 106-176 (m 13H) 250-260 (m 2H) 272-280 (m 2H) 441-449 (m
1H) 674 (dd J = 33 12 Hz 1H) 697-703 (m 3H) 709-738 (m 8H) 13
C
NMR(C6D6) =225 272 277 (br) 315 358 375 739 1247 1253 1261 1272
1285 12856 12861 1306 1335 1419 1427 1437 1491 11
B NMR = 495
HRMS (EI) Calcd for C28H30BClOS (M+) 4601799 Found 4601797
BO
Ph
CF3
TBSO
5m
Chapter 3
84
1H NMR = -014 (s 6H) 079 (s 9H) 095-136 (m 6H) 142-168 (m 7H) 255 (t
J = 72 Hz 2H) 343 (t J = 72 Hz 2H) 435-442 (m 1H) 718-726 (m 3H)
731-737 (m 2H) 747 (d J = 81 Hz 2H) 759 (d J = 81 Hz 2H) 13
C NMR = -54
183 220 259 266 271 (br) 311 377 616 739 1242 (q JC-F = 2694 Hz) 1247
(q JC-F = 36 Hz) 1258 1280 1282 1290 (q JC-F = 320 Hz) 1291 1421 1422
1480 11
B NMR = 505 HRMS (FAB) Calcd for C31H42BF3O2Si (M+) 5422999
Found 5422992 The stereochemistry was assigned by NOE analysis
BO
Ph
Me
OMe
5n
1H NMR = 122-130 (m 4H) 138-162 (m 5H) 168-186 (m 4H) 237 (s 3H)
375 (s 3H) 443-450 (m 1H) 670 (dt J = 90 21 Hz 2H) 690-697 (m 4H)
702-708 (m 3H) 710-720 (m 4H) 13
C NMR = 213 222 269 312 550 738
1132 1260 1272 1285 1301 1307 1310 1362 1369 1423 1429 1483
1571 11
B NMR = 510 HRMS (EI) Calcd for C30H33BO2 (M+) 4362574 Found
4362561
PalladiumTri(o-tolyl)phosphine-Catalyzed Reaction of Alkynylborate 1a with
4-Bromobenzene
B
Ph
Et
+
1 mol (o-tol)3PPdCl(-allyl)
toluene 70 degC
Me3NO BO
Ph
Ph
Et
(Z)-5o
1a
Ph Br
[Me4N]
Under an argon atmosphere a toluene solution (20 ml) of alkynylborate 1a (1952 mg
060 mmol) (o-tol)3PPd(-allyl)Cl (30 mg 60 mol) and 4-bromobenzene (989 mg
063 mmol) was stirred for 30 minutes at 70 ˚C To the reaction mixture were added
Chapter 3
85
Me3NO (678 mg 090 mmol) and CH2Cl2 (20 ml) at room temperature After being
stirred for 2 h the resulting mixture was passed through a pad of Florisil and eluted with
ethyl acetate The residue was purified by preparative thin-layer chromatography on
silica gel (hexaneethyl acetate = 501) to afford the (trisubstituted alkenyl)borinic ester
(Z)-5b (1469 mg 043 mmol 71 yield EZ = 793)
BO
Ph
Ph
Et
(Z)-5o 1H NMR = 101 (t J = 72 H 3H) 139-200 (m 13H) 267 (q J = 72 Hz 2H)
470-475 (m 1H) 685-710 (m 10H) 13
C NMR = 139 224 267 313 317 740
1248 1257 1272 127412938 12941 1421 1425 1275 11
B NMR = 512
HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 344 2310
BO
Ph
Et
Ph
(E)-5o 1H NMR = 081 (t J = 72 Hz 3H) 100-169 (m 13H) 230 (q J = 72 Hz 2H)
438-443 (m 1H) 718-737 (m 10H) 13
C NMR = 137 221 266 274 (br) 277
312 737 1253 1268 1278 1279 1283 1288 1433 1442 1494 11
B NMR =
504 HRMS (EI) Calcd for C24H29BO (M+) 3442311 Found 3442313
Typical Procedure for Palladium-Catalyzed Reaction of Borinic Ester 5o with Aryl
Bromide 2b
+
Br
ONMe2
Ph
Et
PhO
NMe2
25 mol Pd(OAc)25 mol SPhos
THF K3PO4 60 degC
(Z)-Tamoxifen 6
2b
BO
Ph
Et
Ph
(E)-5o
Chapter 3
86
Under an argon atmosphere borinic ester (E)-5o (689 mg 020 mmol) Pd(OAc)2 (11
mg 50 mol) SPhos (41 mg 10 mol) and 2b (512 mg 021 mmol) in THF (10
ml) was stirred for 12 h at 60 ˚C After cooling the reaction mixture to room temperature
water was added The organic layer was separated and extracted with CH2Cl2 (3 times)
and washed with water (once) brine (once) dried over Na2SO4 and concentrated The
residue was purified by preparative thin-layer chromatography on silica gel (CHCl3
EtOHNEt3 = 10051) to afford the (Z)-Tamoxifen 6 (633 mg 017 mmol 85 EZ =
gt595) The spectral data was identical to that reported19
Chapter 3
87
References and Notes
(1) Suzuki A Brown H C Organic Synthesis via Boranes Aldrich Milwaukee WI
2003 Vol 3
(2) (a) Rock F L Mao W Yaremchuk A Tukalo M Creacutepin T Zhou H Zhang
Y-K Hernandez V Akama T Baker S J Plattner J J Shapiro L Martinis
S A Benkovic S J Cusack S Alley M R K Science 2007 316 1759 (b)
Zhu Y Zhao X Zhu X Wu G Li W Ma Y Yuan Y Yang J Hu Y Ai
L Gao Q Z J Med Chem 2009 52 4192
(3) (a) Entwistle C D Marder T B Chem Mater 2004 16 4574 (b) Yamaguchi
S Wakamiya A Pure Appl Chem 2006 78 1413 (c) Jaumlkle F Coord Chem
Rev 2006 250 1107
(4) Salvi L Jeon S-J Fisher E L Carroll P J Walsh P J J Am Chem Soc
2007 129 16119 and references cited therein
(5) For stereoselective synthesis of (trisubstituted alkenyl)(dialkyl)boranes via
addition of XndashBR2 (X = halogen and thiolate) to alkynes see (a) Suzuki A
Pure Appl Chem 1986 58 629 (b) Ishiyama T Nishijima K Miyaura N
Suzuki A J Am Chem Soc 1993 115 7219
(6) For a review of the reactions of alkynyltriorganylborate with electrophiles giving
(trisubstituted alkenyl)(diorganyl)boranes see Negishi E J Organomet Chem
1976 108 281
(7) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381 See also (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279
(8) Whiteley C G S Afr J Chem 1982 35 9
(9) The protonolysis of alkenylboranes with acetic acid proceeds in a stereospecific
fashion Brown H C Zweifel G J Am Chem Soc 1959 81 1512
(10) For substitutive 12- -carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(11) Inversion of the stereochemistry was also observed in the palladium-catalyzed
cross-coupling reaction of 2-bromo-13-dienes with organozinc reagents Zeng X
Hu Q Qian M Negishi E J Am Chem Soc 2003 125 13636
(12) An alternative mechanism is conceivable the arylpalladium bromide A acts as an
Chapter 3
88
electrophile to place the palladium on the carbon to boron and induces migration
of a phenyl group on boron to the -carbon A similar mechanism has been
assumed for analogous reactions of alkynylborates with alkyl halides most of
which lacked in stereoselectivity The high stereoselectivity obtained in the present
reaction led us to favor the mechanism proposed in the text
(13) Soderquist J A Najafi M R J Am Chem Soc 1986 51 1330
(14) Wiseman H Tamoxifen Molecular Basis of Use in Cancer Treatment and
Prevention Wiley Chichester UK 1994
(15) For representative Tamoxifen syntheses see (a) Millar R B Al-Hassan M I J
Org Chem 1985 50 2121 (b) Potter G A McCague R J Org Chem 1990 55
6184 (c) Brown S D Armstrong R W J Org Chem 1997 62 7076 (d)
Studemann T Knochel P Angew Chem Int Ed 1997 36 93 (e) Tessier P E
Penwell A J Souza F E S Fallis A G Org Lett 2003 5 2989 (f) Itami K
Kamei T Yoshida J-i J Am Chem Soc 2003 125 14670 (g) Shimizu M
Nakamaki C Shimono K Schelper M Kurahashi T Hiyama T J Am Chem
Soc 2005 127 12506 (h) Nishihara Y Miyasaka M Okamoto M Takahashi
H Inoue E Tanemura K Takagi K J Am Chem Soc 2007 129 12634
(16) (a) Itami K Mineno M Muraoka N Yoshida J J Am Chem Soc 2004 126
11778 (b) Flynn A B Ogilvie W W Chem Rev 2007 107 4698
(17) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(18) Kramer G W Brown H C J Organomet Chem 1974 73 1
(19) Nishihara Y Miyasaka M Okamoto M Takahashi H Inoue E Tanemura
K Takagi K J Am Chem Soc 2007 12912634
Chapter 4
89
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing
Tetrasubstituted Vinylene Units
Abstract
Monodispersed oligo(arylenevinylene)s containing tetrasubstituted vinylene units were
stereoselectively synthesized in an efficient manner by iteration of two different kinds
of palladium-catalyzed reactions
Reproduced with permission from Org Lett 2010 12 3179-3181
Copyright 2010 American Chemical Society
Chapter 4
90
Introduction
It is one of current topics in organic synthesis to prepare structurally well-defined
oligomeric compounds of higher molecular weight Among various oligomers
oligo(phenylenevinylene)s (OPVs) are of significant interest and have been extensively
studied in the field of organic electronics1 A wide variety of substituted OPVs have
been synthesized and applied to optoelectronic devices such as organic light-emitting
diodes2 and organic solar cells
3 However it is still a formidable task to synthesize
oligo(arylenevinylene)s containing tetrasubstituted vinylene units due to the difficulty
of constructing sterically congested vinylene units in a stereoselective manner4 In this
paper we report an efficient and high yielding method to synthesize such
oligo(arylenevinylene)s of single molecular weight
Results and Discussion
Initially 4-bromoanisole was treated with 10 equiv of alkynylborate 1a in the
presence of (xantphos)Pd(-allyl)Cl (1 mol ) and (trisubstituted alkenyl)-9-BBN 2
was formed in a stereoselective manner as we previously reported (Scheme 1)5
Although the product 2 contained an alkenylborane moiety it did not couple with
4-bromoanisole in the absence of a base After completion of the initial reaction with
alkynylborate 1a 10 equiv of 4-bromoiodobenzene and 3 equiv of NaOH were directly
added to the reaction mixture The Suzuki-Miyaura coupling reaction took place
chemoselectively at the iodo site to give tetrasubstituted olefin 3 in 87 yield with
excellent stereoselectivity (EZ = lt199) The bromoaryl moiety was retained in the
coupling product 3 due to the reactivity difference between the iodo and bromo groups6
Thus the PdXANTPHOS catalyst was proved to be active enough to promote the two
different kinds of carbonndashcarbon bond forming reactions in one-pot without the need for
any additional catalyst or ligand Through this sequential one-pot procedure the initial
aryl bromide (ie 4-bromoanisole) grew into the second-generation aryl bromide 3
which is expected to be directly used in the reaction with the borate 1a again without
intervention of any activation or deprotection step
Chapter 4
91
Scheme 1 One-Pot Synthesis of Tetrasubstituted Olefin
B
MOMO
[Me4N] +
MeO
Br
I
Br
MeO Br
B
MeO
MOMO MOMO
1a
2 3 87EZ = lt199
NaOH
50 degC
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
Next aryl bromide 3 was subjected to the second-round sequential one-pot procedure
Treatment of 3 with alkynylborate 1a (11 equiv) followed by direct addition of
4-bromoiodobenzene (11 equiv) and NaOH to the reaction mixture afforded the
third-generation aryl bromide 4 in 92 yield (Scheme 2) Further application of the
third-round sequential procedure to 4 furnished the fourth-generation aryl bromide 5 in
87 yield The sequential procedure was repeated on 5 once to give the
fifth-generation 6 in 82 yield and twice to give the sixth-generation 7 in 85 yield
These oligomers were readily soluble in common organic solvents like toluene THF
AcOEt and chloroform and therefore were isolated with high purity by column
chromatography on silica gel and identified by 1H and
13C NMR and mass spectroscopy
Importantly the yield of each round did not decrease as the molecular size increased
suggesting that further elongation by the iterative method would be possible Thus one
(tetrasubstituted vinylene)phenylene unit could be added to the chain in a stepwise
manner with high efficiency and stereoselectivity by repetition of the sequential one-pot
procedure
Chapter 4
92
Monodispersed oligomers can be divergently synthesized by repeating an iterative
procedure which generally consists of an extension step and an activation step17
An
extending unit possessing a dormant coupling site is initially added to a main chain (an
extension step) The dormant site is then activated to be subsequently coupled with
another extending unit (an activation step) On the contrary the present method to
synthesize OPVs dispenses with the need for activation8 One cycle adding a
vinylene-phenylene unit consists of two different extension steps one extending a
tetrasubstituted vinylene unit and the other extending a phenylene unit Both extension
steps can be executed by the same catalyst system in one-pot Thus this simple
method makes it practical to synthesize a structurally well-defined oligomer of single
molecular weight in an efficient way
Scheme 2 Repetition of the Sequential Procedure
3
MeO
R
Br
4 92
R
MeO
R
Br
n = 2 5 87
n = 3 6 82n = 4 7 85
n
R
1 mol
(xantphos)Pd(-allyl)Cl1a
toluene 50 degC
I
Br
NaOH
E
EE
R = OMOM
A phenylenevinylene chain could be extended into two directions by using
14-dibromobenzene as the starting aryl bromide (Scheme 3) 14-Dibromobenzene
was reacted with the alkynylborates 1a (21 equiv) under the standard conditions and
the subsequent double cross-coupling reaction with 4-bromoiodobenzene (22 equiv)
furnished the dibromide 8 in 86 yield The dibromide 8 was then reacted with the
alkynylborate 1a (30 equiv) to afford diborylated phenylenevinylene intermediate
which was treated with 4-bromoiodobenzene (40 equiv) and NaOH resulting in the
Chapter 4
93
formation of OPV 9 in 92 yield Interestingly OPV 9 exhibited visible blue
fluorescence in solution whereas OPVs 4-7 did not Thus even a small structural
change of the OPVs may cause a significant influence on their photophysical properties
Scheme 3 Extention into Two Directions
Br
Br
R
R
Br
Br
8 86
R
R
Br
R
R
Br
9 92
E E
R = OMOM
Finally the functional group compatibility of the palladium-catalyzed sequential
procedure was exploited to synthesize the structurally diversified oligo(arylenevinylene)
12 (Scheme 4) 4-Bromotrimethylsilylbenzene was reacted with 10 equiv of the
alkynylborate 1b having a 4-methoxyphenyl group on boron and the reaction mixture
was then treated with 10 equiv of 4-bromo-2-fluoroiodobenzene to give 10 in 88
yield The second-round extension was carried out using the alkynylborate 1a (11
equiv) and then 25-dibromothiophene (30 equiv) and NaOH The bi(arylenevinylene)
11 possesing five different aryl groups and two alkyl groups was obtained in 84 yield
Furthermore 11 was subjected to the third-round extension using 11 equiv of the
alkynylborate 1c with a 4-chlorophenyl group on boron and then 11 equiv of
4-(ethoxycarbonyl)iodobenzene to give the ter(arylenevinylene) 12 in 88 yield The
structure of 12 is highly diversified consisting of seven different aryl groups and three
alkyl groups Thus a wide variety of structural modification could be installed at
desired positions by changing arylene and vinylene modules
Chapter 4
94
Scheme 4 Synthesis of Oligo(arylenevinylene) 12
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
Me3Si
Br
Ph
F
Me3Si
OMe
Br
Ph
F
S
Br
Me3Si
OMe
B
n-Pr
[Me4N]
Cl
B
Ph
[Me4N]
OMe
Br
S
Br
I
EtO2C
MOMO
MOMO
I
Br
F
1b
10 88
11 84
12 88
1a1c
cat Pd
NaOHcat Pd
cat Pd NaOH
Cs2CO3
Conclusions
In conclusion we have developed an efficient iterative method for the synthesis of
oligo(arylenevinylene)s containing tetrasubstituted vinylene units Of note is that an
aryl bromide grew into the next generation aryl bromide in one-pot through two
different kinds of extending steps The method dispenses with the need of activation
steps and thus rapidly increases the molecular complexity Synthesis of new OPVs
and studies on structural features and photophysical properties are now in progress
Chapter 4
95
Experimental Section
General NMR spectra were recorded on a Varian Gemini 2000 (1H at 300 MHz and
13C at 75 MHz) JEOL JNM-A500 (
1H at 500 MHz and
13C at 150 MHz) or Varian
400-MR Auto Tune X5 (11
B at 128 MHz) spectrometers Unless otherwise noted CDCl3
was used as a solvent Chemical Shifts are recorded in ppm referenced to a residual
CDCl3 (= 726 for 1H 770 for
13C) CD3CN ( = 194 for
1H =132 for
13C) and
BF3OEt2 ( = 000 for 11
B) High-resolution mass spectra were recorded on Applied
Biosystems Voyager Elite or JEOL JMS-HX110A spectrometer Infrared spectra were
recorded on a SHIMADZU FT-IR 8100 Column chromatography was performed with
silica gel 60 N (Kanto) Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck) Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204
Materials Unless otherwise noted all chemicals and anhydrous solvents were
obtained from commercial suppliers Toluene was dried over Na-benzophenone ketyl
(XANTPhos)Pd(-allyl)Cl9 Ar-9-BBN
10 and 5-Hexyn-1-yl(methoxymethyl)ether
11
were prepared according to the reported procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a 1b
To a stirred solution of 5-hexyn-1-yl(methoxymethyl)ether (204 g 144 mmol) in THF
(200 ml) at -78 ˚C was added n-BuLi (16 M in hexane 90 ml 144 mmol) After 30
minnutes at this temperature phenyl-9-BBN (260 g 130 mmol) was added and the
cooling bath was removed After being stirred for 1 h at room temperature the
reaction was quenched by adding a small amount of methanol Then volatile
materials were removed under reduced pressure The residue was dissolved in
methanol and tetramethylammonium chloride (160 g 146 mmol) was added with
stirring at -78 ˚C resulting in white solid It was collected by filtration and was
washed with cold methanol to give alkynylborate 1a (320 g 77 mmol 60 yield)
Chapter 4
96
B
MOMO
[Me4N]
1a
1H NMR (CD3CN 300 MHz) = 091 (bs 2H) 110-119 (m 1H) 132-196 (m 15H)
202 (t J = 66 Hz 2H) 236-251 (m 2H) 304 (s 12H) 328 (s 3H) 346 (t J = 69
Hz 2H) 454 (s 2H) 678-685 (m 1H) 698-705 (m 2H) 734 (d J = 72 Hz 2H) 13
C NMR (CD3CN 75 MHz) = 210 267 (br) 271 275 282 297 324 349 551
561 681 928 968 1221 1269 1338 11
B NMR (128 MHz) = -180 HRMS
(FAB) Calcd for C22H32BO2 [M-(NMe4)]- 3392495 Found 3392493
B
Ph
[Me4N]
1b
OMe
1H NMR (CD3CN 300 MHz) = 088 (bs 2H) 110-120 (m 1H) 134-196 (m 9H)
225 (t J = 72 Hz 2H) 234-249 (m 2H) 263 (t J = 72 Hz 2H) 303 (s 12H) 372
(s 3H) 663-669 (m 2H) 711-728 (m 7H) 13
C NMR (CD3CN 100 MHz) = 242
272 275 324 349 381 554 560 1129 1266 1289 1298 1346 1434 1563 11
B NMR (128 MHz) = -182 HRMS (FAB) Calcd for C25H30BO [M-(NMe4)]-
3572390 Found 3572383
One-Pot Synthesis of Tetrasubstituted Olefin 3 A Typical Procedure for the
Synthesis of Tetrasubstituted Oligo(arylenevinylene)s 3-12
B
MOMO
[Me4N]
+
MeO
Br
1 mol
(xantphos)Pd(-allyl)Cl
toluene 50 degC
I
Br
MeO Br
NaOH
3
1a
MOMO
Chapter 4
97
Under an argon atmosphere a mixture of alkynylborate 1 (XANTPhos)Pd(-allyl)Cl
(X mg Y mmol) and aryl halide A in toluene was stirred for time t1 at 50 ˚C Then
aryl halide B and base C were added to the reaction mixture which was stirred for time
t2 and water was added After addition of water the aqueous layer was extracted with
AcOEt (3 times) washed with water (once) brine (once) dried over Na2SO4 and
concentrated The residue was purified by GPC to afford the tetrasubstituted
oligo(arylenevinylene)s
MeO Br
3
MOMONOE
NOE
alkynylborate 1 1a (827 mg 20 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 4-bromoanisole (393 mg 21 mmol) aryl halide B 4-bromoiodobenzene
(566 mg 20 mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h 1H NMR (300 MHz) = 130-158 (m 4H) 241 (t J = 78 Hz 2H) 327 (s 3H) 337
(t J = 66 Hz 2H) 376 (s 3H) 452 (s 2H) 667-675 (m 4H) 697-702 (m 2H)
709-736 (m 7H) 13
C NMR (75 MHz) = 255 298 356 5510 5514 676 964
1134 1196 1267 1282 1294 13046 13049 1323 1339 1376 1408 1420
1430 1580 HRMS (MALDI-TOF-MS (DCTB) calcd for C27H29BrO3 [M]+ 4801300
Found 4801269 The (Z)-stereochemistry was determined by the 2D NOESY
spectroscopy
MeO
R
Br
4
R
R = OMOM
alkynylborate 1 1a (863 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (15 mg 20 micromol)
aryl halide A 3 (963 mg 20 mmol) aryl halide B 4-bromoiodobenzene (622 mg 22
mmol) base C NaOH (240 mg 60 mmol) t1 05 h t2 6 h
Chapter 4
98
1H NMR (300 MHz) = 124-154 (m 8H) 233 (t J = 78 Hz 2H) 242 (t J = 75 Hz
2H) 325 (s 3H) 329 (s 3H) 331-341 (m 4H) 380 (s 3H) 451 (s 2H) 453 (s
2H) 662-678 (m 8H) 697-703 (m 2H) 706-738 (m 12H) 13
C NMR (150 MHz)
= 252 254 295 296 353 354 5502 5504 552 675 676 9629 9632 1131
1196 1265 1267 1281 1282 1285 12941 12942 1303 1304 1306 1324
1343 1377 1385 1390 1400 1413 1414 1418 1429 1435 1579 HRMS
(MALDI-TOF-MS (DIT)) calcd for C47H51BrO5Na [M+Na]+
7972818 Found
7972849
MeO
R
5
R
R = OMOM
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4 (775 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 1 h t2 12 h 1H NMR (300 MHz) = 122-155 (m12 H) 228-239 (m4H) 246 (t J = 75 2H)
325 (s 3H) 327 (s 3H) 328 (s 3H) 330-342 (m 6H) 374 (s 3H) 450 (s 2H)
452 (s 2H) 454 (s 2H) 654-662 (m 4H) 666-678 (m 8H) 696-704 (m 4H)
712-737 (m 15H) 13
C NMR (75 MHz) = 254 256 296 297 298 3526 3534
355 551 675 676 963 1130 1196 1264 1267 1280 1281 1286 1294 1301
1302 1304 1306 1324 1344 1377 1384 1387 1392 1393 1398 1402 1409
1414 1415 1417 1428 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C67H73BrO7Na [M+Na]+
10914437 Found 10914482
Chapter 4
99
MeO
R
6
R
R = OMOM
R
R
Br
alkynylborate 1 1a (434 mg 105 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 5 (107 mg 10 mmol) aryl halide B 4-bromoiodobenzene (310 mg 11
mmol) base C NaOH (120 mg 30 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 120-156 (m 16H) 226-248 (m 8H) 322-328 (m 12H)
330-341 (m 8H) 371 (s 3H) 448-454 (m 8H) 648-675 (m 16H) 695-703 (m
4H) 714-737 (m 20H) 13
C NMR (75 MHz) = 253 254 256 257 2969 2974
298 350 354 356 550 551 675 676 963 1131 1196 1264 1267 1279
1280 1281 1283 1288 1293 1294 1300 1301 1302 1305 1306 1323 1342
1377 1385 1387 1389 1391 1394 1396 1397 1401 1405 1409 1411 1413
1414 1417 1427 1432 1433 1435 1577 HRMS (MALDI-TOF-MS (DIT)) calcd
for C87H95BrO9Na [M+Na]+
13856057 Found 13856062
MeO
R
7
R
R = OMOM
R
R
R
Br
alkynylborate 1 1a (227 mg 055 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 6 (682 mg 050 mmol) aryl halide B 4-bromoiodobenzene (170
mg 060 mmol) base C NaOH (60 mg 15 mmol) t1 15 h t2 12 h 1H NMR (300 MHz) = 118-155 (m 20H) 224-248 (m 10H) 322-340 (m 25H)
374 (s 3H) 447-452 (m 10 H) 649-679 (m 20 H) 690-695 (m 2H) 701-706 (m
2H) 710-736 (m 25H) 13
C NMR (75 MHz) = 2529 2535 256 257 2968
Chapter 4
100
2971 298 351 354 355 356 550 6746 6755 676 963 1131 1195 1264
1267 12795 1280 1281 1283 1285 1287 1293 12937 12944 1301 1302
1304 1306 1322 1343 1377 1384 1387 1389 1390 1391 1394 13976
13979 1401 1404 1408 1409 1412 1413 1416 1427 14318 14321 1434
1435 1578 HRMS (MALDI-TOF-MS (DIT)) calcd for C107H117BrO11Na [M+Na]+
16797677 Found 16797694
8
R
Br
R
Br
R = OMOM
alkynylborate 1 1a (868 mg 21 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 14-dibromobenzene (236 mg 10 mmol) aryl halide B
4-bromoiodobenzene (622 mg 22 mmol) base C NaOH (240 mg 60 mmol) t1 10 h
t2 24 h 1H NMR (300 MHz) = 128-154 (m 8H) 240 (t J = 78 Hz 4H) 330 (s 6H) 339
(t J = 66 Hz 4H) 456 (s 4H) 668-673 (m 4H) 691 (s 4H) 710-721 (m 8H)
722-737 (m 6H) 13
C NMR (75 MHz) = 254 297 354 551 676 963 1198
1268 1282 1291 1293 1303 1323 1380 1400 1411 1417 1427 HRMS
(MALDI-TOF-MS (DCTB)) calcd for C46H48Br2O4Na [M+Na]+ 8221919 Found
8221905
9
R
R
R = OMOM
R
R
Br
Br
alkynylborate 1 1a (620 mg 015 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 8 (412 mg 0050 mmol) aryl halide B 4-bromoiodobenzene
Chapter 4
101
(566 mg 020 mmol) base C NaOH (180 mg 45 mmol) t1 20 h t2 24 h 1H NMR (300 MHz) = 122-154 (m 16H) 229-245 (m 8H) 322 (s 6H) 329 (s
6H) 330-340 (m 8H) 446 (s 4H) 453 (s 4H) 656-672 (m 12H) 688 (s 4H)
704-710 (m 4H) 714-718 (m 4H) 722-740 (m 16H) 13
C NMR (150 MHz) =
254 2962 2963 356 357 5501 5503 674 676 9629 9631 1197 1266
1268 1281 12818 12822 1290 1295 1296 1304 1308 1324 1379 1385
1394 1403 1405 1409 1416 1417 1427 1434 HRMS (MALDI-TOF-MS
(DIT)) calcd for C86H92Br2O8Na [M+Na]+
14335057 Found 14335040
Ph
F
Me3Si
OMe
Br
10
NOE
NOE
alkynylborate 1 1b (432 mg 10 mmol) (XANTPhos)Pd(-allyl)Cl (76 mg 10 micromol)
aryl halide A 4-bromotrimethylsilylbenzene (241 mg 105 mmol) aryl halide B
4-bromo-2-fluoroiodobenzene (301 mg 10 mmol) base C NaOH (120 mg 30 mmol)
t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 260-267 (m 2H) 276-283 (m 2H) 380 (s
3H) 676-686 (m 3H) 694-707 (m 6H) 709-728 (m 5H) 734 (d J = 84 Hz 2H) 13
C NMR (150 MHz) = -11 349 372 552 1135 1189 (d JC-F = 255 Hz)1202
(d JC-F = 92 Hz) 1258 1268 (d JC-F = 35 Hz) 1280 1283 1284 1300 1304 (d
JC-F = 159 Hz) 1326 1329 1332 (d JC-F = 45 Hz) 1339 1387 1417 1418 1430
1585 1596 (d JC-F = 2493 Hz) HRMS (MALDI-TOF-MS (DCTB)) calcd for
C32H32BrFOSi [M]+ 5581390 Found 5581392 The (Z)-stereochemistry was
determined by the 2D NOESY spectroscopy
Chapter 4
102
Ph
F
S
Br
Me3Si
OMe
11
MOMO
alkynylborate 1 1a (219 mg 053 mmol) (XANTPhos)Pd(-allyl)Cl (38 mg 50
micromol) aryl halide A 10 (279 mg 050 mmol) aryl halide B 25-dibromothiophene
(406 mg 15 mmol) base C NaOH (60 mg 15 mmol) t1 05 h t2 12 h 1H NMR (300 MHz) = 024 (s 9H) 116-126 (m 2H) 130-142 (m 2H) 211 (t J
= 78 2H) 264-272 (m 2H) 282-289 (m 2H) 325 (s 3H) 328 (t J = 66 Hz 2H)
382 (s 3H) 448 (s 2H) 587 (d J = 39 Hz 1H) 660 (d J = 39 Hz 1H) 669-676
(m 2H) 684-696 (m 3H) 705-742 (m 16H) 13
C NMR (150 MHz) = -10 244
293 351 362 372 550 552 673 963 1127 1135 1161 (d JC-F = 225 Hz)
1244 (d JC-F = 32 Hz) 1258 1274 12827 12831 12837 12840 12856 12861
1295 1302 1307 (d JC-F = 155 Hz) 1324 1329 1330 (d JC-F = 45 Hz) 1333
1345 1385 1395 (d JC-F = 12 Hz) 1412 1416 (d JC-F = 80 Hz) 1419 1422
1423 1462 1584 1602 (d JC-F = 2465 Hz) HRMS (MALDI-TOF-MS (DCTB))
calcd for C50H52BrFO3SSiNa [M+Na]+ 8582574 Found 8582600
Ph
F
S
n-Pr
Me3Si
OMe
Cl
CO2Et
12MOMO
alkynylborate 1 1c (393 mg 0105 mmol) (XANTPhos)Pd(-allyl)Cl (080 mg 10
micromol) aryl halide A 11 (860 mg 010 mmol) aryl halide B
4-(ethoxycarbonyl)iodobenzene (304 mg 011 mmol) base C Cs2CO3 (977 mg 030
mmol) t1 10 h t2 12 h
Chapter 4
103
1H NMR (300 MHz) = 021 (s 9H) 077 (t J = 72 Hz 3H) 112-143 (m 9H)
210-224 (m 4H) 264-272 (m 2H) 279-287 (m 2H) 323-333 (m 5H) 373 (s
3H) 434 (q J = 69 Hz 2H) 451 (s 2H) 580 (d J = 36 Hz 1H) 613 (d J = 39 Hz
1H) 666-672 (m 2H) 679-694 (m 5H) 703-737 (m 20H) 773 (d J = 84 Hz
2H) 13
C NMR (150 MHz) = -11 141 143 225 244 293 350 359 370 385
550 551 607 674 963 1134 1159 (d JC-F = 224 Hz) 1243 (d JC-F = 29 Hz)
1258 1269 1271 12808 12811 12815 12820 12823 12838 12844 1290
1293 1300 1301 (d JC-F = 158 Hz) 1302 1307 1323 (d JC-F = 47 Hz) 13258
13261 1328 1336 1344 1356 1379 1382 1390 (d JC-F = 12 Hz) 1409 14190
14191 14216 (d JC-F = 80 Hz) 14219 14222 1438 1446 1476 1583 1600 (d
JC-F = 2448 Hz) 1664 IR (KBr) = 2955 1717 1509 1273 1248 1111 837 cm-1
HRMS (MALDI-TOF-MS (DIT)) calcd for C70H72ClFO5SSiNa [M+Na]+
11294440
Found 11294465
Chapter 4
104
References and Notes
(1) For reviews see (a) Tour J M Chem Rev 1996 96 537 (b) Martin R E
Diederich F Angew Chem Int Ed 1999 38 1350 (c) Scherf U Top Curr
Chem 1999 201 163
(2) (a) Burroughs J H Bradley D D Brown A R Marks R N Mackey K
Friend R H Burns P L Holmes A B Nature 1990 347 539 (b) Grimsdale A
G Chan K L Martin R M Jokisz P G Holmes A B Chem Rev 2009 109
897
(3) (a) Yu G Hummelen J C Wudl F Heeger A J Science 1995 270 1789 (b)
Segura J L Martin N Guldi D M Chem Soc Rev 2005 34 31 (c) Guumlnes
S Neugebauer H Sariciftci N S Chem Rev 2007 107 1324 (d) Cheng Y-J
Yang S-H Hsu C-S Chem Rev 2009 109 5868
(4) Flynn A B Ogilvie W W Chem Rev 2007 107 4698 and references therein
(5) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(6) Unrau C M Campbell M G Snieckus V Tetrahedron Lett 1992 33 2773
(7) For iterative synthesis of OPVs by an extensionactivation sequence see (a)
Schenk R Gregorius H Meerholz K Heinze J Muumlllen K J Am Chem Soc
1991 113 2634 (b) Xue C Luo F-T J Org Chem 2003 68 4417 (c) Iwadate
N Suginome M Org Lett 2009 11 1899
(8) For activation-free iterative synthesis of OPVs by two different extension steps
see (a) Maddux T Li W Yu L J Am Chem Soc 1997 119 844 (b) Itami K
Tonogaki K Nokami T Ohashi Y Yoshida J Angew Chem Int Ed 2006 45
2404
(9) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
(10) Kramer G W Brown H C J Organomet Chem 1974 73 1
(11) Sun W C Ng C S Prestwich G D J Org Chem 1992 57 132
Chapter 5
105
Chapter 5
Regioselective Construction of Indene Skeletons by
Palladium-Catalyzed Annulation of Alkynylborates with
o-Iodophenyl Ketones
Abstract
A palladium-catalyzed annulation reaction of alkynylborates with o-iodophenyl ketones
to form indenes is described Highly substituted indene skeletons are efficiently
constructed with site-specific installation of substituents
Reproduced with permission from Eur J Org Chem 2013 1421-1424
Copyright 2013 Wiley-VCH Verlag GmbH amp Co KGaA Weinheim
Chapter 5
106
Introduction
Indenes are important structural motif found in a number of biologically active
compounds1 For example an indene framework with an exo-alkylidene moiety is
imbedded in sulindac which is a non-steroidal anti-inflammatory drug1a
Dimethindene an oral antihistamine agent has an indene core tethered to an amine
moiety1b
In addition to these commercial medicines indene derivatives have also
been exploited as materials for optoelectronics2 and ligands for transition metal
complexes3 Consequently development of a new method to construct indene
skeletons has been an attractive subject in organic synthesis4
Alkynylboron compounds have been utilized as useful intermediates in organic
synthesis5 We have previously developed the palladium-catalyzed reaction of
alkynylborates with aryl halides6 (Trisubstituted alkenyl)boranes which are otherwise
difficult to synthesize are readily obtained in a regio- and stereoselective fashion
Now the palladium-catalyzed reaction is extended to the construction of indene
skeletons Alkynylborates react with o-iodophenyl ketones to afford 23-disubstituted
indenols with specific installation of 2- and 3-substituents
Results and Discussion
Alkynylborate 1a and its constitutional isomer 1b were prepared from the
corresponding B-aryl-9-borabicyclo[331]nonane (Ar-9-BBN) and terminal alkyne
according to the reported method6c
The borate 1a (10 equiv) was treated with
o-iodoacetophenone (2a 105 equiv) in the presence of (dpephos)Pd(p-allyl)Cl (1
mol ) at 50 for 1 h (Scheme 1) The reaction mixture was then treated with
hydrogen peroxide to oxidize the organoboron residue Purification by column
chromatography on silica gel afforded 23-diarylindenol 3a in 85 yield In sharp
contrast the reaction of the borate 1b with 2a selectively provided the regioisomeric
indenol 3b in 88 yield Thus the present palladium-catalyzed reaction makes
possible selective production of both regioisomers of 23-diarylindenols which is
difficult to perform using the conventional annulation reaction of o-halophenyl ketones
with 12-diarylalkynes4b
Chapter 5
107
Scheme 1 Reactions of Alkynylborates 1 and o-Iodoacetophenone 2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
OHMe
Ph
1a
3a 85
MeO
OMe
2a
B
Ph
Me
O
I
+
1 mol
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
1b
OMe
2a
OHMe
Ph
OMe
3b 88
[Me4N]
[Me4N]
The selective formation of 3a from 1a and 2a can be explained by the mechanism
shown in scheme 2 which is based on the proposed mechanism of the
palladium-catalyzed reaction of alkynylborates with simple aryl halides6c
Oxidative
addition of 2a to palladium(0) forms arylpalladium A Regioselective
cis-carbopalladation across the carbonndashcarbon triple bond of 1a gives alkenylpalladium
B so that the phenyl group on the anionic boron migrates onto the a-carbon The
carbonndashpalladium bond is substituted with inversion of the stereochemistry to afford
alkenylborane C7 The ketone moiety remains intact during the course of the
palladium-catalyzed reaction The generated B-alkenyl-9-BBN moiety undergoes
intramolecular addition to the carbonyl group8 to form the boron indenolate B Upon
the following oxidative work-up with NaOHH2O2 B is hydrolyzed to the indenol 3a
Chapter 5
108
Scheme 2 Mechanism Proposed for the Formation of 3a
O
I
O
PdI
Pd(0)
B
1a
C
Pd(0)3a
Ar = p-MeOC6H4-
Me Me
OMe
Ar
Ph
B
D
A
Pd
O
ArB
Me
Ph
B
O
ArPh
Me
Me4NI
2a
The present reaction successfully furnished a wide variety of highly-substituted
indenols (Table 1) For example thiophene-substituted 3d and alkyl-substituted 3e
were obtained in 82 and 92 yield respectively The use of o-iodobenzaldehyde
and o-iodobenzophenone gave the corresponding indenols 3f and 3g The indenols
equipped with alkoxy trifluoromethyl and fluorine groups on the aromatic ring (3h-i)
could also be synthesized
Chapter 5
109
Table 1 Synthesis of Indenols 3a
R3
O
I
B
R2
R1
+1 mol Pd
toluene50 degC 1 h
OHR3
R1
R2
OHMe
Ph
S
OHMe
OMe
OHPh
Ph
OMe
3f 72
3h 763j 80
3g 84
3d 82
3c 83
OHMe
Ph
CF3
1 2 3
OHH
Ph
OMe
OHPh
Ph
OMe
O
O
OHPh
3e 92
F
OMe
OHPh
Ph
OMe
F3C
3i 62
R4R4
MeO
[Me4N]
a Reagents and conditions 10 equiv of alkynylborates 1 105 equiv of o-iodophenyl
ketone 2 1 mol of [(dpephos)PdCl(-allyl)] toluene 50 degC 1 h then aq H2O2 aq
NaOH MeOH room temp 2 h Isolated yields are shown
Alkenyl-substituted 3k and alkyl-substituted 3l were also synthesized from
B-alkenyl-9-BBN 1c and B-alkyl-9-BBN 1d respectively [Eqs (1) and (2)] The
formation of 3l is noteworthy from the mechanistic point of view the n-butyl group on
the anionic boron migrates onto the a-carbon in preference to the bridgehead sp3 carbon
of the 9-BBN framework9 This selectivity stands in sharp contrast to that observed in
the reaction with iodine10
Chapter 5
110
OHMe
t-Bu
S
3k 89
B +1 mol Pd
toluene
50 degC 1 h
2a
t-Bu
S
(1)
1c
[Me4N]
OHMe
n-Bu
Me
3l 80
B
n-Bu
+1 mol Pd
toluene50 degC 1 h
2a
Me
(2)
1d
[Me4N]
It was possible to directly synthesize 23-dialkylindenol 3m in one-pot starting from
1-octene 4-phenylbut-1-yne and o-iodoacetophenone 2a without isolation of the
intermediates (Scheme 3) Hydroboration of 1-octene with H-9-BBN in THF afforded
B-n-octyl-9-BBN which was then treated with 4-phenylbut-1-ynyllithium to form the
corresponding lithium alkynylborate A toluene solution containing
o-iodoacetophenone (2a) and (dpephos)Pd(p-allyl)Cl was added to the reaction mixture
which was heated at 50 for 1 h Oxidative work-up and purification by column
chromatography furnished 3m in 91 isolated yield based on 2a
Scheme 3 Synthesis of indenol 3m from 1-octene
n-Hex
13 equiv
Ph
Li
065 equiv
(H-9-BBN) 2
THF rt 1 h -78 degC to rt 1 h
1 mol Pd
toluene 50 degC 1 h
10 equiv 2aOH
Me
n-Oct
11 equiv
3m 91 (based on 2a)
B
n-Oct
PhLi
Ph
The palladium-catalyzed annulation of 1a with 2b gave indenol 3n in 74 yield
which was subjected to further derivatization (Scheme 4) Oxidation of 3n with
manganese(IV) oxide furnished the indenone 4 The following Wolff-Kishner reaction
Chapter 5
111
reduced the carbonyl group without isomerization of the double bond to give indene 5
in 59 yield11
Scheme 4 Synthesis of Indenone 4 and Indene 5
OHH
Ph
OMe
MnO2
DCM rt
Ph
OMe
O
NH2NH2 KOHPh
OMe
4 96 5 59
3n 74
(CH2OH)2 150 C
1a +
CHO
I2b
1 mol Pd
Conclusions
We have described the palladium-catalyzed annulation reaction of alkynylborates with
o-iodophenyl ketones A wide variety of highly-substituted indenols are
regiospecifically synthesized by this method
Chapter 5
112
Experimental Section
General NMR spectra were recorded by a Varian Mercury-vx400 (1H at 40044 MHz
and 13
C at 10069 MHz) or Varian 400-MR Auto Tune X5 (11
B at 128 MHz)
spectrometers Unless otherwise noted CDCl3 was used as a solvent Chemical Shifts
were recorded in δ ppm referenced to a residual CDCl3 (δ = 726 for 1H δ = 770 for
13C) CD3CN (δ = 194 for
1H δ = 132 for
13C) and BF3OEt2 (δ = 000 for
11B) IR
measurements were performed by a FTIR SHIMADZU DR-8000 spectrometer fitted
with a Pike Technologies MIRacle Single Reflection ATR adapter High-resolution mass
spectra were recorded by a Thermo Scientific Exactive (ESI) spectrometer Column
chromatography was performed with silica gel 60N (Kanto) Preparative thin-layer
chromatography (PTLC) was performed on silica gel plates with PF254 indicator
(Merck)
Materials Unless otherwise noted all chemicals and anhydrous solvents were obtained
from commercial suppliers and used as received Toluene was dried over
Na-benzophenone ketyl Ar-9-BBN12
(DPEPhos)[Pd(π-allyl)Cl]13
and alkynylborate14
were prepared by according to literature procedure
Preparation of Alkynylborates 1a A Typical Procedure for the Preparation of
Alkynylborates 1a1b1d-1f
Li
BPh
+
B
Ph
1a
1) THF -78 degC to rt
2) Me4NCl MeOH
[Me4N]
MeO
MeO
To a stirred solution of p-ethynylanisole (145 g 110 mmol) in THF (200 mL) at
-78 was added n-BuLi (16 M in hexane 69 mL 110 mmol) After 30 minutes at
this temperature Ph-9-BBN (198 g 100 mmol) was added and the cooling bath was
removed After being stirred for 1 h at room temperature the reaction was quenched by
adding a small amount of methanol Then volatile materials were removed under
reduced pressure The residue was dissolved in methanol and tetramethylammonium
chloride (121 g 110 mmol) was added with stirring at room temperature resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1a (27 g 67 mmol 67 yield)
Chapter 5
113
B
Ph
1a
[Me4N]
MeO
1H NMR (CD3CN) δ = 106 (bs 2H) 116-124 (m 1H) 141-202 (m 9H) 241-254
(m 2H) 296 (s 12H) 372 (s 3H) 668-675 (m 2H) 685-691 (m 1H) 700-712 (m
4H) 743 (d J = 64 Hz 2H) 13
C NMR (CD3CN) δ = 256-272 (m) 270 274 322
350 557 560 955 1145 1227 (2C) 1273 1324 1341 1578 The boron-bound
sp2 and sp carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -177 HRMS (FAB-) Calcd for C23H26BO [M-(NMe4)] 3292082 Found
3292079
B
Ph
1b
[Me4N]
OMe
1H NMR (CD3CN) δ = 104 (bs 2H) 114-126 (m 1H) 140-202 (m 9H) 240-253
(m 2H) 295 (s 12H) 374 (s 3H) 666-675 (m 2H) 702-718 (m 5H) 733 (d J =
84 Hz 2H) 13
C NMR (CD3CN) δ = 254-274 (m) 270 273 321 350 554 560
962 1130 1253 1289 1302 1313 1346 1565 The boron-bound sp2 and sp
carbons were not detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -180
HRMS (ESI-) Calcd for C23H26BO [M-(NMe4)]- 3292082 Found 3292088
B
nBu
1d
[Me4N]
Me
1H NMR (CD3CN) δ = 022 (bs 2H) 036 (bs 2H) 089 (t J = 72 Hz 3H) 122-134
(m 4H) 136-157 (m 6H) 170-196 (m 4H) 220-234 (m 5H) 304 (s 12H)
697-701 (m 2H) 704-709 (m 2H) 13
C NMR (CD3CN) δ = 152 212 270
271-290 (m) 282 288 318 324 357 561 1279 1296 1314 1344 The
Chapter 5
114
alkyne carbons and boron-bound sp3 carbon of n-Bu group were not detected due to
quadrupolar relaxation 11
B NMR (CD3CN) δ = -178 HRMS (ESI-) Calcd for C21H30B
[M-(NMe4)]- 2932446 Found 2932454
B
Ph
1e
[Me4N]
F3C
1H NMR (CD3CN) δ = 115 (bs 2H) 121-130 (m 1H) 148-207 (m 9H) 243-255
(m 2H) 292 (s 12H) 690-696 (m 1H) 710-718 (m 2H) 728 (dd J = 88 08 Hz
2H) 744-752 (m 4H) 13
C NMR (CD3CN) δ = 252-270 (m) 269 273 321 351
560 958 1230 1256 (q JC-F = 2687 Hz) 1258 (q JC-F = 37 Hz) 1262 (q JC-F =
315 Hz) 1275 1317 1342 1343 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ = -176 HRMS (FAB-)
Calcd for C23H23BF3 [M-(NMe4)]- 3671850 Found 3671849
B
Ph
1f
[Me4N]
S
1H NMR (CD3CN) δ = 090 (bs 2H) 120-130 (m 1H) 143-167 (m 4H) 173-198
(m 5H) 238-250 (m 2H) 304 (s 12H) 679 (dd J = 88 08 Hz 1H) 691 (dd J =
48 32 Hz 1H) 703-719 (m 6H) 13
C NMR (CD3CN) δ = 266 272 270-286 (m)
323 348 560 962 1231 1256 1266 1274 1290 1300 1314 The boron-bound
sp2 and sp
3 carbons were not detected due to quadrupolar relaxation
11B NMR
(CD3CN) δ = -181 HRMS (ESI-) Calcd for C20H22BS [M-(NMe4)]
- 3051541 Found
3051541
Chapter 5
115
Preparation of Alkynylborates 1c
(H-9BBN) 2
H tBu
THF 0 degC
THF -78 degC to rt
2) Me4NCl MeOH
Li
1)S
B
1c
[Me4N]
S
tBu
Under an argon atmosphere a solution of 33-dimethyl-1-butyne (084 g 10 mmol) in
THF (15 mL) was added to (H-9-BBN)2 (122 g 50 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask nBuLi (156 M in hexane 73 mL
114 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (130 g 100 mmol)
in THF (15 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature the reaction was quenched by adding a small amount of
methanol Then volatile materials were removed under reduced pressure The residue
was dissolved in methanol and tetramethylammonium chloride (121 g 110 mmol) was
added with stirring at room temperature After being concentrated under reduced
pressure the residue was dissolved in methanol again and stirred at -78 resulting in
white precipitates It was collected by filtration and washed with cold methanol to give
alkynylborate 1c (760 mg 20 mmol 20 yield)
B
1c
[Me4N]
S
tBu
1H NMR (CD3CN) δ= 038 (bs 2H) 096 (s 9H) 136-156 (m 6H) 173-204 (m
4H) 222-235 (m 2H) 306 (s 12H) 552 (d J = 172 Hz 1H) 591 (d J = 176 Hz
1H) 691 (dd J = 52 12 Hz 1H) 698 (dd J = 28 12 Hz 1H) 722 (dd J = 28 50
Hz 1H) 13
C NMR (CD3CN) δ = 273 276 278-296 (m) 311 327 341 352 561
908 1228 1251 1298 1314 1411 The boron-bound sp2 and sp carbons were not
detected due to quadrupolar relaxation 11
B NMR (CD3CN) δ= -181 HRMS (ESI-)
Calcd for C20H28BS [M-(NMe4)]- 3112010 Found 3112016
Chapter 5
116
PalladiumDPEPhos-Catalyzed Reaction of Alkynylborate 1a with
o-Iodoacetophenone (2a)
Under an argon atmosphere a toluene solution (10 mL) of alkynylborate 1a (8068 mg
020 mmol) dpephos)PdCl(π-allyl) (144 mg 0002 mmol) and o-iodoacetophenone
(2a) was stirred for 1 h at 50 To the reaction mixture were added aqueous H2O2 (05
mL 30 wt) aqueous NaOH (05 mL 20 wt) and MeOH (05 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was diluted with water
and extracted with ethyl acetate (3times15 mL) The combined organic layers were washed
by brine dried over MgSO4 and concentrated under reduced pressure The residue was
purified by preparative thin-layer chromatography on silica gel (hexaneethyl acetate =
51) to afford the indenol 3a (559 mg 017 mmol 85 yield)
OHMe
3aOMe
NOE
no NOE
IR (ATR) 3315 1508 1248 752 694 cm-1
1H NMR δ = 159 (s 3H) 204 (bs 1H)
382 (s 3H) 684-690 (m 2H) 721-730 (m 8H) 742-748 (m 2H) 751-755 (m
1H) 13
C NMR δ = 239 552 832 1139 1208 1218 1265 1268 1272 1280
1284 1294 1305 1350 1382 1423 1462 1496 1589 HRMS (ESI+) Calcd for
C23H21O2 [M+H]+ 3291536 Found 3291556
OHMe
OMe
3b
NOE
no NOE
IR (ATR) 3319 1508 1248 760 702 cm-1
1H NMR δ = 160 (s 3H) 208 (s 1H)
378 (s 3H) 674-680 (m 2H) 718-723(m 1H) 724-744 (m 9H) 750-755 (m
1H) 13
C NMR δ = 241 551 833 1134 1205 1218 1263 1270 1274 1284
1286 1293 1306 1350 1376 1423 1464 1495 1587 HRMS (ESI-) Calcd for
Chapter 5
117
C23H20O2Cl [M+Cl]- 3631146 Found 3631148
OHMe
Ph
3cCF3
IR (ATR) 3298 1319 1121 750 696 cm-1
1H NMR δ = 160 (s 3H) 210 (bs 1H)
716-722 (m 1H) 723-732 (m 5H) 737-747 (m 4H) 752-764 (m 3H) 13
C NMR
δ = 240 833 1205 1221 1241 (q JC-F = 2701 Hz) 1255 (q JC-F = 37 Hz) 1269
1277 1282 1286 1293 1295 (q JC-F = 322 Hz) 1296 1341 1373 1385 1414
1485 1493 HRMS (APCI-) Calcd for C23H16F3O [M-H]
- 3651159 Found 3651159
OHMe
Ph
3d
S
IR (ATR) 3319 1350 1088 752 694 cm-1
1H NMR δ = 177 (s 3H) 209 (bs 1H)
696-702 (m 2H) 718 (dd J = 52 Hz 12Hz 1H) 723-730 (m 2H) 735-740 (m
3H) 742-752 (m 3H) 753-758 (m 1H) 13
C NMR δ = 254 833 1207 1216
1259 1265 1266 1275 1282 1287 1290 1294 1347 1360 1374 1410 1426
1493 HRMS (ESI+) Calcd for C20H17OS [M+H]
+ 3050995 Found 3050992
OHMe
OMe
3e
IR (ATR) 3310 1508 1244 1034 758 cm-1
1H NMR δ = 144 (s 3H) 158-202 (m
9H) 307 (quintet J = 88 Hz 1H) 385 (s 3H) 696 (d J = 88 Hz 2H) 718-738 (m
5H) 747 (d J = 68 Hz 1H) 13
C NMR δ = 238 266 267 305 311 382 552
822 1136 1211 1219 1257 12789 12793 1304 1406 1409 1467 1499
1588 HRMS (ESI+) Calcd for C22H28O2N [M+NH4]
+ 3382115 Found 3382104
Chapter 5
118
OHH
Ph
3fOMe
MeO
IR (ATR) 3472 1601 1508 1244 704 cm-1
1H NMR δ = 174 (d J = 88 Hz 1H)
379 (s 3H) 386 (s 3H) 563 (d J = 84 Hz 1H) 674 (d J = 24 Hz 1H) 679 (dd J
= 80 Hz 24 Hz 1H) 692-697 (m 2H) 718-730 (m 5H) 732-736 (m 2H) 753 (d
J = 84 Hz 1H) 13
C NMR δ = 552 555 766 1072 1109 1143 1244 1267 1272
1283 1292 1303 1342 1363 1390 1445 1457 1592 1606 HRMS (ESI+)
Calcd for C23H21O3 [M+H]+ 3451485 Found 3451484
OHPh
Ph
3gOMe
IR (ATR) 3422 1508 1244 1028 746 698 cm-1
1H NMR δ = 248 (s 1H) 385 (s
3H) 695 (d J = 88 Hz 2H) 704-714 (m 5H) 715-732 (m 7H) 736-740 (m 2H)
755 (d J = 88 Hz 2H) 13
C NMR δ = 552 868 1141 1210 1231 1250 1268
12698 12702 1271 1278 12836 12844 1294 1304 1340 1402 1417 1427
1466 1508 1591 HRMS (ESI+) Calcd for C28H23O2 [M+H]
+ 3911693 Found
3911718
OHPh
Ph
3hOMe
O
O
IR (ATR) 3362 1470 1244 1034 696 cm-1
1H NMR δ = 239 (s 1H) 385 (s 3H)
591 (dd J = 164 16 Hz 2H) 673 (d J = 44 Hz 2H) 690-696 (m 2H) 702-708
(m 5H) 720-736 (m 5H) 749-754 (m 2H) 13
C NMR δ = 552 863 1012 1024
Chapter 5
119
1049 1142 1249 12690 12692 1270 1278 1285 1292 1304 1340 1367
1398 1420 1450 1458 1469 1478 1592 HRMS (EI+) Calcd for C29H22O4 [M]
+
4341518 Found 4341505
OHPh
Ph
3iOMe
F3C
IR (ATR) 3545 1508 1321 1115 696 cm-1
1H NMR δ = 249 (s 1H) 387 (s 3H)
694-700 (m 2H) 704-715 (m 5H) 723-738 (m 6H) 742-755 (m 4H) 13
C NMR
δ = 553 866 1145 1177 (q JC-F = 37 Hz) 1233 1241 (q JC-F = 36 Hz) 1242 (q
JC-F = 2702 Hz) 1249 1260 1275 1276 1280 1287 1295 1304 1308 (q JC-F =
323 Hz) 1334 1393 1407 1437 1481 1542 1595 HRMS (APCI-) Calcd for
C29H21F3O2Cl [M+Cl]- 4931177 Found 4931192
OHPh
3j
F
OMe
IR (ATR) 3356 1242 1028 741 696 cm-1
1H NMR δ = 164-178 (m 2H) 183-208
(m 7H) 316 (quintet J = 84 Hz 1H) 376 (s 3H) 675-680 (m 2H) 686-698 (m
4H) 719-737 (m 6H) 13
C NMR δ = 2675 2681 308 310 383 551 862 1114
(d JC-F = 233 Hz) 1136 1143 (d JC-F = 218 Hz) 1220 (d JC-F = 80 Hz) 1252
1268 1271 1283 1303 1371 (d JC-F = 29 Hz) 1410 1418 (d JC-F = 15 Hz)
1474 (d JC-F = 43 Hz) 1538 (d JC-F = 73 Hz) 1589 1619 (d JC-F = 2443 Hz)
HRMS (EI+) Calcd for C27H25OF2 [M]
+ 4001839 Found 4001835
OHMe
S
tBu
3k
Chapter 5
120
IR (ATR) 3298 1358 1078 756 689 cm-1
1H NMR δ = 111 (s 9H) 168 (s 3H)
188 (s 1H) 640 (d J = 164 Hz 1H) 656 (d J = 164 Hz 1H) 718-730 (m 4H)
739-751 (m 3H) 13
C NMR δ = 257 295 340 822 1169 1204 1215 1242
1255 1262 1283 1285 1324 1346 1415 1452 1462 1506 HRMS (ESI+)
Calcd for C20H23OS [M+H]+ 3111464 Found 3111464
OHMe
nBu
OMe3l
IR (ATR) 3335 1508 1084 918 758 cm-1
1H NMR δ = 085 (t J = 72 Hz 3H) 130
(tt J = 72 72 Hz 2H) 141-167 (m 6H) 229-250 (m 5H) 702-706 (m 1H)
716-728 (m 6H) 744-748 (m 1H) 13
C NMR δ = 138 213 232 237 252 314
829 1198 1215 1256 1282 1286 1291 1318 1370 1374 1430 1492 1496
HRMS (APCI+) Calcd for C21H25O [M+H]
+ 2931900 Found 2931890
The Synthesis of 23-Dialkylsubstituted Indenol 3m from 1-Octene
4-Phenyl-1-butyne and o-Iodoacetophenone (2a)
nHex
(H-9BBN) 2
THF rt THF -78 degC to rt
Li
Ph
B
nOct
Li
Ph
Me
O
I
(dpephos)Pd(-allyl)Cl
toluene 50 degC 1 h
H2O2 aq
NaOH aq
OHMe
nOct
Ph3m
MeOH
Under an nitrogen atmosphere a solution of 1-octene (1459 mg 130 mmol) in THF
(20 mL) was added to (H-9-BBN)2 (1586 mg 065 mmol) and then the mixture was
stirred for 1 h at room temperature In another flask n-BuLi (069 mL 16 M in hexane
Chapter 5
121
110 mmol) was added dropwise to a solution of 4-phenylbut-1-yne (1432 mg 110
mmol) in THF (2 mL) at -78 After stirred for 30 minutes at this temperature the two
solutions were combined and then the cooling bath was removed After being stirred for
1 h at room temperature (dpephos)PdCl(π-allyl) (721 mg 0010 mmol) and a solution
of o-iodoacetophenone (2461 mg 100 mmol) in toluene (2 mL) were added The
reaction mixture was stirred for 1 h at 50 To the mixture were added aqueous H2O2
(1 mL 30 wt) aqueous NaOH (1 mL 20 wt) and MeOH (1 mL) at 0 After
being stirred for 2 h at room temperature the resulting mixture was quenched by adding
water and extracted with ethyl acetate (3times10 mL) The combined organic layers were
washed by brine dreid over MgSO4 and concentrated under reduced pressure The
residue was purified by preparative thin-layer chromatography on silica gel
(hexaneethyl acetate = 101) to afford the indenol 3m (3323 mg 092 mmol 92
yield)
OHMe
nOct
Ph3m
IR (ATR) 3335 1456 1078 752 698 cm-1
1H NMR δ = 096 (t J = 68 Hz 3H)
129-156 (m 15H) 160 (s 1H) 208-227 (m 2H) 274-281 (m 2H) 287-294 (m
2H) 719-728 (m 5H) 729-736 (m 3H) 742 (d J = 72 Hz 1H) 13
C NMR δ = 141
226 234 247 277 293 294 295 304 319 345 825 1186 1213 1252 1260
1282 1283 1284 1351 1417 1425 1489 1494 HRMS (EI+) Calcd for C26H34O4
[M]+ 3622610 Found 3622619
OHH
Ph
OMe
3n
IR (ATR) 3354 1508 1246 764 692 cm-1
1H NMR δ = 185 (bs 1H) 386 (s 3H)
567 (s 1H) 692-697 (m 2H) 718-738 (m 10H) 763-766 (m 1H) 13
C NMR δ =
552 773 1143 1206 1237 1263 1268 1272 1283 1287 1292 1303 1342
1393 1432 1440 1443 1592 HRMS (APCI-) Calcd for C22H17O2 [M-H]
- 3131234
Found 3131237
Chapter 5
122
The 1H
13C NMR and HRMS spectra were agreed with the reported value
15
Synthesis of indenone 4 and indene 5
OHH
Ph
OMe
3n
MnO2
DCM rt
Ph
OMe
4
O
MnO2 (170 mg 2 mmol) was dried under vacuum for 5 h at 120 Under an argon
atomosphere the solution of indenol 3n (314 mg 01 mmol) was added at room
temperature After being stirred for 3 h the reaction mixture was filtered through a pad
of celite and concentrated under reduced pressure The residue was purified by
preparative thin-layer chromatography on silica gel (hexaneethyl acetate = 101) to
afford the indenone 4 (299 mg 0096 mmol 96 yield)
The 1H
13C NMR spectra were agreed with the reported value
16
Ph
OMe
4
O
(CH 2OH)2
NH2NH2
KOH Ph
OMe
5
Under an argon atomosphere an ethylene glycol solution (1 mL) of indenone 4 (312
mg 01 mmol) hydrazine (04 mL) and 2N KOH aq (10 L 002 mmol) was stirred for
5 h at 150 and water was added The aqueous layer was extracted with AcOEt (3
times) washed with water (once) brine (once) dried over MgSO4 and concentrated
under reduced pressure The residue was purified by preparative thin-layer
chromatography on silica gel (hexaneethyl acetate = 41) to afford the indene 5 (176
mg 0059 mmol 59 yield)
The 1H
13C NMR spectra were agreed with the reported value
5
Chapter 5
123
References and Notes
(1) (a) Brogden R N Heel R C Speight T M Avery G S Drugs 1978 16
97ndash114 (b) Nicholson A N Pascoe P A Turner C Ganellin C R
Greengrass P M Casy A F Mercer A D Br J Pharmacol 1991 104
270ndash276 (c) Huffman J W Padgett L W Curr Med Chem 2005 12
1395ndash1411
(2) (a) Zhu X Mitsui C Tsuji H Nakamura E J Am Chem Soc 2009 131
13596ndash13597 (b) Zeng X Ilies L Nakamura E J Am Chem Soc 2011 133
17638ndash17640
(3) (a) Cadierno V Diez J Gamasa M P Gimeno J Lastra E Coord Chem Rev
1999 193ndash195 147ndash205 (b) Stradiotto M McGlinchey M J Coord Chem Rev
2001 219ndash221 311ndash378 (c) Zargarian D Coord Chem Rev 2002 233ndash234
157ndash176 (d) Leino R Lehmus P Lehtonen A Eur J Inorg Chem 2004
3201ndash3222
(4) (a) Liebeskind L S Gasdaska J R McCallum J S Tremont S J J Org
Chem 1989 54 669ndash677 (b) Robinson N P Main L Nicholson B K J
Organomet Chem 1989 364 C37ndashC39 (c) Romines K R Lovasz K D
Mizsak S A Morris J K Seest E P Han F Tulinsky J Judge T M
Gammill R B J Org Chem 1999 64 1733ndash1737 (d) Quan L G Gevorgyan
V Yamamoto Y J Am Chem Soc 1999 121 3545ndash3546 (e) Halterman R L
Zhu C Tetrahedron Lett 1999 40 7445ndash7448 (f) Xi Z Guo R Mito S Yan
H Kanno K Nakajima K Takahashi T J Org Chem 2003 68 1252ndash1257
(g) Lautens M Marquardt T J Org Chem 2004 69 4607ndash4614 (h) Chang
K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69 4781ndash4787 (i)
Ming-Yuan L Madhushaw R J Liu R-S J Org Chem 2004 69 7700ndash7704
(j) Miura T Murakami M Org Lett 2005 7 3339ndash3341 (k) Shintani R
Okamoto K Hayashi T Chem Lett 2005 34 1294ndash1295 (l) Kuninobu Y
Kawata A Takai K J Am Chem Soc 2005 127 13498ndash13499 (m) Tsukamoto
H Ueno T Kondo Y Org Lett 2007 9 3033ndash3036 (n) Harada Y Nakanishi
J Fujihara H Tobisu M Fukumoto Y Chatani N J Am Chem Soc 2007
129 5766ndash5771 (o) Tsuchikama K Kasagawa M Endo K Shibata T Synlett
2010 97ndash100 (p) Zhou F Han X Lu X J Org Chem 2011 76 1491ndash1494
Chapter 5
124
(q) Patureau F W Besset T Kuhl N Glorius F J Am Chem Soc 2011 133
2154ndash2156 (r) Tran D N Cramer N Angew Chem Int Ed 2011 50
11098ndash11102 and references cited therein
(5) (a) Negishi E J Organomet Chem 1976 108 281ndash324 (b) Molander G A
Katona B W Machrouhi F J Org Chem 2002 67 8416ndash8423 (c) Goswami
A Maier C-J Pritzkow H Siebert W Eur J Inorg Chem 2004 2635ndash2645
(d) Yamamoto Y Ishii J Nishiyama H Itoh K J Am Chem Soc 2004 126
3712ndash3713 (e) Suginome M Shirakura M Yamamoto A J Am Chem Soc
2006 128 14438ndash14439 (f) Browne D L Vivat J F Plant A Gomez-Bengoa
E Harrity J P A J Am Chem Soc 2009 131 7762ndash7769 (g) Iannazzo L
Vollhardt K P C Malacria M Aubert C Gandon V Eur J Org Chem 2011
3283ndash3292
(6) (a) Ishida N Miura T Murakami M Chem Commun 2007 4381ndash4383 (b)
Ishida N Narumi M Murakami M Org Lett 2008 10 1279ndash1281 (c) Ishida
N Shimamoto Y Murakami M Org Lett 2009 11 5434ndash5437 (d) Ishida N
Shimamoto Y Murakami M Org Lett 2010 12 3179ndash3181 (e) Ishida N
Ikemoto W Murakami M Org Lett 2011 13 3008ndash3011 (f) Ishida N
Narumi M Murakami M Helv Chim Acta 2012 95 2474ndash2480
(7) For substitutive 12-migration from boron to the α-carbon with inversion of
stereochemistry see Koumlbrich G Merkle H R Angew Chem Int Ed 1967 6
74
(8) Jacob III P Brown H C J Org Chem 1977 42 579ndash580
(9) For related reactions involving the preferential migration of the alkyl groups on
boron over the bridgehead carbon of the 9-BBN framework see (a) Brown H C
Nambu H Rogic M M J Am Chem Soc 1969 91 6852ndash6854 (b) Miyaura
N Tagami H Itoh M Suzuki A Chem Lett 1974 3 1411ndash1414
(10) Slayden S W J Org Chem 1981 46 2311ndash2314
(11) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485ndash1491
(12) Kramer G W Brown H C J Organomet Chem 1974 73 1
(13) Johns A M Utsunomiya M Incarvito C D Hartwig J F J Am Chem Soc
2006 128 1828
Chapter 5
125
(14) Ishida N Shimamoto Y Murakami M Org Lett 2009 11 5434
(15) Chang K-J Rayabarapu D K Cheng C-H J Org Chem 2004 69
4781-4787
(16) Anstead G M Ensign J L Peterson C S Katzenellenbogen J A J Org
Chem 1989 54 1485
Chapter 5
126
127
List of Publication
Chapter 1
Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Angew Chem Int Ed 2012 51 11750-11752
Chapter 2
15-Rhodium Shift in Rearrangement of N-Arenesulfonylazetidin-3-ols into
Benzosultams
Naoki Ishida Yasuhiro Shimamoto Takaaki Yano Masahiro Murakami
J Am Chem Soc 2013 135 19103-19106
Chapter 3
Stereoselective Synthesis of (E)-(Trisubstituted alkenyl)borinic Esters
Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of
Alkynylborates with Aryl Halides
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2009 11 5434-5437
Chapter 4
Iterative Approach to Oligo(arylenevinylene)s Containing Tetrasubstituted Vinylene
Units
Naoki Ishida Yasuhiro Shimamoto and Masahiro Murakami
Org Lett 2010 12 3179-3181
Chapter 5
Regioselective Construction of Indene Skeletons by Palladium-Catalyzed
Annulation of Alkynylborates with o-Iodophenyl Ketones
Yasuhiro Shimamoto Hanako Sunaba Naoki Ishida and Masahiro Murakami
Eur J Org Chem 2013 1421-1424
Other Publication
Construction of Indole Skeletons by Sequential Actions of Sunlight and Rhodium on
α-Amino Acetophenones
Naoki Ishida David Nečas Yasuhiro Shimamoto and Masahiro Murakami
Chem Lett 2013 42 1076