PREPARATION OF SOME ORGANOZINC COMPOUNDS AND THEIR ENANTIOSELECTIVE ADDITION TO ALDEHYDES THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY Mr. RAVINDRA SUBHASH JAGTAP DR. N. N. JOSHI (RESEARCH SUPERVISOR) DIVISION OF ORGANIC CHEMISTRY NATIONAL CHEMICAL LABORATORY PUNE 411 008, INDIA
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PREPARATION OF SOME ORGANOZINC COMPOUNDS
AND THEIR ENANTIOSELECTIVE ADDITION TO
ALDEHYDES
THESIS
SUBMITTED TO THE
UNIVERSITY OF PUNE FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY
BY
Mr. RAVINDRA SUBHASH JAGTAP
DR. N. N. JOSHI
(RESEARCH SUPERVISOR)
DIVISION OF ORGANIC CHEMISTRY
NATIONAL CHEMICAL LABORATORY
PUNE 411 008, INDIA
Dedicated to my beloved parents
CERTIFICATE
The research work presented in thesis entitled “Preparation of some
organozinc compounds and their enantioselective addition to aldehydes” has
been carried out under my supervision and is a bonafide work of Mr. Ravindra
Subhash Jagtap. This work is original and has not been submitted for any other
degree or diploma of this or any other university.
March, 2012 Dr. N. N. Joshi
(Research Supervisor)
National Chemical Laboratory, Pune (India)
DECLARATION
I hereby declare that the thesis entitled “Preparation of some organozinc
compounds and their enantioselective addition to aldehydes” submitted for Ph.
D. degree to the University of Pune has been carried out at National Chemical
Laboratory, under the supervision of Dr. N. N. Joshi. This work is original and has
not been submitted in part or full by me for any degree or diploma to this or any
other university.
March, 2012 Ravindra S. Jagtap
Acknowledgements First of all I wish to express my deep sense of gratitude and profound thanks to my
teacher and research supervisor Dr. N. N. Joshi for introducing me in the fascinating field of asymmetric synthesis. I am indebted to him for his personal care and his enthusiastic encouragement in the progress of my research work. His wide knowledge and logical way of thinking have been of great value for me. My interaction with him have improved my quality of research and developing me a critical research attitude. I will be always obliged to him for teaching me the finest skill and giving excellent training required for the research as well as for his constant effort to instill us with several essential habits, like group meeting, monthly report and daily planning of work. His systematic working style, discipline and humanitarianism is an attribute that I wish to take forward with me along with the chemistry that I learnt from him. My sincere regards and respect are for him forever.
I would like to thank Dr. S. P. Chavan and prof. D. D. Dhawale for their valuable suggestions and scientific discussion during assessment of my Ph.D. work.
I would like to thank the Council of Scientific and Industrial Research (CSIR), New Delhi for the award of fellowship. I am thankful to Dr. G. P. Pandey, Head of organic chemistry division and Dr. Sivram (ex. Director, NCL), Dr. Sourav Pal, Director, NCL who gave me an opportunity to work in this prestigious research institute and providing all necessary infrastructure and facilities.
My sincere thanks to Dr. M. S. Shasidhar, Dr. C. V. Ramana, Dr. U. R. Kalkote, Dr. N. P. Argade, Dr. H. B. Borate, Dr. P. K. Tripathi, Dr. B. G. Hazara, Dr. H. V. Thulasiram, Dr. D. Dethe, Dr. G. Sanjayan, Dr. Gumaste, Dr. (Mrs) A. P. Likhithe, Dr. (Mrs) S. P. Maybhate, Dr. Gajbhiye, Dr. Muthukrishnan, Dr. M. K. Dongare, Dr. P. P. Wadgaonkar, Dr. B. Idage Dr. (Mrs). Idage, Dr. (Mrs) Umbharkar and to other scientist of NCL.
I take this opportunity to express my great sense of gratitude to thank my teachers; Prof. R. A. Mane, Prof. M. S. Shingare, Prof. B. R. Arbad, Prof. T. K. Chondekar, Dr. Lande (M. Sc., Dr. B. A. M. university, Aurangabad), Dr. Nalawade, Mrs. Nalawade madam, Dr. Mahadik, Dr. Dhumure, Dr. Ghodke, Mungare sir, Fulsagar sir, Thorat sir (B. Sc., R. P. College Osmanabad), Bhosale Sir and Mahadik Sir (I. T. I. Osmanabad), late Sarang Sir, Bangar Sir, Naikawadi Sir, Padwal Sir, Raut Sir, Shinde Sir, Salunke Guruji, Sheikh Guruji, Nimbalkar Sir (School teachers) for their support and constant encouragement.
Help from spectroscopy, microanalysis and X-ray crystallographic groups is greatfully acknowledged. I sincerely thanks to Dr. Rajmohan, Dr. (Mrs) Phalgune, Mr. Sathe for NMR, Mrs. S. P. Kunte for recording chiral HPLC, Mr. Kalal, Dr. Borikar for GC analysis, Dr. P. L. Joshi for microanalysis. Help from IR and mass facility is also acknowledged. I express my thanks to the office staff, Library members and administrative staff for their timely help.
It gives me immense pleasure to express my sincere thanks to my senior colleagues; Dr. Kartick Bhoumick, Dr. Anamitra Chatterjee, Dr. M. Sasikumar for their friendly nature, giving excellent training, valuable discussion and support. I am very thankful my senior colleague Dr. Mannamth Patil for helpful scientific discussion, moral support and being a good fried.
I also would like to mention special thanks to Dr. (Mrs) B. N. Joshi and Rohit Joshi for rendering pleasant association during my research period.
I feel very fortunate to have friends like Kishor, Rahul, Ramchandra and seema. I have no word to express my emotions for their love, care and support in a tough time of my stay. I thank them and their family for everything that they gave.
Special thanks to dear friends; Amol, Goroba (samya), Sunil, Tirupati, Dr. Sanjay, Kiran, Jayant, Nana, Praveen, Ajit, Madhav, Kalyan, Appa, Ravi, Sanjay Chavan, Rajkanya, Shubhangi, Deepali, Meera, Dr. Sachin Navle, Prashant Mangshetti, Sunil sontakke, Tanaji gapat, Gurunath, Laxman, Sanjay, and Sakharam, Sambhaji, Sachin, Sandeep, Amar.
Help from my seniors, Dr. Bapu Shingate, Dr. Bhaskar Sathe, Dr. Rajiv Sawant and Dr. Sandeep Udawant is greatfully and sincerely appreciated.
It is a pleasure to thank all my friend at NCL, Scientist apartment and GJ hostel for their cheerfull company, which made my stay at NCL memorable one, especially Nilesh, Lalit, Dhanlaxmi, Namrata, Satish biradar, Ganesh Gogdand, Dr. Sudhir bavikar, Dr. Kondekar, Dr. Giri, Dr. Sharad, Amrut, Deepak, Ganesh, Ankush, Prakash, Bhausaheb, Dr. Bhange, Dhanu, Kiran, Pankaj, Abhijeet, Dayanand, dattatraya, Dr. Aabasaheb, Dr. Suleman, Sumantho, Prakash, Pradeep, kailash, Harshali, Balaji selukar, Pitambar, Dr. Sunil Pandey, Sachin, Dr. Vikhe, Dr. Pushpesh, Dr. Abhishek, Krishanu, Sangmash, Gopi, Dhiraj, Dr. Pandurang, Dr. Amol, Dr. Shriram, Dr. Deepak, Dr. Murli, Dr. Ajay kale, Dr. Shafi, Dr. Manish Shimpi, Dr. Kalpesh Rana, Dr. Haval, Dr. Umesh, Dr. Ramesh, Dr. Prasad, Mandeep, Tukaram, Sangram, Vijaykumar, Prasana, Swaroop, Priyanka, Ravindra, Debashish, Sridhar, Mahesh, Rohan, Ganesh, Nitin, Prakash sultane, Sachin mali, Jaman, Eknath, Anand (bapu), Kedar, Vinay, Dr. Omprakash bande, Dr. Viswas, Amit, Mahendra, Balaji Bhosale.
My special thanks to Madhuri patil, Dr. Rajendra, Bharat, Shobhana, Alson, Richa, and Majid for their support, help and cheerful atmosphere during my thesis writing.
There are no words to acknowledge my parents (Baba and Aai) for their blessing, love, care and continuous encouragement throughout all my life. Whatever I am and whatever I will be in future is because of their commitment to my ambitions, their patience and selfless sacrifices. I also express my heartfelt gratitude to my elder brother (Aaba) and my sister-in-law (Archana), younger brother Manojkumar, Sharad and sister in law (Laxmi), late Grandfather and grandmother for their moral support, love and blessing. Thanks to little members of my family Amar (dada) and Amruta (didi), for giving happiness to all of us.
I also express my heartfelt gratitude to my dear wife Bhakti for her constant support and love and my dear son Atharva for giving happiness and love.
I also express my heartfelt gratitude to late dada, Aai, Bhau, Nani, Bapu, Appa, Tatya, Babasaheb, Vahini, Mama, Mami, Kaka, Mavsi for their support and love.
Finally I thank God for giving me strength to carry out this work. Ravi
CONTENTS Page No. Abbreviations i
General remarks iv
Abstract v Chapter 1: Preparation and applications of organozinc compounds:
A literature survey
Introduction 1
Organozinc halides 2
Organozincates 42
Summary and Outlook 54
References 55
Chapter 2: Present work on organozinc compounds
Introduction 62
Section 2A: Preparation of alkylzinc halides and alkylzinc acetates 63
Section 2B: Enantioselective addition of RZnX to benzaldehyde 72
Section 2C: Organozincates and their enantioselective addition to
benzaldehyde 84
Conclusions 91
Experimental section 92
References 102
Spectra 109
Chapter 3: Potential chiral ligands
Introduction 117
Section 3A: Synthesis and resolution of cis- and trans-2,3-diphenyl
Morpholines 118
Section 3B: Attempted resolution of 2,3-diphenylbuatane-2,3-diol 146
Conclusions 159
Experimental section 160
References 172
Spectra 179
i
ABBREVIATIONS
Ac Acetyl
AcOH Acetic acid
Ar Aryl
aq Aqueous
acac acetylacetone
BINOL 2,2’-Dihydroxy-1,1’-binaphthol
BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
Bn Benzyl
i-Bu Iso-butyl
n-Bu n-butyl
n-BuLi n-butyllithium
t-Bu tertiary butyl
Cat. Catalytic oC Temperature in degrees Centigrade
Config. Configuration
DCM Dichloromethane
DEPT Distortionless Enhancement by Polarization
Transfer
DIBAL-H Diisobutylaluminium hydride
DIEA Diisopropylethyl amine
DMA N,N-dimethylacetamide
DMAP 4-Dimethylaminopyridine
DME Dimethoxy ethane
DMF N,N-Dimethylformamide
DMI 1,3-dimethyl-2-imidazolidinone
DMPU N,N-dimethylpropyleneurea
DMSO Dimethyl sulfoxide
Dpp Diphenylphosphino
Dppf (diphenylphosphino)ferrocene
de Diastereomeric excess
ee Enantiomeric excess
ii
eq Equation
equiv. Equivalent
Et Ethyl
ET electron transfer
Et3N Triethyl amine
EtOAc Ethyl acetate
EtOH Ethyl alcohol
EWG Electron withdrawing group
FG Functional group
g Gram(s)
GC Gas Chromatography
h Hour(s)
HMPA Hexamethylphosphoramide
HPLC High Performance Liquid Chromatography
Hz Hertz
IR Infrared
M Molar
Me Methyl
MeOH Methanol
min. Minute(s)
mL Milliliter(s)
mmol Millimole
mp Melting point
Ms Mesyl
MS Mass spectroscopy
MsCl Methanesulfonyl chloride
MTBE Methyl tert-butyl ether
NaH Sodium hydride
NMP N-methyl-2-pyrrolidone
NMR Nuclear magnetic resonance
ORTEP Oak Ridge Thermal Ellipsoid Plot
Oct Octyl
PE Pet ether
Ph Phenyl
iii
Piv Pivaloyl
i-Pr Isopropyl
PTSA para-Toluene sulfonic acid
Py Pyridyl
Red-Al bis(2-methoxyethoxy)aluminumhydride
RT Room temperature
TADDOL α,α,α´,α´-Tetraaryl-1,3-dioxolan-4,5-
dimethanol
TBAB Tetrabutylammonium bromide
TBAF Tetrabutylammonium fluoride
TBAI Tetrabutylammonium Iodide
TEEDA N,N,N,N-Tetraethylethylenediamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin Layer Chromatography
TMEDA N,N,N,N-tetramethylethylenediamine
TMSCl Trimethylsilyl chloride
TMU 1,1,3,3-tetramethyl urea
Tr Triphenylmethyl
Ts Tosyl
iv
GENERAL REMARKS
• Independent compound numbering, scheme numbers and reference numbers
have been employed for abstract, as well as each chapter (Chapter 1-3).
• All the solvents and reagents were purified and dried according to procedures
given in D. D. Perin’s “Purification of Laboratory Reagents.” All reactions were
carried out under argon atmosphere using freshly distilled solvents, unless
otherwise specified. Yields refer to isolated product unless otherwise mentioned.
Column chromatographic separations were carried out by gradient elution using
silica gel (100-200 mesh / 230-400 mesh) using light petroleum ether-ethyl
acetate as the eluent, unless otherwise mentioned. Petroleum ether used in the
experiments was of 60-80 °C boiling range.
• TLC was performed on E-Merck pre-coated silica gel 60 F254 plates and the spots
were rendered visible by exposing to UV light, iodine, charring or staining with
ninhydrin, p-anisaldehyde or phosphomolybdic acid solutions in ethanol.
• All the melting points reported are uncorrected and were recorded using Buchi
melting point B-540 apparatus.
• IR spectra were recorded on Shimadzu FTIR instrument, for solid in chloroform
and neat in case of liquid compounds and are measured in cm-1.
• 1H NMR spectra were recorded on Bruker ACF 200 MHz, AV200 MHz, AV 400
MHz, DRX 500 MHz spectrometers using tetramethylsilane (TMS) as an internal
standard in CDCl3. Chemical shifts have been expressed in parts per million
(ppm) on δ scale downfield from TMS. The abbreviations s, bs, d, t, dd, dt, td
and m refer to the singlet, broad singlet, doublet, triplet, doublet of doublet,
doublet of triplet, triplet of doublet and multiplet respectively. Coupling
constants whenever mentioned have been given in MHz.
• 13C NMR spectra were recorded at 50 MHz and 75 MHz with CDCl3 (δ = 77
ppm) as the reference.
• Microanalytical data were obtained using a Carlo-Erba CHNS-O EA 1108
Elemental Analyzer.
• Optical rotations were obtained on Bellingham & Stanley ADP-220 Polarimeter.
Specific rotations, [α]D are reported in deg, and the concentration (c) is given in
g/100 mL in the specific solvent.
v
ABSTRACT
Introduction
Enantioselective addition of organometallic reagents to aldehydes is one of the most
important contemporary reactions. Such asymmetric reaction allows the preparation
of enantioriched secondary alcohols, which are building blocks for the synthesis of
natural products and pharmaceuticals. Enantioselctive addition of alkyllithium and
Grignard reagents is a straightforward approach to synthesize optically active
alcohols. However the method is of limited use due to the need of stoichiometric
amount of valuable chiral ligand to achieve high enantioselectivity. Use of less
reactive organozinc reagents has emerged as the solution to overcome above
difficulties. Organozinc reagents are very attractive owing to their mild reactivity
and excellent chemoselectivity. Amongst different approaches, catalytic
enantioselective addition of dialkylzincs to aldehydes is the most studied reaction.
However lack of wide commercial availability of dialkylzincs, high cost and their
pyrophoric nature demands an easy in situ preparation of these reagents. The
reagents of type RZnX (X = Cl, Br, I) which are easily accessible, represent the best
choice in this context. However, these reagents are not much explored in asymmetric
catalysis. The present work deals with the preparation of RZnX (X = Cl, Br, I, OAc)
and the corresponding organozincates and their applications in enantioselective
alkylation of aldehydes. The thesis entitled “Preparation of some organozinc
compounds and their enantioselective addition to aldehydes” is divided into three
chapters.
Chapter 1: Preparation and applications of organozinc compounds: A literature
survey
This chapter is a review of the literature on preparation of RZnX (X = Cl, Br, I,
OAc) and organozincates and their applications in various asymmetric reactions.
Chapter 2: Present work on organozinc compounds
This chapter is divided into three sections. Section 2A describes the preparation of
RZnX (X=Cl, Br, I) by oxidative insertion and preparation of RZnX (X = Cl, OAc)
by transmetallation or ligand exchange method. Section 2B deals with a detailed
vi
study on reactivity and enantioselective addition of RZnX to benzaldehyde. Section
2C describes the preparation, reactivity and enantioselective addition of
organozincates to benzaldehyde.
Section 2A: Preparation of alkylzinc halides and alkylzinc acetates
1. Preparation of RZnX (R= alkyl, allyl, benzyl, X= Cl, Br, I) by oxidative
insertion
Apart from the preparation of organozinc halides using highly reactive Rieke Zinc,
which is tedious, there are very few methods for the preparation of alkylzinc
bromides from commercial zinc and unactivated alkyl bromides. The two reliable
methods known in the literature require use of polar solvents like N,N-dimethyl
acetamide (DMA) or use of 1,2-dibromoethane as activator. However DMA is not
suitable for large scale preparation, whereas dibromoethane has limitations due to its
carcinogenic toxicity. Our aim was to develop easier preparative method for
alkylzinc halides in solvent like tetrahydrofuran which is more convenient and easy
to handle.
In our initial effort, the reaction of zinc dust and BuBr was carried out to
explore the reactivity pattern (Table 1).
Table 1. Oxidative insertion of zinc dust into butyl halides
a Isolated yield. b Determined by chiral GC analysis
Section 3B: Attempted resolution of 2,3-diphenylbuatane-2,3-diol
C2-Symmetric chiral diols have found numerous applications in asymmetric
synthesis as chiral auxiliaries, chiral ligands as well as chiral building blocks. We
wanted to explore sterically demanding chiral tertiary diol like 2,3-diphenyl-butane-
2,3-diol 18 in asymmetric synthesis. Although synthesis of enantiopure 18 was
reported by Cram et. al. resolution of this diol is not known in the literature. The
resolution of diols could be accomplished through diasereomeric esters or ketals, and
also through borate esters.
We have prepared dl-18 by pinacol coupling of acetophenone according to
the literature procedure, with excellent diastereoselectivity, equation 10.
xvii
+ Mn*25 oC, 2h
THF
Mn* = highly reactive manganese dl-1849%, >99% de
(10)Ph Me
O MePh
PhMe
OH
OH
1. Attempted resolution of dl-18 through addition complex
This method is based on formation of diastereomeric addition complex
between diol and resolving agent through hydrogen bonding. We examined various
resolving agent like trans-(−)-1,2-diamino cyclohexane, trans-(−)-1,2-
diphenylethane-1,2-diamine, (+)-cinchonine, and (−)-cinchonidine using various
solvents. However no addition compound could be isolated.
2. Resolution of dl-18 through chiral borate complex
This method involves formation of well defined covalent borate complex
between boric acid, diol and a resolving agent. We examined (−)-α-methyl benzyl
amine and (−)-phenyl glycinol as resolving agents. Only partial resolution of 18
could be realized using (S)-Proline as resolving agent (Scheme 10).
(S)-Proline
+ B(OH)3(i) Toluene, Reflux, 12 h
(ii) dl-18, Toluene reflux, 12 h
PPT-1+ Filtrate
PPT-1
PPT-2
Filtrate
THF, RT, 24h
Aq. 3N HCl:THF(-)-18
29%, 30% eeRT, 4h
N COOH
H
Scheme 10. Resolution of 18 by (S)-Proline and boric acid
CHAPTER-1
Preparation and applications of organozinc compounds: A
literature survey
1
Introduction
Enantioselective addition of organometallic reagents to aldehydes is one of
the fundamental asymmetric reactions and it is a powerful tool for the construction of
chiral carbon-carbon bond. This method provides enantiorich secondary alcohols,
which are building blocks for the synthesis of natural products and pharmaceuticals.1
Asymmetric addition of alkyllithium and Grignard reagents is a straightforward
approach for the synthesis of optically active alcohols. Although several examples
involving organolithium and Grignard reagents have been reported, these usually
require stoichiometric amounts of valuable chiral ligands.2 Due to the high
background reactivity of these reagents, catalytic version remained unexplored until
the recent report of Harada and co-workers.3 Furthermore, these reagents preclude
the presence of many functional groups due to their high reactivity which reduces
their attractiveness in organic synthesis. In contrast, organozinc reagents show very
mild reactivity and excellent chemoselectivity.4 In addition to the Reformatsky
reaction5 and the Simmons−Smith6 reaction, a number of carbon-carbon bond
forming reactions using organozinc reagents have been reported.4 Organozinc
reagents can be classified as four types,
(I) Organozinc halides (R-Zn-X, X = Cl, Br, I)
(II) Diorganozincs (R-Zn-R)
(III) Organozincates R3ZnM (M= MgX, Li) or R4ZnLi2
(IV) Reformatsky reagentOR
OZnX
Despite their discovery in 1849 by Frankland,7 organozinc reagents were
unexplored in asymmetric synthesis for a long period of time due to their poor
reactivity. After the report of Oguni and Omi in 1984,8a the enantioselective addition
of diorganozinc reagents to carbonyl compounds emerged as one of the attractive
tools for the preparation of optically active alcohols.1c,8 However lack of wide
commercial availability, high cost and pyrophoric nature limits their use to only
lower homologues.9 Therefore a search for the other alternatives is desirable. The
reagents of type RZnX (X = Cl, Br, I) which are easily accessible, are good
2
alternatives to diorganozincs. Organozinc halides have very less reactivity towards
most class of organic electrophiles due to high covalent character of carbon-zinc
bond and less Lewis acidity of Zn(II) metal centre. However, transmetallation with
transition metals such as Pd, Ni, Cu etc. generates reactive complex which shows
excellent reactivity.4b Their use has been mainly in Ni and Pd-catalyzed cross-
coupling reactions.10
Organozincates11 is another class of organozinc compounds which are more
reactive as compared to organozinc halides and diorganozincs. These reagents were
found to be attractive by synthetic organic chemists due to their unique reactivity and
excellent chemoselectivity.4a Organozincates have shown their usefulness in many
chemoselective organic transformations.4a,11c,d,g As compared to diorganozinc
reagents, reagent of type I and III are not much explored in asymmetric synthesis.
The present chapter will focus on reviewing the literature on preparation and
applications of organozinc halides and triorganozincates in asymmetric synthesis.
1. Preparation of organozinc halides
There are three general methods for the preparation of organozinc halides;
(i) Oxidative insertion (direct insertion of metallic zinc into carbon-halogen bond)
(ii) Transmetallation (the reaction of RM (M = Li or MgX) with zinc salt) and
(iii) Ligand exchange (the exchange of ligands between R2Zn and zinc salt)
1.1. Preparation of organozinc halides by oxidative insertion
The oxidative insertion is the most general and attractive protocol for the
preparation of organozinc halides. This method shows very broad scope and it is
applicable to the preparation of a number of simple as well as functionalized
organozinc reagents. In 1942 Hunsdiecker12a reported the preparation of number of
functionalized alkylzinc iodides 1 by the reaction of zinc with corresponding alkyl
iodide in ethyl acetate (Scheme 1).
RO2C(CH2)nI + ZnEtOAc
refluxn > 5
RO2C(CH2)nZnI
1
Scheme 1. Oxidative insertion of zinc into alkyl iodide in EtOAc
3
After this report, various other procedures have been reported. Some of the
important ones are described below.
In 1962, Gaudemar et al.12b reported that the primary alkyl iodide reacts with
zinc foil in THF at 50 oC in few hours to give corresponding alkylzinc iodide
whereas secondary iodide reacts at ambient temperature (Scheme 2).
RI + Zn RZnITHF, 25−50 oC
RI = primary or secondary alkyl iodide
Scheme 2. Preparation of alkylzinc iodides in THF
In 1964 Paleeva et al.12c reported the preparation of ethylzinc iodide by the
reaction of zinc-copper couple13 (8% copper) with ethyl iodide under reflux
condition (Scheme 3).
EtI + Zn-Cureflux
EtZnI
68%
Scheme 3. Preparation of ethylzinc iodide using Zn-Cu couple
In 1988 Knochel et al.14a observed fast reaction rates when zinc was
activated successively with a catalytic amount of 1,2-dibromoethane and TMSCl.
Thus, in the case of primary alkyl iodides insertion is complete in 2−3 h in THF at 40 oC, whereas secondary iodides react at room temperature. Under the optimized
conditions, various simple as well as functionalized alkylzinc iodides (RZnI) were
prepared in good yield (Scheme 4).
RI + Zn RZnITHF, 25−40 oC
Up to 90% yield
(CH2Br)2 (4 mol%)TMSCl (3 mol%)
R = alkyl, FG-alkyl; FG = CN, CO2R'
Scheme 4. Preparation of alkylzinc iodides using in situ activated zinc
4
In the same year Knochel′s group observed that the presence of cyano group
at β-carbon greatly accelerates the rate of the insertion reaction.14b The reaction of 2-
cyano iodides 2 with in situ activated zinc14c (cut foil or dust) in THF provided
corresponding zinc reagents 3 in good yield14d (Scheme 5).
R
CNI
R
CNIZn
80-90% yieldR = H, Pr
+ Zn
2 3
THF
5−30 oC, 3−5 h
Scheme 5. Preparation of 2-cyanozinc iodides
Knochel et al. also observed the presence of oxygen at α-carbon accelerates
the rate of the insertion reaction.15a,b For example, treatment of iodomethyl pivalate 4
with activated zinc foil14c in THF at 12 oC furnished PivOCH2ZnI 5 in excellent
yield15a (Scheme 6).
O
O
I
4
THF, 12 oC, 1 h+ Zn PivOCH2ZnI
5>85% yield
Scheme 6. Preparation of iodomethylzinc pivalate 5
Later in 2004 Kimura and Seki15c reported the preparation of alkylzinc iodide
7 by the treatment of zinc dust (activated with bromine) with corresponding alkyl
iodide 6 in excellent yield (Scheme 7). In comparison with other activators such as
TMSCl or 1,2-dibromoethane, use of bromine proved better for the large scale
preparation.
EtO2CI + Zn
Br2 (0.5 equiv)
THF:toluene50-60 oC, 1 h
EtO2CZnI
6 794% yield
Scheme 7. Preparation of ethyl iodovalerate
5
Simple alkyl bromides and chlorides usually cannot be converted to the
corresponding organozinc compounds in THF under the normal reaction conditions.
In 1990 Knochel et al.15d reported that the presence of phosphate group
considerably accelerates the rate of formation of organozinc bromides. Thus, the
treatment of primary bromophosphonates 8a with activated zinc dust14c in THF at 30 oC for 12 h gave the corresponding alkylzinc bromide 9a in excellent yield.
Secondary bromophosphonates 8b-d requires only 0.5 h for completion of the
Later in 2003 Huo et al.16b reported a very efficient method for the
preparation of alkylzinc bromides in DMA. The treatment of zinc metal (activated by
5 mol % iodine) with primary alkyl bromide 14a in polar solvent such as DMA at 80 oC afforded the corresponding alkylzinc bromide 15a in excellent yield (Scheme 12).
Number of simple as well as functionalized alkyl bromides 14b-i (Figure 1) were
reacted with zinc under the optimized conditions to obtain corresponding zinc
reagent in >90% yield. However, the reaction of secondary alkyl bromides was
sluggish whereas, tertiary alkyl bromide did not even require iodine for activation.
7
On the other hand, no zinc reagent was formed when less polar solvents such as
diethyl ether, THF, dioxane, DME and acetonitrile were used.
n-OctBr + ZnDMA, 80 oC, 3 h
n-OctZnBrI2 (5 mol%)
14a 15a
Scheme 12. Preparation of n-Octylzinc bromide in DMA
Cl Br6
O Br5
O
NC Br4
Br3
EtO
O
Br Br Br Br
14b 14c 14d 14e
14f 14g 14h 14i
Figure 1
Use of other polar solvents such as DMF, DMSO, DMPU or NMP, and also
the various forms of zinc metal provided comparable results (Table 1).
8
Table 1. Direct insertion of zinc into n-Octyl bromide under various conditions
n-Oct-Br + Zncat. I2
80 oCn-OctZnBr
14a 15a
Entry Zn I2 (mol %) Solvent Time (h) Conversion (%)
1 dust 5 DMA 3 >99
2 dust 1 DMA 9 >98
3 dust 5 DMF 4.5 >99
4 dust 5 DMSO 3 >99
5 dust 5 DMPU 3 >99
6 dust 5 NMP 6 >98
7 powder 5 DMA 3 >99
8 granule 5 DMA 3 >98
9 shot 5 DMA 12 >98
Using this methodology alkylzinc chlorides 17a,b were also prepared from
the corresponding alkyl chlorides 16a,b in very good yield. The presence of
stoichiometric amount of salts like LiBr or R4NBr is required to achieve efficient
conversion (Scheme 13).
RCl + Zn
I2 (5 mol%) LiBr or Bu4NBr (1 equiv)
DMA, 80 oC, 12 hRZnCl
RCl = Cl7
Cl3EtO
O
16a,b 17a,b
16a 16b
Scheme 13. Preparation of alkylzinc chlorides in DMA
Later in 2006 Knochel et al.16c described LiCl-accelerated preparation of
alkylzinc bromides in THF. This method allows the preparation of alkylzinc
bromides from simple as well as functionalized alkyl bromides. Thus, the treatment
of zinc powder in situ activated by catalytic 1,2-dibromoethane and TMSCl, with
9
primary or secondary alkyl bromides (14a-c and 14j-o) in the presence of
stoichiometric amount of LiCl furnished the corresponding alkylzinc bromides in
excellent yield (Scheme 14). Author proposed that LiCl rapidly removes the formed
organozinc reagent from the metal surface by generating highly soluble RZnX⋅LiCl
complex, and freshly activated metal surface gets exposed to further insertion
process.
RBr + Zn 50 oC, 1−50 h
LiCl, THFRZnBr LiCl
Cl Br5
O Br4
O
Br
5
Br Br
Br
14k
14m 14n 14o
14j 14l
14a-c, 14j-o >92% yield
Scheme 14. LiCl-accelerated preparation of alkylzinc bromides
Unlike alkyl iodides, vinyl or aryl iodides do not undergo insertion in THF
under normal conditions and requires higher temperature or polar solvents such as
DMF, DMA.
In 1990 Knochel et al.17a reported the preparation of arylzinc iodides by the
reaction of commercial zinc with aryl iodides. The treatment of aryl iodides 18 with
zinc dust (in situ activated using 1,2-dibrmoethane) in DMF or DMA at 25 to 55 oC
afforded the corresponding arylzinc iodides 19 in good yield (Scheme 15). It was
observed that the substituent on the aromatic ring strongly influence the rate of the
zinc insertion. For example, iodobenzene requires 22 h at 55 oC for 80% conversion
whereas 2-iodobenzonitrile undergoes complete insertion within 2 h at 35 oC. A
comparison between the zinc insertion rates of o-, m- and p-iodobenzonitrile
indicated that o-iodobenzonitrile reacts significantly faster.
10
I
FG
+ Zn25−55 oC, 2−22 h
DMF or DMA ZnI
FG
FG = CN, Cl, COR, CO2Et
18 19
65-85% yield
Scheme 15. Preparation of arylzinc iodides in polar solvent
Author has also reported the preparation of alkenylzinc iodide 20 under these
conditions. The (E)-1-iodo-1-octene reacts with zinc in 14 h at 70 oC (Scheme 16).
H
Hex
I + Zn70 oC, 14 h H
Hex
E :Z(1:1 to 1 :1.5)
DMF
ZnI20
Scheme 16. Preparation of alkenylzinc iodide
In 1993 Takagi et al.17b reported the ultrasound-promoted insertion of zinc
into functionalized aryl iodides. Various functionalized aryl iodides were reacted
under different reaction conditions to obtain the corresponding arylzinc iodides in
good yield. One representative example is described below. Under ultrasound-
irradiation, the reaction of methyl 2-iodobenzoate with zinc powder in TMU (1,1,3,3-
tetramethyl urea) at 30 oC for 5 h gave arylzinc iodide 21 in good yield (Scheme 17).
Same reaction without irradiation of ultrasound requires 15 h for the completion.
CO2Me
I+ Zn
TMU, 30 oC
CO2Me
ZnI
ultrasound-irradiation 5 hwithout ultrasound-irradiation 15 h 87% yield
21
Scheme 17. Ultrasound-promoted preparation of arylzinc iodide
11
Later in 2003 the same author17c reported the preparation of functionalized
arylzinc iodides in ethereal solvents such as THF, diglyme or triglyme. The reaction
of zinc powder with functionalized aryl iodides 18 provided corresponding arylzinc
iodides 19 in good yield (Scheme 18).
I
FG
+ ZnZnI
FG
FG = H, CN, Cl, Br, CO2R', CH3, OCH3
18 19
TMSCl (3 mol%)
THF or diglymeor triglyme70−180 oC
Up to 95% yield
Scheme 18. Preparation of arylzinc iodides in ethereal solvents
It was observed that the aryl iodides containing EWG at the ortho-position
smoothly reacts in THF at 70 oC (Table 2), whereas those containing EWG at the
meta- and para-position or electron-rich aryl iodides were less reactive and requires
elevated temperature as well as solvents such as diglyme or triglyme.
Table 2. Preparation of various arylzinc iodides in etheral solvents
I
FG
+ ZnZnI
FG18 19
TMSCl (3 mol%)
24 h
Entry R Solvent Temp (oC) Yield (%)
1 o-CO2Me THF 70 87
2 m-CO2Me THF 70 20
3 m-CO2Me diglyme 100 84
4 p-CO2Me diglyme 100 89
5 p-CH3 diglyme 130 87
6a p-CH3 triglyme 180 83 a The reaction time was 1.5 h.
12
In the same year Gosmini et al.18a reported a new method for the preparation
of arylzinc bromides and iodides. In this method the treatment of aryl halide 22a-c
with zinc dust in the presence of catalytic amounts of PhBr, CoBr2, ZnBr2 and TFA
in acetonitrile furnished corresponding arylzinc halide 23 in moderate to excellent
yield (Scheme 19). In their initial study, they observed the formation of byproducts
such as reduction product (ArH) and the homocoupling product Ar-Ar. The addition
of catalytic amount of phenyl bromide prior to the addition of aryl halide (the
substrate) allows this side reaction to proceed on PhBr rather than on aryl halide
which results in increased yield of the desired product. Number of simple as well as
functionalized aryl and hetero arylzinc halides were prepared under mild reaction
conditions in good yield. The role of TFA was to activate the zinc metal. Author
proposed that the activated zinc reduces the Co(II) to Co(I) species which initiates
(c) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron Lett. 2009, 50, 3198. (d)
Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron Lett. 2009, 50, 4188. (e)
Almansa, R.; Collados, J. F.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry,
2010, 21, 1421.
51. (a) Houpis, I. N.; Molina, A.; Dorziotis, I.; Reamer, R. A.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 1997, 38, 7131. (b) Studte, C.; Breit, B.
Angew. Chem. Int. Ed. 2008, 47, 5451. (c) Brand, G. J.; Studte, C.; Breit, B.
Org. Lett. 2009, 11, 4668.
61
CHAPTER-2
Present work on organozinc compounds
62
Introduction As discussed in the Ist chapter, organozinc reagents are important
organometallics in asymmetric synthesis. Amongst these, dialkylzincs have proved to
be excellent nucleophiles in asymmetric addition to carbonyl compounds mainly
because of well established methods and use of simple ligands.1 However, lack of
wide commercial availability, high cost and their pyrophoric nature demands an easy
in situ preparation of these reagents. Significant efforts have been made by various
research groups to circumvent these difficulties,2 which includes preparation of
diorganozincs by boron-zinc3 or iodine-zinc4 exchange and transmetallation of
alkyllithium or Grignard reagents with zinc salts.5 One of the major drawbacks in the
case of in situ preparation of diorganozinc reagents from alkyllithium or Grignard
reagent and ZnX2, is the formation of lithium and magnesium salts which affect
enantioselectivity.5c,e To overcome this difficulty, additional tasks like centrifugation
/ filtration5a-c or the use of complexing agent like TMEDA have been explored.5d,e
Therefore search for other alternatives is desirable. We have been interested in the
reagents of type RZnX6 (X = Cl, Br, I) which are easily accessible and represent the
best choice in this context. Organozinc halides have been used as nucleophiles in few
asymmetric reactions like catalytic enantioselective 1,4-addition7 and asymmetric
Negishi coupling.8 Only few examples of the use of organozinc halides in catalytic
enantioselective addition to aldehyde are known.9 Similar to organozinc halides,
triorganozincate reagents are also less explored in asymmetric synthesis.10-13
Development of new methods for their application in asymmetric synthesis would
lead these reagents as a valuable organometallics.
The present chapter describes the preparation of RZnX (X = Cl, Br, I, OAc)
and the corresponding organozincates and their applications in enantioselective
alkylation of aldehyde. It has been divided into three sections.
Section 2A: Preparation of alkylzinc halides and alkylzinc acetates
Section 2B: Enantioselective addition of RZnX to benzaldehyde
Section 2C: Organozincates and their enantioselective addition
to benzaldehyde
63
Section 2A
Preparation of alkylzinc halides and alkylzinc acetates
1. Preparation of RZnX by oxidative insertion
It is evident from the literature that the oxidative insertion of zinc into organic
halides is the most studied reaction. The oxidative insertion is most general and
attractive protocol for the preparation of organozinc halides. After the discovery of
first oxidative addition of zinc into a carbon-halogen bond in 1849 by Frankland,14
numerous procedures have been developed for the activation of zinc15 to achieve
efficient conversion. The heterogeneous reaction conditions and the nature of zinc
often pose a problem of reproducibility in the oxidative insertion. After longer
expose to air, the surface of metallic zinc gets coated with a layer of zinc oxide that
creates the difficulty in initiating the insertion reaction. Therefore the oxide layer
must be removed before the zinc metal gets engaged in insertion process with
organic halide. The most common initial step for the activation of zinc metal
involves washing of the commercial zinc with aqueous HCl.16 Further activation can
be done by making alloys with Cu,17 Ag,18 Hg.19 Another methods for in situ
activation of zinc metal includes treatment of the zinc metal with activators such as
1,2-dibromoethane,20 TMSCl,21 Bromine,22 Iodine,23 DIBALH24 and ultrasound
irriadiation.25
The rate of oxidative insertion of zinc depends on various factors such as,
nature of organic moiety in the substrate, the halide, method for activation of zinc
and reaction parameters such as temperature, concentration and the solvent. Apart
from the preparation of organozinc halides using highly reactive Rieke Zinc,26 which
is tedious, there are very few methods for the preparation of alkylzinc bromides from
commercial zinc and unactivated alkyl bromides. The two reliable methods known in
the literature require use of polar solvents like N,N-dimethyl acetamide23c or use of
1,2-dibromoethane27 as activator. However DMA is not suitable for large scale
preparation, whereas 1,2-dibromoethane has limitations due to its carcinogenic
toxicity.28 Our aim was to develop a easier preparative method for alkylzinc halides
in solvent like tetrahydrofuran which is more convenient and easy to handle.
We examined various additives / activators for the preparation of alkylzinc
bromides by oxidative insertion and the results obtained are discussed below.
64
Results and discussion
The efficiency of oxidative insertion into carbon-halogen bond can be
increased in number of ways like activation of zinc and use of additives which can
form soluble complex with zinc reagent to give freshly active metallic surface for
further reaction.
We examined various additives / activators for the reaction of primary alkyl
bromides with zinc dust in THF at 50 to 55 oC (Table 1). Initially we have reacted
zinc dust with RBr (R = Et, n-Bu) using catalytic amount of zinc activators like MeI,
Br2, and HCl (in Et2O). Most of the zinc was unreacted in all the cases (Table 1,
entries 1−3). Similar kind of results were obtained in the case of radical initiator such
as CuI, CeCl3 and InCl3 (entries 4−6). The examination of iodide salts such as LiI
and TBAI, which can convert alkyl bromide into more reactive iodide, also failed to
give the zinc reagent (entries 7 and 8). We also examined the complexing agents like
TBAB and ethane-1,2-dimethyl thioether in stoichiometric amount. But in both the
cases most of the zinc was unreacted (entries 9 and 10).
65
Table 1. Reaction of alkyl bromides with zinc
RBr + ZnTHF
50-55 oCRZnBr
R = Et, n-Bu
Entry RBr Additives (equiv) Time (h) Result
1 EtBr MeI (0.1) 24
Most of
the zinc
was
unreacted
2 BuBr Br2 (0.2) 24
3 BuBr HCl in Et2O (0.2) 24
4 EtBr CuI (0.05) 40
5 EtBr CeCl3 (0.1) 48
6 EtBr InCl3 (0.1) 48
7 EtBr LiI (0.1) 48
8 EtBr TBAI (0.1) 48
9 BuBr Bu4NBr (1.0) 24
10 BuBr MeSCH2CH2SMe (1.0) 24
We therefore decided to investigate the reaction systematically using n-BuX
(X = Cl, Br, I). Without the use of any additive, more than 95% zinc was consumed
in the reaction of butyl iodide (1.1 equiv) with zinc dust (1 equiv) in THF at 50−55 oC in 24 h (Table 2, entry 1). However iodometric titration29 revealed yield of 60%.
When 1.1 equivalent of LiCl was used, the rate of the reaction was dramatically
increased and the reaction was completed in only 2 h under similar reaction
conditions (entry 2). However, butyl bromide was found to be unreactive under these
reaction conditions (entry 3). We then employed activators like TMSCl, 1,2-
dibromoethane and iodine in catalytic amount. Most of the zinc was unreacted in all
the cases (entries 4−6). Use of catalytic amount of TMSCl in combination with
stoichiometric LiCl gave only 8% yield of the butylzinc bromide after 48 h (entry 7),
whereas 1,2-dibromoethane did not initiate the reaction (entry 8). Interestingly, in the
presence of 5 mol% I2 and 1.1 equivalents of LiCl, butylzinc bromide was obtained
in 65% yield (entry 9). The reaction was completed in 18 h with high reproducibility.
The presence of both LiCl and iodine is necessary for the complete conversion
66
(comparison between entries 3, 6 and 9). Encouraged by these results, we examined
other activators such as LiI and TBAI. Comparable results were obtained in both the
cases with slight longer reaction time (entries 10 and 11). We also studied the effect
of iodine loading on the reaction rate. When iodine loading was reduced to 2 mol %,
the reaction proceeds much slowly (entry 12). Similar results were observed in the
case of LiI (entry 13). Next, less reactive butyl chloride was subjected to the
oxidative insertion in the presence of LiCl and catalytic amount of iodine and
TMSCl. However most of the zinc was unreacted even after 48 h (entry 14). Use of
polar solvents such as EtOAc and DMA also did not help (entries 15 and 16).
The mechanism of zinc insertion is well studied by Rieke et al.26h In the
course of our study, GC-MS analysis of the hydrolyzed reaction mixture (entries 9,
10 and 11, Table 2) showed the formation of a small amount of butyl iodide. On the
basis of these results, we proposed the possible mechanism as shown in scheme 1.
The formation of butyl iodide could be explained by the nucleophilic displacement of
bromide of BuBr by I¯ generated from the reaction of zinc and I2. This more reactive
butyl iodide reacts with zinc in the presence of LiCl to form the complex A. The
complex A exchanges30 the iodide with butyl bromide to give complex B and BuI is
recycled back in the insertion process.
BuBr + I BuI + Br
BuI + ZnLiCl
BuZnI LiCl
(A)
BuZnI LiCl
(A)
BuBrBuZnBr LiCl + BuI
(B) (recycled)
Scheme 1. Proposed mechanism for the oxidative insertion
Since iodides provided good results, we further examined these reaction
conditions for the preparation of various alkylzinc bromides. Under optimized
reaction conditions, various alkyl bromides were reacted with zinc dust (Table 3).
Thus, the reaction of ethyl bromide with zinc dust (1.5 equiv) in the presence of LiCl
(1.1 equiv) and 5 mol% iodine provided EtZnBr·LiCl in 75% yield (entry 1). Other
68
Table 3. Preparation of RZnX (X = Br, Cl) using LiCl and catalytic I2
RX + Zn + LiClTHF, 50-55 oC
RZnX LiCl
(1.0) (1.5) (1.1)
5 mol% I2
Entry RX Time (h) Yielda (%)
1 Ethyl bromide 14 75
2 n-Butyl bromide 18 74
3 n-Hexyl bromide 20 74
4 n-Octyl bromide 24 72
5 Ethyl-4-bromo-butyrate 10 73
6 iso-Butyl bromide 48 42
7 iso-Propyl bromide 48 25
8 tert-Butyl bromide 24 40
9 Allyl chloride 10 68
10 Benzyl chloride 5 75 a Yields were determined by iodometric titration.
bromides like n-butyl, n-hexyl and n-octyl bromide were also converted to the
corresponding zinc reagent in good yield (entries 2–4). Functionalized alkyl bromide
like ethyl 4-bromo-butyrate provided corresponding zinc reagent in 73% yield (entry
5). Due to the steric bulk around bromide, the reaction of iso-butyl and iso-propyl
bromide was slow and incomplete after 48 h (entries 6 and 7). In the case of tert-
butyl bromide only 40% yield of the product was obtained although zinc was used
quantitatively. To find out the reason for this abnormal result, we performed the
above reaction without LiCl under similar reaction conditions (eq 1). In this case,
t-BuBr + Zn5 mol% I2, THF
50-55 oC, 24 ht-BuZnBr
Zinc consumed 84%Yield 0%
(1)
69
iodometric titration of the reaction mixture did not show the presence of zinc reagent
although 84% zinc was reacted. The GC-MS analysis of reaction mixture showed
two major peaks at (m/z 168) and (m/z 226) which corresponds to the probable
structures of 1 and 2 respectively (Figure 1). The above results clearly indicates that
LiCl stabilizes the zinc reagent by forming the complex t-BuZnBr⋅LiCl and also
explain the reason for low yield.
21
Figure 1
At this stage, the mechanism for the formation of 1 and 2 is not clear.
However, it can be explained by assuming the formation of tert-butyl radical (I)
(Scheme 2), which can decompose to give 2-methyl-1-propene (II). The intermediate
II can generate radical at allylic positions (path-a) and consequent coupling with I
gives hydrocarbon 1. The formation of 2 can be explained by generation of radical
III by coupling of I with II at vinylic position (path-b), which on homocoupling
gives hydrocarbon 2.
ZnBr
(I)
1
homocoupling(II)
(III)
2path-a
path-b
2
Scheme 2. Proposed mechanism for the formation of hydrocarbon 1 and 2
Allyl chloride and benzyl chloride were also reacted under the above
optimized conditions. Corresponding zinc reagents were obtained in good yield
(Table 3, entries 9 and 10).
70
To confirm the formation of the above described reagents, some of these were
reacted with carbonyl electrophiles. Thus, the reaction of BuZnBr⋅LiCl with benzoyl
chloride in the presence of CuCN⋅2LiCl20d provided 1-phenyl-1-pentanone (3) in
86% isolated yield (eq 2). Also the treatment of benzylzinc chloride with
benzaldehyde gave expected product 4 in good yield (eq 3).
BuZnBr LiCl
O
Cl +CuCN 2LiCl
THF−10 to 0 oC, 6 h
O
Bu
86% yield
3
O
H + 0 oC to RT, 6 h
OH
85% yield
4
PhCH2ZnCl LiCl PhTHF
(2)
(3)
2. Preparation of RZnX by transmetallation or ligand exchange
Organozinc halides also can be prepared by transmetallation31,32 that is,
reaction of RLi or RMgX with zinc halide. We have prepared EtZnCl⋅Mg(Br)Cl (5)
by stoichiometric reaction of RMgBr (R = alkyl) with ZnCl2 (eq 4). To study the
ligand effect in RZnX, we extended this method for the preparation of RZnOAc.
Thus, the reaction of EtMgBr with Zn(OAc)2 gave EtZnOAc⋅Mg(OAc)Br (6) with
more than 95% yield (eq 5). The yield was determined by iodometric titration. Using
this method, there is always formation of magnesium salts in stoichiometric amount
EtMgBr + ZnCl2THF
0 to 25 oC, 1 h(4)
EtMgBr + Zn(OAc)2THF
0 to 25 oC, 1 h(5)
Et2Zn + ZnCl2THF:hexane
25 oC, 1 h2 EtZnCl (6)
Et2Zn + Zn(OAc)2THF:hexane
25 oC, 1 h2 EtZnOAc (7)
EtZnCl Mg(Br)Cl
EtZnOAc Mg(OAc)Br
5
6
7
8
71
along with zinc reagent. To study the magnesium / lithium salt effect on the
reactivity of RZnX, we also prepared salt-free alkylzinc halides. The salt-free RZnX
(X = Cl, Br, I, OAc) can be prepared by reaction of R2Zn and ZnX2, the so called
“ligand exchange.”33 Thus ethylzinc chloride (7) and ethylzinc acetate (8) were
obtained by the reaction of diethylzinc with ZnCl233c and Zn(OAc)2
33d respectively
(eq 6 and 7) according to the literature procedures. All these reagents can be stored
for several days as a THF solution under inert atmosphere.
72
Section 2B
Enantioselective addition of RZnX to benzaldehyde
Enantioselective addition of diorganozinc reagents to carbonyl compounds
emerged as one of the powerful tools for the preparation of optically active alcohols.
Introduction of chiral heteroatom containing ligands to the zinc complex allows
facial differentiation in the addition of the alkyl group to carbonyl substrate. After
the first report of Oguni and Omi34 and pioneering work of Noyori and Soai,
numbers of ligand accelerated methods have been developed for the catalytic
enantioselective addition of dialkylzinc reagents to aldehyde. A majority of the
catalyst for this reaction were based on chiral β-amino alcohols.1 Our interest in this
field led us to study the reagent of type RZnX (X = Cl, Br, I, OCOR′) which have
been rarely studied. High covalent character and less Lewis acidity of zinc centre are
responsible for the poor reactivity of these reagents. The reactivity of these reagents
towards carbonyl substrates can be enhanced by, (i) substrate activation with Lewis
acid (Figure 2a), (ii) Reagent activation with Lewis base catalyst (Figure 2b). Lewis
acid coordinates with carbonyl oxygen resulting in increased electrophilicity of
carbonyl carbon. Organozinc halides (RZnX) have bent structure and differ
fundamentally from diorganozinc compounds (RZnR) which occur as monomers
with sp-hybridized linear geometry.35a Due to the presence of electronegative atom,
accepter character of zinc in RZnX is enhanced. This leads to association of
molecules and hence such compounds are always exists as dimers or higher
associates.35b Addition of nitrogen/oxygen containing ligand can break this
unreactive oligomeric association and provide reactive organozinc halides
monomeric species.
R' R''
O
Lewis Base
R' R''
O
Lewis acid
(a) (b)
ZnR X
YX
(c)
(tetrahedral complex)R-Zn-X
R-Zn-X
Figure 2
73
We presumed that a bidentate chelating agent can coordinate with zinc centre
and forms tetrahedral complex33a,36 (Figure 2c), resulting in enhanced metal-alkyl
bond polarity and hence increased nucleophilicity of the alkyl group. We have done a
systematic study on the reactivity of alkylzinc halides towards aldehyde by
examining various catalysts / chelating agent derived from N-Me ephedrine and
simple diols. These results are discussed below.
Results and discussion
For our present study, we chose simple chiral ligands (9−14) as shown in
figure 3.
Ph OH
NMe2Me
Ph OH
NHTsMe
OHPh
OHPh
O
O
OHOH
Ph Ph
Ph Ph
OHOH
N
OPh
PhMe
(1R,2S)-(−)-9 (1R,2S)-(−)-10
(R)-(+)-14
(2R,3S)-(−)-11
(1S,2S)-(−)-12 (4R,5R)-(−)-13
Figure 3
Preparation of catalysts
Several catalysts 15−24 (Figure 4) were prepared by the treatment of chiral
ligand with organometallic reagent. The change in the metal center (aluminum,
titanium, zinc, magnesium, lithium) provides change in Lewis acidities and also the
coordinating ability of nitrogen/oxygen atoms.
74
Ph O
NMeM
Ph O
NMeZn
Ts
O
O
OO
Ph Ph
Ph Ph
Al Cl
Ph O
NMeTi
Ts
OiPr
OiPr
Ph
OM
OM
Ph
M = Li 20 = MgBr 21
O
O
OMOM
Ph Ph
Ph Ph
M = Li 22 = MgBr 23
OMgBrOMgBr
24
15M = Li = 16M = MgBr = 17 18 19
Figure 4
Aluminum alkoxide 15 was prepared by the reaction of (−)-13 with Et2AlCl
(Scheme 3).
O
O
OHOH
Ph Ph
Ph Ph
(−)-13
Et2AlCl
toluene, RT, 1 h − 2 EtH
O
O
OO
Ph Ph
Ph Ph
Al Cl
15
Scheme 3. Preparation of catalyst 15
N-Me ephedrine derived alkoxides 16 and 17 were prepared by treatment of
(−)-9 with BuLi/EtMgBr (Scheme 4).
Ph OH
NMe2Me
n-BuLi, THF
0 oC to RT, 15 min.
EtMgBr, THF
0 oC to RT, 15 min.
(-)-9
Ph O
NMeLi
Ph O
NMeMgBr
16 17
Scheme 4. Preparation of catalyst 16 and 17
75
Catalysts 18 and 19 were prepared by the treatment of (−)-10 with diethylzinc
and Ti(OiPr)4 respectively (Scheme 5).
Ph OH
NHTsMe
(-)-10
8 0 oC, 30 min.
Et2Zn, toluene Ti(OiPr)4, toluene
0 oC to RT, 1 h
Ph O
NMeZn
Ts
19
Ph O
NMeTi
Ts
OiPr
OiPr
18
Scheme 5. Preparation of catalyst 18 and 19
Magnesium-dialkoxides 21, 23 and 24 were prepared by the treatment of
corresponding diols (12, 13 and 14) with 2 equivalent of EtMgBr (Scheme 6).
0 oC to RT, 15 min.
2 EtMgBr, THF OMgBr
OMgBr
*
OH
OH
*
12−14 21, 23, 24
Scheme 6. Preparation of magnesium-dialkoxides
Lithium-dialkoxides 20 and 22 were prepared by the treatment of n-BuLi
with corresponding diols (−)-12 and (−)-13 respectively (Scheme 7).
OHPh
OHPh
O
O
OHOH
Ph Ph
Ph Ph
(−)-13
orn-BuLi, THF
0 oC to RT, 15 min.20 or 22
(−)-12
Scheme 7. Preparation of lithium-dialkoxides
We then evaluated these catalysts for the addition of RZnX to benzaldehyde.
Alkylzinc halides (RZnX) are known to be weakly active nucleophiles.6b,37 Initially
we examined the reactivity of salt free RZnX 7 and 8 (prepared by ligand exchange
method, R = Et, X = Cl, OAc) with benzaldehyde in the presence of various
76
catalysts/chelating agent (Table 4). Without any additive, both the reagents 7 and 8
do not react with benzaldehyde (Table 4, entry 1). Similar kind of reactivity was
observed in the case of catalytic amount of Lewis acid catalyst 15 (entry 2). We then
examined N-Me ephedrine derived bifunctional catalysts 16 and 18. These catalysts
can play a dual role by acting as Lewis acids to activate the carbonyl substrate and
also as Lewis base to activate the zinc reagent38 (Figure 5). However the strategy did
not prove fruitful (entries 3 and 4).
N
O
R2
R1M
O
ZnXEt
PhH
Figure 5
We decided to examine next bidentate chelating agents. First we used
chelating agent like N-Me morpholine. But these reagents did not reacted with
benzaldehyde in the presence of catalytic or stoichiometric amount of N-Me
morpholine (entries 5 and 6). We then employed metal dialkoxides39 20 and 23
which are stronger chelating agent. Only starting material was recovered in both the
cases (entries 7 and 8). When the reaction of EtZnCl 7 was carried out in the
presence of one equivalent of MgCl2, alkylated product (25) was obtained in 31%
yield along with the formation of propiophenone (26) and benzyl alcohol (27) (entry
9). Origin of byproducts can be explained by Oppenauer oxidation40 of intermediate
zinc-alkoxide I (Scheme 8). The zinc reagent 8 also gave similar kind of results in
the presence of Mg(OAc)Br (entry 10). However other Lewis acids such as ZnCl2
and LiCl failed to provide the alkylated product (entries 11 and 12).
77
Table 4. Addition of EtZnX (X = Cl, OAc) to benzaldehyde
EtZnX + PhCHOTHF:Hexane
0 oC to RT, 24 hPh Et
OH
Ph Et
O
Ph OH+ +
25 26 27Salt free
(X= Cl, OAc)
Entry Catalyst (equiv) RZnXa Productb (%)
25 26 27
1 none EtZnCl or EtZnOAc <1 - -
2 15 (0.1) EtZnOAc <1 - -
3 16 (0.1) EtZnOAc <1 - -
4 18 (0.1) EtZnCl <1 - -
5 N-Me morpholine (0.1) EtZnCl or EtZnOAc <1 - -
6 N-Me morpholine (1.0) EtZnCl or EtZnOAc <1
7 20 (0.2) EtZnOAc <1 - -
8 23 (0.1) EtZnOAc <1 - -
9 MgCl2 (1.0) EtZnCl 31 19 20
10 Mg(OAc)Br (1.0) EtZnOAc 28 15 28
11 ZnCl2 (1.0) EtZnCl or EtZnOAc 1 - -
12 LiCl (1.0) EtZnCl or EtZnOAc <1 - - a Prepared from Et2Zn and ZnX2, (X= Cl , OAc). b Yields by GC analysis; remaining unreacted benzaldehyde.
PhCHO + EtZnX Ph
OZnX
O
ZnO
H
Ph
H
PhX
Ph
O
Ph OH+
PhCHO
(I)
26 27
Scheme 8. Proposed mechanism for the formation of byproducts 26 and 27
78
Above results suggest that the reaction is not a Lewis catalyzed one. Instead,
MgX2 in stoichiometric amount forms addition complex32f (Figure 6), which is
responsible for the reaction.
Zn
Cl
X
MgS
S
X
R Zn
OMg
O
O
X
Ac
R
S = solvent molecule
S
S
Figure 6
We also examined reactivity of RZnX⋅LiX (prepared by insertion method) in
the presence of various catalysts (Scheme 9). Only trace amount of expected product
was observed in all the cases.
RZnX LiCl + PhCHOcatalyst (10 mol%)
THF, 0 oC to RT, 24 h Ph R
OH
R = Me, Et (X= Br, I) trace
N
O
Me
O
O
OMgBrPh Ph
OMgBrPh Ph
Ph O
NMeTi
Ts
OiPr
OiPr
Ph O
NMeMgBr
Catalysts
17 19 23
Scheme 9. Reaction of RZnX⋅LiCl with benzaldehyde
Since MgX2 has role on the reactivity of RZnX, we next examined the
reactivity of the zinc reagents 5 and 6 in which stoichiometric amount of MgX2 is
present. In our initial experiment, the reaction of reagent 5 with PhCHO without any
additive gave only 11% 1-phenyl-1-propanol (25) in 4 h at 25 oC (Table 5, entry 1).
This suggested that the effect of MgX2 is not very pronounced.
79
Table 5. Addition of EtZnCl⋅Mg(Br)Cl to benzaldehyde
EtZnCl Mg(Br)Cl + PhCHOPh
OHcatalyst (10 mol%)
THF
Entry Catalyst
Temp (oC)
Time (h) Yield a (%) ee
1 none 0 to 25 4 11 -
2 11 0 to 25 16 63 <1
3 20 0 8 66 <1
4 21 0 8 62 <1
5 23 0 8 64 <1 a Isolated yields; remaining was PhCOCH2CH3, PhCH2OH and unreacted PhCHO.
We therefore proceeded to evaluate various dicordinating ligands for the
reaction. These were, chiral chelating agent like (2R,3S)-(−)-4-methyl-2,3-diphenyl
morpholine (11) and lithium/magnesium dialkoxides 20, 21 and 23. One equivalent
of 1,4-dioxane was added to reduce the Lewis acidic effect of Mg(Br)Cl. Although
good yields were obtained, negligible enantioselectivity was realized in all the cases.
One of the difficulties in handling the zinc halides is their hygroscopic nature.
We decided to use zinc acetate which is non-hygroscopic and can be a good
alternative to zinc halides. The zinc reagent EtZnOAc⋅Mg(OAc)Br (6), prepared by
the transmetallation of EtMgBr with zinc acetate, was reacted with benzaldehyde
without any additive. It revealed reactivity pattern similar to that of reagent 5. In the
presence of chiral chelating agent 11, expected product 25 was obtained in 18% yield
as a racemate (Table 6, entry 2). Interestingly, the reaction of 6 in the presence of
lithium-dialkoxide 22 provided 31% yield with 13% ee (entry 3). The corresponding
magnesium-dialkoxide 23 furnished 34% yield with 28% ee (entry 4). Our attempts
to isolate the reagent 6 were unsuccessful. To verify the formation of EtZnOAc from
EtMgBr and Zn(OAc)2, salt free zinc reagent 8 was reacted with benzaldehyde in the
presence of stoichiometric amount of Mg(OAc)Br (prepared by stoichiometric
reaction of EtMgBr with AcOH) (eq 8).
80
i) Mg(OAc)Br (1 equiv)
ii) 23 (10 mol%)iii) PhCHO, THF
8Ph
OH
(S)
33% yield, 25% ee
(8)
These results obtained were comparable to the results with the reagent 6. Also
the comparison of reactivity difference between the reagent 8 (Table 4, entry 8) and
reagent 6 (Table 6, entry 4) revealed that the presence of MgX2 was crucial. One of
the reasons for moderate selectivity was attributed to MgX2-promoted background
reaction.41 To overcome this problem, we added complexing agents like 1,4-dioxane
or TMEDA. However, this modification proved inconsequential (entries 5 and 6). By
changing the solvent from THF to methyl tert-butyl ether (MTBE), enantioselectivity
increased to 50% (entry 7). Enantiomeric excess was determined by chiral HPLC.
When the reaction was carried out at room temperature, the product was isolated in
60% yield but the enantioselectivity was dropped to 39% (entry 8). Similar results
were obtained when diethyl ether was used as the solvent (entry 9). Other
magnesium-dialkoxides 21 and 24 proved inferior to 23 (entries 10 and 11).
81
Table 6. Enantioselective addition of EtZnOAc⋅Mg(OAc)Br to benzaldehyde
EtZnOAc Mg(OAc)Br + PhCHO Ph
OHcatalyst (10 mol%)
(S)
Entry Catalyst Solventa Temp (oC) Time (h) Yield b (%) eec
1 none THF 0 4 29 -
2 11 THF 0 8 18 -
3 22 THF 0 8 31 13
4 23 THF 0 8 34 28
5 d 23 THF 0 8 37 18
6 e 23 THF 0 8 22 21
7 23 MTBE 0 8 44 50
8 23 MTBE 25 24 60 39
9 23 Et2O 25 24 54 38
10 21 MTBE 25 24 45 <5
11 24 MTBE 25 24 49 <1
a The reactions were carried out at 0.4-0.5 molar concentrations. b Isolated yields of the desired product. c Determined by comparison of optical rotation with known literature value or chiral GC / HPLC analysis. d One equivalent of 1,4-dioxane was added. e One equivalent of TMEDA was added.
Heterogeneous reaction mixtures result during the use of solvents other than
THF. After extensive optimization, it was found that by adding the Grignard reagent
to a suspension of zinc acetate and (−)-13 in THF, homogenous solution was
obtained at 0 oC. This reagent was then reacted with benzaldehyde to obtain 30%
yield of the product with 40% ee (Table 7, entry 1). We also studied the effect of
stoichiometry of Grignard reagent with respect to zinc acetate. It was found that the
rate of the reaction as well as enantioselectivity varied with the change in
stoichiometry. Best results were obtained when the ratio was 1:1 (entries 1, 2 and 3).
In the case of 1.2 equivalent EtMgBr (Table 7, entry 3), the excess Grignard reagent
can generate diethylzinc by reacting with preformed EtZnOAc. This hypothesis was
supported by addition of commercial diethylzinc to benzaldehyde, which gave
82
comparable results (eq 9). In terms of halide effect in RMgX, bromide and iodide
were found to be better than chloride (entries 4, 5 and 6). We also examined other
Grignard reagents under these conditions. n-Butyl and iso-butyl magnesium bromide
provided 13% and 16% enantioselectivity respectively (entries 5 and 7). In the case
of t-BuMgCl, no reaction took place at all.
Table 7. Enantioselective addition of various RZnOAc⋅Mg(OAc)X to benzaldehyde
a The stoichiometric ratio of RMgX:Zn(OAc)2:(−)-13:PhCHO was 1.7:1.5:0.1:1.0 respectively unless otherwise noted. b Isolated yields of the desired product. c ee Was determined by chiral GC or HPLC analysis. d 0.8 equiv. EtMgBr was added with respect to Zn(OAc)2.
e 1.2 equiv. EtMgBr was added with respect to Zn(OAc)2. f The reaction was carried out in THF:Et2O. g The starting material was recovered.
H
O
+ Et2Zn23 (10 mol%)
THF:Hexane 0 oC, 2 h
Ph
OH
(S)76% yield14% ee
(9)
83
Mechanism:
The difference in the selectivity showed by ligand (−)-13 compared to other
diols was attributed to the rigid backbone and the steric bulk due to phenyl rings
present in the molecule. At this stage a precise model which explains the outcome of
stereoselectivity using reagent 6 is not clear. However we presume that the oxygen
atoms of the metal alkoxide 23, EtZnOAc, BrMg(OAc), and PhCHO bind as
depicted in figure 7a. The resulting cyclic transition state could be responsible for
stereoselection. This would also explain the lack of enantioselectivity with the
reagent 5, which proceeds through MgX2-catalyzed acyclic pathway (Figure 7b).
O
O
Ph
Ph
O
O
M
Zn
Cl
R HPh
O
M = MgX
Ph
Ph
M
Mg(Br)Cl
(acyclic-TS)(cyclic-TS)
O
O
Ph
Ph
O
O
M
Zn
O
Et
O
Mg
Br
OAc
HPh
O
Ph
Ph
M
(a) (b)
Figure 7. Proposed mechanism for enantioselective alkylation
84
Section 2C
Organozincates and their enantioselective addition to
benzaldehyde
Addition of organozinc reagents to various organic electrophiles has become
one of the common methods to construct carbon-carbon bond. The preparation of
dialkylzincs2,31 and organozincates6a,32f,42 is well documented in the literature.
Diorganozinc reagents have sp-hybridized linear geometry (Figure 8a). Pure
dialkylzinc reagents react sluggishly with aldehydes and ketones. However, their
reactivity can be enhanced by incorporation by a third substituent like alkyl or
heteroatom containing ligand on zinc centre (Figure 8b). Richey et al.42f reported that
the treatment of alkali metal alkoxide with diethylzinc produces triorganozincates
species (R2ZnOR)M, which reacts rapidly with aldehyde and ketones. We envisaged
that introduction of two chiral alkoxides would form chiral-zincate species (Figure
8c) which can react enantioselectively with aldehyde. In this context, optically active
diols would be ideal ligands.
R-Zn-RR
ZnR
R'
R' = alkyl, OR''
(less reactive) (reactive)
RZn
OR**RO
R* = chiral alkyl group
(a) (b) (c)
Figure 8
We have prepared various chiral-zincates using optically active diols. The present
section deals with the results obtained in this study.
Results and discussion
In our initial study, we examined the reactivity pattern of alkylzincates
prepared from ZnX2 and RMgX. In the present work, alkylzinc reagents were
prepared by the reaction of ZnX2 (X = Cl, OAc) with n equivalent of EtMgBr (n = 2
and 3) (eq 10, 11 and 12).
85
2 EtMgBr + ZnCl2THF Et2Zn 2Mg(Br)Cl
X= Cl, OAc
(10)
3 EtMgBr + ZnX2THF
(12)[Et3Zn]MgBr
2 EtMgBr + Zn(OAc)2THF
Et2Zn 2Mg(OAc)Br (11)
The reaction of Et2Zn⋅2Mg(X)Br (X = Cl, OAc) with 0.9 equivalent
benzaldehyde proceeds quantitatively in 1 h at 0 oC (Table 8, entries 1 and 2). This
indicates the presence of magnesium salt (Mg(X)Br (X = Cl, OAc)) increases the
reactivity of diethylzinc reagent. In addition to this, we observed that there is
dramatic decrease in reactivity when Mg(X)Br is replaced by less Lewis acidic
Mg(OAc)2. It was done by the reaction of Zn(OAc)2 with two equivalent of EtMgBr
in the presence of excess NaOAc (Scheme 10). The treatment of in situ formed
reagent with benzaldehyde provided only 49% yield of the product.
2 EtMgBr + Zn(OAc)2 + 2.5 NaOAc
ii) PhCHO (0.9 equiv) 0 oC to RT, 24 h
i) THF 0 oC to RT, 4 h
Ph
OH
49% yield
Scheme 10
Next, the reagent prepared from two equivalent of EtMgBr with ZnCl2/Zn(OAc)2
was reacted with 1.9 equivalent benzaldehyde. After 1 h GC analysis revealed
formation of 73% product in both the cases (entries 3 and 4). These results indicate
that more than one equivalent32c,41 of alkyl group gets transferred, which can be
explained by scheme 11. When the mixture of ZnX2 (X = Cl, OAc) and 2EtMgBr
was equilibrated for longer time (16 h) at room temperature, approximately 50%
yield of the product was obtained in both the cases (entries 5 and 6). This difference
in the reactivity can be attributed to the formation of ate complexes I and II depicted
in eq 13 and 14 respectively. After longer stirring ate complex decomposes to give
Et2Zn, which can transfer only one alkyl group.
86
2 EtMgBr + ZnCl2THF
0 oC MgCl
ZnBr
Et
Et
ate complex-I
25 oC
overnightEt2Zn + 2Mg(Br)Cl (13)
2 EtMgBr+Zn(OAc)2THF0 oC
BrMg
O
OZnEt
Et
ate complex-II
25 oC
overnightEt2Zn + 2Mg(OAc)Br (14)
MgEt
ZnEt
3 EtMgBr + ZnX2
X = Cl, OAc
THFEt Br
ate complex-III
+ 2Mg(X)Br (15)0 oC
Table 8. Addition of ethylzincates to benzaldehyde
n EtMgBr + ZnX2 + PhCHOTHF
0 oC, 1 h Ph
OH
X = Cl, OAc
Entry n EtMgBr + ZnX2 [Temp (oC), Time (h)]a PhCHO
(equiv.)
Productb (%)
1 2 EtMgBr + ZnCl2 0−25, 1 h 0.9 94
2 2 EtMgBr + Zn(OAc)2 0−25, 1 h 0.9 quantitative
3 2 EtMgBr + ZnCl2 0, 0.5 1.9 73
4 2 EtMgBr + Zn(OAc)2 0, 0.5 1.9 73
5 2 EtMgBr + ZnCl2 0−25, 16 h 1.9 58
6 2 EtMgBr + Zn(OAc)2 0−25, 16 h 1.9 48
7 3 EtMgBr + ZnCl2 0, 0.5 2.9 78
8 3 EtMgBr + Zn(OAc)2 0, 0.5 2.9 86
a The mixture of EtMgBr and ZnX2 was stirred at mentioned temperature and time before the addition of aldehyde. bYields by GC analysis; remaining propiophenone benzyl alcohol and unreacted benzaldehyde.
We also studied the reactivity of trialkylzincates with benzaldehyde. In the
present study, the triethylzincate III was prepared by reacting ZnX2 (X = Cl, OAc)
87
with three equivalents of EtMgBr at 0 oC (eq 15). The reaction of III with 2.9
equivalent PhCHO gave 78% and 86% yield of the product in case of ZnCl2 and
Zn(OAc)2 respectively. These results indicate that more than two equivalents of alkyl
group can transfer in both cases. The possible explanation for the above results can
be that the ate complex III first reacts with one equivalent of PhCHO via a six-
membered42g TS-1 (Scheme 11) to give the expected product and Et2Zn. The
resulting ate complex I / II further react with 2nd equivalent of PhCHO via TS-2 and
gives product and EtZnX, (X = Cl or OAc). Finally EtZnX then reacts with 3rd
equivalent of PhCHO in the presence of Mg(X)Br via TS-3. From the above results it
can be concluded that the zincate species generated from ZnX2 and RMgBr can
transfer all the three alkyl groups to benzaldehyde. Based upon these findings we
planned to prepare optically active triorganozincates10b to achieve enantioselective
version.
MgEt
ZnEt
Et Br
ate complex-III
1st PhCHO Mg
Zn
BrO
PhH
EtEt
Et
TS-1
Ph
OMgBr+ Et2Zn
Mg(X)Br I (or II)
ate complex
2nd PhCHO Mg
Zn
BrO
PhH
EtX
Et
TS-2
Ph
OMgBr+ EtZnX
3rd PhCHO
Mg(X)Br
Zn
Et
MgXX Br
OH
PhTS-3
Ph
OH
Scheme 11. Possible mechanism for the transfer of all three alkyl group.
88
Enantioselective addition of organozincates to benzaldehyde
We anticipated that simple C2-symmetric chiral diols43 would serve as non
transferrable ligand and effective chiral inducer for this transformation. We chose
simple chiral diols such as (−)-12, (−)-13 and (+)-14 as chiral source. Diols are
known39f to form alkoxide 30 when reacted with diethylzinc at 80 oC (Scheme 12,
path-a). Alkoxide 30 also can be prepared from sodium/magnesium dialkoxide and
ZnCl2 (path-b and path-c respectively). The alkoxide 30 on treatment with
stoichiometric Grignard reagent would give chiral zincate complex-IV, which can
react with aldehyde enantioselectively.
OH
OH* + Et2Zn
Toluene
80 oC, 30 min.−2 EtH
O
OZn*
Chiral diol 30
OH
OH*
Chiral diol
ONa
ONa*
ZnCl2
THF
OH
OH*
Chiral diol
2 RMgXOMgX
OMgX*
ZnCl2
THF
Path-a
Path-b
Path-c
RMgX O
OZn R*
Chiral zincate complex- IV
MgXTHF
2 NaH
Scheme 12
In our initial study, zincate complex prepared from diol (−)-13 via path-b (or
path-c) on reaction with benzaldehyde gave desired product in low enantioselectivity
(Scheme 13). Increased enantioselectivity was realized when the chiral zincate-
complex was prepared using path-a. Therefore we prepared chiral zinc-alkoxides
30a, 30b and 30c (Figure 9) by heating the equimolar quantity of diethylzinc and
corresponding diols at 80 oC according to path-a in scheme 12.
89
i) 2 EtMgBr, THF
ii) EtMgBr, 0 oCiii) PhCHO, 0 oC, 2 h
Ph
OH
(S)
71% yield16% ee
(-)-13i) 2 NaH, THF
ii) EtMgBr, 0 oCiii) PhCHO, 0 oC, 2 h
Ph
OH
(S)
44% yield6% ee
Scheme 13
O
OZn
O
O
Ph PhO
OPh Ph
ZnPh O
OPh
Zn
30a 30b 30c
Figure 9
We then examined these in situ generated zinc-alkoxides (30a-c) in
enantioselective addition to benzaldehyde under different reaction conditions (Table
9). First we examined the zinc-alkoxide 30a. One equivalent of EtMgBr was added
to a suspension of 30a in toluene at oC. The resulting zincate complex was then
treated with benzaldehyde at 0 oC (Condition A). The product was isolated in 66%
yield with 24% ee (Table 9, entry 1). Low enantioselectivity was observed when
addition sequence of Grignard reagent and aldehyde was reversed (Condition B)
(entry 2). The enantioselectivity was increased substantially (to 50%) when the
addition was done simultaneously (Condition C) (entry 3). Lowering the temperature
from 0 to −78 oC diminished the enantioselectivity (entry 4). Less solubility of 30a at
low temperature promotes the direct addition of Grignard regent to aldehyde, which
could be the reason for lower enantioselectivity. The use of EtMgBr⋅LiCl (a
structurally different Grignard reagent44) did not help (entry 5). Poor
enantioselectivity was realized in the case of zinc-alkoxides 30b and 30c (entries 6
and 7).
90
Table 9. Enantioselective addition of chiral-zincates to benzaldehyde
O
OZn*
30a-c
PhCHO Ph
OH
(S)
EtMgBr THF:Toluene
Entry Alkoxidea Conditionb Temp (oC), Time (h) Yieldc (%) eed
1 30a A 0 2 66 24
2 30a B 0 2 72 9
3 30a C 0 2 59 50
4 30a C −78 to 0 2 64 2
5e 30a C 0 2 67 5
6 30b C 0 2 74 <1
7 30c C 0 2 69 6
a The ratio of zinc-alkoxide:RMgX:PhCHO was 1:1:1 respectively. b Condition A:
Grignard reagent was added to zinc-alkoxide and after 15 minutes benzaldehyde was added; Condition B: Benzaldehyde was added before the addition of Grignard reagent; Condition C: Grignard reagent and aldehyde were added simultaneously. cIsolated yields of the desired product. d Determined by comparison of optical rotation with known literature value. eEtMgBr⋅LiCl complex was added instead of EtMgBr.
91
Conclusions
We have found a simple procedure for the preparation of alkylzinc bromides
in THF by the use of LiCl as additive and I2 as activator. Using optimized
conditions, various alkylzinc bromides were prepared in good yields. We
have also prepared successfully alkylzinc acetates by transmetallation
method.
Salt-free RZnX exhibit poor reactivity towards benzaldehyde. Moderate
enantioselectivity was achieved in the case of TADDOL-magnesium
dialkoxide using RZnOAc as alkylating agent.
We have also observed that ate complex formed by the reaction of ZnX2 and
RMgX can transfer all alkyl groups to benzaldehyde. Moderate
enantioselectivity was realized in the case of TADDOL-zincate.
92
Experimental Section
General
All the solvents and reagents were purified and dried according to procedures
given in D. D. Perrin’s purification of Laboratory chemicals.45 Zinc dust (325 mesh)
was purchased from Sisco Research Laboratories, India. Diethylzinc was purchased
from Sigma-Aldrich chemical company. Benzaldehyde was freshly distilled before
use. THF was freshly distilled over sodium benzophenone ketyl. Anhydrous zinc
acetate was obtained by heating Zn(OAc)2.2H2O at 90 oC for 4 h under the reduced
pressure. All the reactions were performed in oven dried (120 oC) glasswares under
an argon atmosphere. Ligand 10 was prepared by reacting (1R,2S)-(-)-norephedrine
and p-toluenesulfonyl chloride following literature procedure.46a Diol 13 was
prepared according to the literature procedure.46b GC analysis was carried out using
HP-5 (30m x 0.25 m x 0.25 μ) column.
Preparation of organozinc halides by oxidative insertion using LiCl as additive
and I2 as catalyst.
The following procedure for preparation of n-BuZnBr⋅LiCl is representative (entry 2
in table-3)
To a 25 mL two-necked round bottom flask equipped with a stir bar and a
reflux condenser was added zinc dust (0.490 g, 7.5 mmol) and LiCl (0.233 g, 5.5
mmol). The mixture was heated at 150 oC for 1 h under high vacuum and cooled to
room temperature under argon. Anhydrous THF (5 mL) and I2 (0.063 g, 0.25 mmol)
were introduced in the flask and the mixture was stirred at room temperature for 15
minutes (red color of I2 disappears completely). n-Butyl bromide (0.53 mL, 5 mmol)
was then added and the reaction mixture was stirred at 50−55 oC for 18 h. The flask
was cooled to room temperature and mixture was allowed to settle for 1 h. The yield
of the zinc reagent was determined by iodometric titration.
Iodometric titration:
One mL of supernatant aliquot from the reaction mixture was transferred to
10 mL round bottom flask under argon atmosphere. To this, I2 (0.5 M solution in
benzene or THF) was added dropwise at 0 oC until solution becomes brown. The
93
amount of I2 consumed corresponds to one equivalent of alkylzinc halide.29
Calculation for total volume indicated 74% yield of the n-butylzinc bromide.
Reaction of butylzinc bromide with benzoyl chloride
A 50 ml two neck round bottom flask was charged n-BuZnBr⋅LiCl (6 mmol,
8.1 mL of 0.74 M solution in THF) and cooled to −10 oC. CuCN⋅2LiCl (6 mmol, 6
mL of 1 M solution in THF) was added to the solution. The resulting faint green
colored solution was stirred for 15 minutes. Then benzoyl chloride (0.58 mL, 5
mmol) was added dropwise over 5 minutes and the reaction mixture was allowed to
warm to 0 oC and stirred for 6 h. The reaction mixture was quenched cautiously by 2
mL saturated aqueous NH4Cl, acidified with 1N HCl and extracted with diethyl ether
(3 x 20 mL). The combined extract was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by “flash
chromatography” on silica gel (230-400 mesh) using ethyl acetate: petroleum ether
In a 25 mL two neck round bottom flask, anhydrous zinc chloride (0.654 g,
4.8 mmol) was dissolved in anhydrous THF (3.4 mL). The solution was cooled to 0 oC, treated with EtMgBr (4.8 mmol, 6.15 mL of 0.78 M solution in THF) dropwise
over 10 minutes. The resulting solution was stirred at 0 oC for 1 h. Ice bath was then
removed and reaction mixture was stirred for 1 h at room temperature to provide 0.5
M solution (by iodometric titration) of 5.
Preparation of EtZnOAc·Mg(OAc)Br (6)
To the suspension of anhydrous Zn(OAc)2 (2.75 g, 15 mmol) in anhydrous
THF (13.3 mL) was added EtMgBr (15 mmol, 16.66 mL of 0.9 M solution in THF)
dropwise at 0 oC over 10 minutes. Zinc acetate was dissolved within 10–15 min. and
solution became clear. Resulting solution was stirred at 0 oC for 1 h and then at room
temperature for 1 h to obtain 0.5 M solution (by iodometric titration) of 6.
96
Preparation of reagent (7) and (8)
To a solution of ZnCl2 (or Zn(OAc)2) (5 mmol) in 16.5 mL THF was added
diethylzinc (5 mmol, 3.44 mL of 1.45 M solution in hexane) dropwise at room
temperature over 5 minutes. The resulting clear solution was then stirred for 1 h to
obtain 0.5 M solution (by iodometric titration) of 7 or 8.
General procedure for the preparation of magnesium-dialkoxides (21, 23 and
24)
In a 10 mL round bottom flask containing magnetic stir bar and rubber
septum, the diol ((−)-12 or (−)-13 or (+)-14) (0.4 mmol) was dissolved in 2 mL
anhydrous THF. The solution was cooled to 0 oC and treated with EtMgBr (0.8
mmol, 0.84 mL of 0.95 M solution in THF). After 15 minutes ice bath was removed
and the mixture was stirred at room temperature for 15 minutes. The resulting
solution of magnesium-dialkoxides (21, 23 and 24 respectively) was used as it is for
alkylation step.
General procedure for the preparation of lithium-dialkoxides (20 and 22)
In a 10 mL round bottom flask containing magnetic stir bar and rubber
septum, the diol ((−)-12 or (−)-13) (0.22 mmol) was dissolved in 1.5 mL anhydrous
THF. The solution was cooled to 0 oC and treated with n-BuLi (0.44 mmol, 0.27 mL
of 1.6 M solution in cyclohexane). After 15 minutes ice bath was removed and
stirring was continued at room temperature for 15 minutes to obtain lithium-
dialkoxides 20 and 22 respectively.
Magnesium-dialkoxide catalyzed addition of EtZnCl·Mg(Br)Cl (5) to
benzaldehyde
The following procedure for the addition of EtZnCl·Mg(Br)Cl to benzaldehyde
catalyzed by 23 is representative (entry 5 in table-5).
To a 50 mL two necked round bottom flask was added EtZnCl·Mg(Br)Cl (5)
(4.8 mmol, 9.6 mL of 0.5 M solution in THF) followed by 1,4-dioxane (0.41 mL, 4.8
mmol) at 0 oC. After 15 minutes, the catalyst 23 (0.4 mmol, solution in THF) was
added. The resulting heterogeneous reaction mixture was stirred for next 10 minutes
and was treated with benzaldehyde (0.4 mL, 4 mmol). After 8 h at 0 oC, the mixture
was cautiously quenched with MeOH (1 mL), diluted with EtOAc (20 mL), washed
97
with saturated NH4Cl solution and dried over anhydrous Na2SO4. Evaporation of the
solvent followed by Kugelrohr distillation (150 oC, 0 torr) provided the product
contaminated with benzyl alcohol and unreacted benzaldehyde. The crude compound
was then purified by flash chromatography on silica gel (230-400 mesh) using ethyl
acetate: petroleum ether as the eluent to obtain 25 as an oil.
In 1999 Quirion et al.23a reported the preparation of 2,5-disubstituted
morpholine 20 starting from chiral epoxide 15 (Scheme 5). The O-protected amino
alcohol 14 was reacted with epoxide 15 in methanol at 40 °C to furnish amino
alcohol 16. Subsequent condensation of 16 with chloroacetyl chloride gave amide 17
which on cyclization using sodium hydride followed by deprotection of silyl group
provided lactam 18. Next, the amide enolate of compound 18 was generated by
treatment with sec-BuLi in the presence of HMPA which on treatment with MeI
provided alkylated product 19 with >95% diastereoselectivity. Compound 19 was
converted to morpholine 20 by reduction with LiAlH4 followed by removal of chiral
121
auxiliary under hydrogenation. This methodology was also applied for the
preparation of other chiral morpholines derivative by using various enantiopure
epoxides.
14
OTBDMS
NH2Ph
a NH
Ph
OTBDMS
OHR
N
OHR
bOTBDMS
O
Cl
Ph
O
N
R
OHPh
O
O
N
R
OHPh
O
MeO
N
R
H
Me
O
R
+
16 17
181920
15
c, d
ef
R = Ph, PhCH2OCH2
Scheme 5. Reagents and conditions: (a) MeOH, 40 oC, 78%; (b) ClCH2COCl, 50% aq. NaOH, THF, 76%; (c) NaH, THF, 90%; (d) TBAF, THF, 0 oC to RT, 96%; (e) sec-BuLi, HMPA, THF, −78 oC then MeI, 74%; (f) (i) LiAlH4, THF; (ii) H2, Pd/C, MeOH, 50%. In 2004 Myers et al.23b described the preparation of trans 2,5-disubstituted
morpholine. Treatment of epoxide (S)-21 with excess of D-alaninol 22 in n-propanol
provided exclusively monoalkylated product 23 (Scheme 6). Compound 23 on
treatment with p-toluenesulfonyl chloride gave N-tosyl diol 24, which was cyclized
to 25 using sodium hydride and p-toluenesulfonyl imidazole. Deprotection of N-tosyl
group using sodium in ethanolic ammonia provided desired morpholine derivative 26
in excellent yield.
122
O
TBSO
H
CH3HO
NH2
+
aTBSO
OHN
H
CH3
OH
33 b
TBSO
OHN
Ts
CH3
OH
3
O
NTs
TBSO3
CH3
O
NH
TBSO3
CH3
c
d
21
22
2324
2526
Scheme 6. Reagents and conditions: (a) n-PrOH, 97 oC, 99%; (b) p-TsCl, Et3N, DCM, 77%; (c) NaH, TsIm, THF, 99%; (d) Na, NH3, EtOH, 100%. In 2007 Bruening et al.23c reported one pot procedure for the preparation of
various optically active morpholine derivatives by the reaction of chiral β-amino
alcohols with optically pure epichlorohydrin. Initial investigation showed that
LiClO4 as Lewis acid and NaOMe as Lewis base proved better as compared to other
reagents. Thus, the reaction of chiral β-amino alcohol 27 with (S)-epichlorohydrin 28
furnished desired morpholine derivative 29 in moderate to good yield with excellent
stereoselectivity (Table 1).
123
Table 1. LiClO4 mediated one-pot preparation of morpholine derivatives
NHR1
OH
R
R2 +
O
ClLiClO4, toluene 20−50 oC
thenNaOMe, MeOH 20−50 oC
O
NR1
R2
R
OH
27a-f 28 29a-f
Entry 27 R R1 R2 Yield of 29 ee/de
1 a Bn H H 59 94
2 b Bn i-Pr H 63 >97
3 c Bn t-Bu H 60 >97
4 d Bn H Ph 77 >97
5 e Bn Me H 57 97
6 f Me H H 61 >97
1.3 From β-amino alcohol and alkenes
In 1993 Hayashi et al.24b reported Pd-BINAP catalyzed preparation of vinyl
morpholines. Initial screening of the phosphorous ligand showed that BINAP 32 was
proved the best ligand. Under the optimized conditions, treatment of protected
ethanol amine 30 with activated alkene 31 in the presence of chiral Pd-BINAP
catalyst provided optically active vinyl morpholine 33 with moderate
enantioselectivity (Scheme 7).
124
X
X
31
31a = X = OCOCH331b = X = OCO2CH331c = X = OCO2
tBu
OH
NHR
30
30a = R = CH2Ph30b = R = SO2C6H4-p-CH3
+Pd(0)/L*, THF
40 oC, 24 h
O
NR
32-64% yield50-61% ee
33a-b
PPh2
PPh2
(R)-BINAP (32)
*
L* =
Scheme 7. Pd-catalyzed enantioselective synthesis of 33
In 2000 Nishi et al.24c prepared morpholine derivative (R)-38, which is key
intermediate for tachykinin receptor antagonist, starting from alkene 35. In this
protocol, excess N-Boc-aminoethanol 34 was reacted with styrene derivative 35 in
the presence of N-iodosuccinimide in acetonitrile to obtain iodide 36 (Scheme 8).
Treatment of 36 with sodium hydride furnished N-Boc morpholine 37, which on
deprotection of both the triphenylmethyl (Tr) and Boc group by treatment with 4N
HCl provided racemic 38 in good yield. Morpholine 38 was resolved using D-(−)-
tartaric acid to obtain (R)-38 with high optical purity.
Pyroglutamic acid and (+)-O-acetyl mandelic acid for the resolution of cis-2,3-
diphenyl morpholine. The salt obtained from (−)-menthoxyacetic acid, (−)-mandelic
acid and (−)-glutamic acid failed to crystallize due to gummy nature. (−)-
Pyroglutamic acid or (+)-O-acetyl mandelic acid provided resolution, but needed
multiple crystallizations which resulted in low yield (Table 3, entries 1 and 2).
Finally the resolution of (±)-79 was accomplished through sequential use of L- and
D-tartaric acid. It was observed that stoichiometry of the resolving agent affects the
yield as well as enantiomeric excess. A ratio of 1:1 did not provide any resolution at
all (Table 3, entry 3). When (±)-79 and L-(+)-tartaric acid were used in 1:0.5 ratio,
(−)-79 and (+)-79 were isolated in 39% and 42% yields with 94% and 72% ee
respectively (entry 4). Best results were obtained with the ratio 1:0.25 (entry 5). This
proportion separates (−)-79 as salt leaving (+)-79 in solution. Optically enriched and
free amine (+)-79 was then purified through the salt of D-(−)-tartaric acid.
141
Table 3. Resolution of 79 by using various chiral acids.
N
OPh
PhH
(±)-79
Resolving agent(−)-79 + (+)-79
Entry Resolving agent equiv. (−)-79 (+)-79
Yield
(%)
ee
(%)
Yield
(%)
ee
(%)
1 (−)-pyroglutamic acid 1 19 >99 - -
2 (+)-O-Acetyl mandelic acid 1 33 >99 - -
3 L-(+)-tartaric acid 1 - a - a
4 L-(+)-tartaric acid 0.5 39 94 42 72
5 L-(+)-tartaric acid 0.25 36 99 - -
6 D-(−)-tartaric acid 0.25 - - 43 >99 a Racemic 79 was obtained.
In an optimized protocol, (±)-79 and L-(+)-tartaric acid (0.25 equiv) were
mixed in ethanol and stirred overnight (Scheme 26). Evaporation of the solvent
followed by addition of diethyl ether and filtration gave tartarate salt.
Recrystallization of crude salt from ethanol provided pure L-tartarate salt in 36%
yield [mp 181-184 oC, [α]25 D ─19.0 (c 0.42, MeOH)]. Basification of the salt using
aqueous NaOH gave (−)-79 ([α]25 D −77.2 (c 2.59, CHCl3)). The (+)- enantiomer was
obtained from mother liquor by similar treatment with D-(−)-tartaric acid. The
obtained crude salt after recrystallization from ethanol provided D-tartarate salt in
43% yield [mp 182-185 oC, [α]25 D +19.7 (c 0.44, MeOH)], which on basification
provided (+)-79 ([α]25 D +76.4 (c 2.59, CHCl3)). Both the enantiomers were obtained
in good yields and high enantiomeric purity after single crystallization of the
corresponding tartarate salts. Optical purity of both the enantiomers was found to be
≥99% by chiral HPLC. Solvent played crucial role in the resolution process as
revealed by the fact that racemic 79 was obtained when the salt was prepared in
methanol.
142
solid salt
filtrate
1. recrystallization
2. aq. NaOH, DCM(2R, 3S)-(−)-79
36%, 99% ee
(±)-79
1. L-(+)-Tartaric acid (0.25 equiv.) EtOH
2. Et2O
1. D-(-)-Tartaric acid2. recrystallization
3. aq. NaOH, DCM(2S, 3R)-(+)-79
43%, >99% ee
N
OPh
PhH
Scheme 26. Resolution of cis-2,3-diphenyl morpholine 79
3.2. Resolution of (±)-80
To resolve the corresponding racemic trans-2,3-diphenyl morpholine 80, first
we examined L-(+)-tartaric acid. However, we could isolate only one enantiomer in
very low yield with 95% enantiomeric excess. Success was achieved using (−)-
mandelic acid as the resolving agent (Scheme 27). The diastereomeric salt was
prepared by mixing the acid and racemic 80 in methanol. However we could not
(R)-(−)-mandelic acid diastereomeric salt (DS)
(±)-80
filtrate
aq. NaHCO3, DCM (2S, 3S)-(−)-80
39%, 92% eepreferentialprecipitation
1.recrystallization
2. aq. NaHCO3, DCM(2R, 3R)-(+)-80
44%, >99% ee
MeOH
(DS)iso-propanol
precipitate
N
OPh
PhH
+
Scheme 27. Resolution of trans-2,3-diphenyl morpholine 80
separate the diastereomeric salts by crystallization. Gratifyingly, the preferential
precipitation26c method resulted in clean separation. The resulting solid was dissolved
in boiling isopropanol and then stirred at room temperature for 2 h followed by
filtration gave solid salt in 39% yield [mp 175-177 oC, [α]25 D −116 (c 1, MeOH)]. The
purified salt after basification gave (−)-80 (39% yield, [α]25 D −100 (c 2, CHCl3)). The
143
mother liquor from the aforementioned resolution process was evaporated to dryness
and the solid was crystallized from ethyl acetate [44% yield, mp 150-151 oC, [α]25 D
+32 (c 1, MeOH)]. The basification of the salt provided (+)-80 (44% yield, [α]25 D
+102 (c 2, CHCl3)). Enantiomeric purity was determined by chiral HPLC. We
observed higher specific rotation for cis- as well as trans-isomers as compared to the
known values reported in literature27a (see experimental section for details).
4. Application of 2,3-diphenyl morpholines in enantioselective diethylzinc
addition
The enantioselective addition of Et2Zn to aldehydes is one of the most
intensely investigated carbon-carbon bond forming reactions and serves as a test for
new ligands. A variety of ligands such as chiral amino alcohols, amino thiols, amino
disulfides, amino diselenides, diamines and diols, for the asymmetric diethylzinc
addition reactions have been reported.8 Among these chiral β-amino alcohols are
most used ligands. Previously our research group26a had reported conceptually
different and efficient catalytic system viz zinc-amide, derived from oxazolidines
(Scheme 28). In this method, catalyst 91, prepared from oxazolidine ligand 90,
efficiently catalyzed the addition of diethylzinc to benzaldehyde to give (S)-1-
phenyl-1-propanol 92 with high enantioselectivity.
NH
OPh
Ph Et2Zn, Toluene
80 oC, 30 min.
Et2Zn, PhCHOPh
OH
85% yield> 99% ee
(S)-92N
OPh
Ph
ZnEttoluene, 0 oC
(10 mol%) 91
90
Scheme 28. Enantioselective diethylzinc addition catalyzed by chiral zinc-amide
In the proposed mechanism, zinc atom in 91 activates the aldehyde. Due to
steric bulk around oxygen atom, the diethylzinc molecule coordinates to the nitrogen
atom of the catalyst 91 and both the zinc centre becomes tri-coordinate as shown in
figure 4. Transfer of ethyl group from diethylzinc molecule gives enantiopure
alcohol.
144
We anticipated that morpholine based catalytic system would be more
efficient due chelation of both heteroatoms to zinc centre. Both the heteroatoms
(oxygen and nitrogen) in morpholine ligand can co-ordinate with diethylzinc and
forms a tetra-coordinate zinc centre, which could have enhanced nucleophilicity as
compared to tri-coordinate zinc (Figure 5).
NEtZn Zn Et
O
Ph
EtH
O
PhPh
(tri-coordinate zinc centre)
N O
Ph
Zn
EtO
PhH
EtZn Et
Ph
Figure 5Figure 4
(tetra-coordinate zinc centre)
We examined both the ligands 79 and 80 for the addition of diethylzinc to
benzaldehyde. The results obtained are described below.
Present work
Results and discussion
Chiral zinc-amide was prepared in situ by heating the mixture of diethylzinc
and chiral morpholine ligand [(−)-79 or (−)-80] at 80 oC for 30 minutes according to
the literature procedure.26a Treatment of diethylzinc with benzaldehyde in the
presence of above prepared catalyst (10 mol%) provided alcohol (S)-92. In the case
of (−)-(79), although good yields were obtained only moderate enantioselectivity was
realized (Table 4, entries 1 and 2).
145
Table 4. Enantioselective addition of Et2Zn to benzaldehyde
N
OPh
PhH
i) Et2Zn, Toluene 80 oC, 30 min.
Ph
OH
N
OPh
PhZnEt
PHCHO
toluene:Hexane
(S)-92
(−)-79 or (−)-80
Entry Ligand
(10 mol%)
Temp. (oC) Time (h) Yielda (%) eeb (%)
1 (−)-79 0 8 68 40
2 (−)-79 25 4 86 36
3 93 25 2 85 29
4 (−)-80 25 24 73 12 a Isolated yield. b Determined by chiral GC analysis.
We have also examined lithium amide 93. Catalyst 93 was prepared by the reaction
of (−)-(79) with BuLi (eq 2). However this modification did not help (entry 3) either.
Trans isomer (−)-80 proved inferior to corresponding cis-isomer.
N
OPh
PhH
toluene-hexane0 oC to RT, 15 min.
N
OPh
PhLi
n-BuLi
(−)-79 93
(2)
At this stage we are unable to provide reason for low enantioselectivity.
However, one of the reasons for moderate results can be explained by intramolecular
coordination of zinc centre to the oxygen atom (Figure 6), which results in the
reduced reactivity of the catalyst.
N O
Ph
Zn
Ph
Et
Figure 6
146
Section 3B
Attempted resolution of 2,3-diphenylbuatane-2,3-diol
Introduction
Chiral diols are an important class of organic compounds in asymmetric
synthesis because of their applications in various asymmetric transformations. A
variety of chiral 1,2-, 1,3-, and 1,4-diols have been used as chiral auxiliaries, chiral
ligands as well as chiral building blocks in asymmetric synthesis.7 Presence of C2
symmetry axis within the chiral auxiliary / ligand is advantageous, serving the very
important function of reducing the number of possible diastereomeric transition
states to achieve high level of asymmetric induction.7a Consequently synthesis of C2
symmetric chiral diols has been of deep interest. In continuation of our work on
asymmetric catalysis,26 we wanted to explore sterically more demanding C2
symmetric chiral diol such as 2,3-diphenylbuatane-2,3-diol 94 (Figure 7) in
asymmetric synthesis. As described in section-2 of the chapter-2, moderate
enantioselectivity was realized for the enantioselective addition of RZnOAc to
benzaldehyde. We anticipated that use of bulky diol such as 94 will be more effective
for the above transformation.
MePh
PhMe
OH
OH
94
Figure 7
Various methods are available in the literature for the synthesis of C2-
symmetric chiral diols. These methods include resolution, asymmetric
dihydroxylation, asymmetric reduction, enantioselective Pinacol coupling and other
synthetic transformations.7a
In 1959 Cram et. al.34 reported the synthesis of enantiopure (−)-94 (eq 3). In
this method, the treatment of chiral ketone (−)-95 with methylmagnesium iodide at 0 oC gives mixture of (−)-94 and corresponding meso-isomer, which upon repeated
crystallization provided enantiopure (−)-94 in 20% yield.
147
MePh
OHO
Ph
MeMgI, Et2O
0 oC, 5 h
(−)-95
20% yield
(3)
PhMe
MePh
OH
OH
(−)-94
To the best of our knowledge, the resolution of 94 is not known in the
literature. The chiral resolution method is advantageous because it provides both the
enantiomers in a single step. The resolution of diols could be accomplished through
diastereomeric esters, or ketals, borate esters and inclusion complexes.7a,35 Tertiary
diols are sensitive to strong acidic as well as basic conditions. Therefore, last two
methods would be more suitable for the resolution of 94 because of the mild reaction
conditions. We examined various resolving agents for the resolution 94. The results
obtained are described below.
1. Attempted resolution of dl-94 through addition complex
The resolution of diol through formation of diastereomeric addition complex
(also called inclusion complex) is a very simple and preferred method. In this
method, the formation of diastereomeric addition complex between diol and the
resolving agent through hydrogen bonding favors the resolution. During 1980’s Toda
et al. have done pioneering work in this area and variety of inclusion complexes of
diols (host compounds) with various organic guest compounds such as alcohols,
ketone, amine, amides, xylene, benzene, CCl4, CHCl3 etc. were reported.36 The X-ray
crystal analysis of these complexes showed that the host and guest molecules are
associated with each other through hydrogen bond formation and van der Wall’s
interactions.37
Some important literature reports for the resolution of diol through addition
complex are described below.
In 1975 Cripps et al.38 reported the resolution of prefluoro(2,3-
diphenylbuatane-2,3-diol 96 using (−)-cinchonidine 97 as the resolving agent.
Treatment of diol 96 with 97 in CHCl3:hexane gave 1:1 adduct (Scheme 29).
Repeated crystallization of residue followed by treatment with aqueous hydrochloric
acid provided (+)-96. While (−)-96 was obtained from mother liquor. No details for
the yield and optical purity are mentioned.
148
N
HO NH
cinchonidine
C6F5
F3C
F3CC6F5
OH
OH
(±)-96 (−)-97
+ (+)-96 + (−)-96
CHCl3:hexane RT, 3 days
Scheme 29. Resolution of diol 96 using cinchonidine
In 1988 Toda et al.39a reported the resolution of BINOL 98 using (+)-2,3-
dimethoxy-N,N,N',N'-tetramethylsuccinamide 99 as the resolving agent (Scheme 30).
In this procedure, racemic 98 was treated with (+)-99 in benzene:hexane solvent to
give mixture of diastereomeric addition complex. Precipitated complex on
recrystallization furnished pure complex of (−)-98 with (+)-99. X-ray
crystallographic analysis39b of this complex showed presence of hydrogen bonds
between carbonyl oxygen of 99 and OH-hydrogen of 98. The silica gel column
chromatography of this complex provided (−)-98 with high optical purity. While (+)-
98 was obtained from filtrate. Using similar strategy, diols 100 and 101 (Figure 8)
were resolved using resolving agents 102 and 103 respectively. Later in 2004 Zhou
et al.39c reported the X-ray crystal structure obtained from (+)-101 and 103.
OMeMe2N
O OMeNMe2
O
OH
OH(±)-98
(+)-99
benzene:hexane
RT, 12 h
precipitate
i) crystallizationii) silica gel chromatography
(−)-98
36% yield100% ee
filtrate
i) silica gel chromatographyii) (−)-99
iii) crystallizationiv) silica gel chromatography
(+)-98
29.5% yield100% ee
+
Scheme 30. Resolution of 98 using (+)-99
149
OMe(C6H11)2N
O OMeN(C6H11)2
O
OH
OH
(±)-100
(+)-102
OH
OH
(±)-101
O
O
O
CONMe2
O
CONMe2
(+)-103
Figure 8
In 1990 Kawashima et al.40a reported the resolution of 98 using (1R,2S)-(−)-
1,2-diamino cyclohexane 104. In this method, heating the mixture of racemic 98 and
(–)-104 in benzene forms diastereomeric addition complex (Scheme 31). Separation
of these complexes by filtration and recrystallization from benzene followed by
treatment with aqueous hydrochloric acid provided both the enantiomers of 98 in
good yield with high enantiomeric excess.
(±)-98
NH2
NH2
(1R,2R)-(−)-104
+benzene:hexane
heat
i) crystallizationii) aq. HCl
(+)-98
43% yield 94% ee
filtrate
i) crystallizationii) aq. HCl
(−)-98
42% yield 96% ee
precipitate
Scheme 31. Resolution of 98 using (−)-104
In 1991 the same author40b extended the above methodology for the
resolution of various aliphatic 1,2-diols. Racemic trans-cyclohexane-1,2-diol 105
was resolved in moderate ee by using (−)-104 as the resolving agent (Scheme 32).
150
OH
OH
trans-(±)-105
+ (−)-104
i) benzene, heatii) filtration followed by silica gel chromatography
OH
OH
36.4% yield67% ee
(-)-105
Scheme 32. Resolution of aliphatic diol using (−)-104
Using this method, diols 106, 107, 108 (Figure 9) were also resolved with
good enantiomeric excess.
OH
OH
trans-(±)-106
OH
OH
threo-(±)-107
Ph OH
OHPh
threo-(±)-108
Figure 9
In 1993 Toda et al.41a reported the use of cihchonidium halide salt 109
(Figure 10) as the resolving agent for the resolution of diols. In this protocol, the
N
HO NH
R X
109
109a = R = PhCH2, X = Cl109b = R = n-Bu, X = Br
Figure 10
mixture of racemic 98 and N-benzyl cinchonidium chloride 109a at room
temperature gave diastereomeric complex (Scheme 33). The X-ray analysis study of
resulting diastereomeric complex showed hydrogen bonding between chloride anion
of 109a and OH-hydrogen of 98 (O-H---Cl, bond distance 3.1−3.2 Ao).41b
151
(±)-98 + 109aMeOH, RT
Diastereomeric complexes
i) aq. HClii) crystallization
(+)-98
30% yield100% ee
filtrate aq. HCl
(−)-98
62% yield42% ee
precipitate
Scheme 33. Resolution of 98 using 109a
(+)-Enantiomer of 98 was obtained in good yield with very high enantiomeric purity
by usual separation method. However, corresponding (−)-isomer was obtained from
mother liquor with moderate ee. Author also resolved diol 100 with high optical
purity using 109b as the resolving agent.
One of the disadvantage of the above method was only one enantiomer was
obtained with high enantiomeric purity. Later in 1995 Cai et al.41c described
improved procedure for the resolution of 98. The key success in this method was
selection of suitable solvent. In the modified procedure, heating the mixture of
racemic 98 and 109a (0.55−0.6 equiv) in acetonitrile under reflux gives complex-I
and (−)-98 (Scheme 34). Treatment of complex-I with aqueous hydrochloric acid
provided (+)-98 with >99% ee, whereas (−)-98 was obtained from mother liquor in
good yield with high enantiomeric purity.
(±)-98109a (0.55−0.6 equiv)
CH3CN, reflux(+)-98 109a + (−)-98
complex-I
aq. HCl
(+)-98
>99% ee
>99% ee
Scheme 34. Modified procedure for the resolution of 98 using 109a
152
Present work
Results and discussion
Various methods are available in the literature for the preparation of diol 94.
42-44 We have prepared dl-94 by manganese mediated pinacol coupling of
acetophenone (Scheme 35), according to the method of Rieke et al.44a Treatment of
anhydrous MnCl2 with lithium metal in the presence of catalytic amount of
naphthalene gave black slurry of highly reactive manganese (Mn*). The reaction of
in situ prepared Mn* with acetophenone gave mixture of dl- and meso isomers in the
ratio of (70:30) in 95% yield. The ratio was determined by 1H NMR by comparison
of the δ value of methyl protons with the literature.44g Recrystallization of the
mixture from ethyl acetate / petroleum ether provided pure dl-94 in 49% yield with
>99% diastereomeric excess.
MnCl2 + Li + Naphthalene
(cat.)RT, 3 h
THFMn*
Highly reactive manganese
Ph Me
O
dl-94
49% yield>99% de
MePh
PhMe
OH
OH
MePh
PhMe
OH
OH
MePh
MePh
OH
OH+
dl meso70:30
recrystallization
(95% yield)
Scheme 35. Preparation of dl-94
Next, we examined various resolving agents for the resolution of 94 (Table
5). Initially we tried (−)-104 as resolving agent. The 1:1 complex of racemic 94 and
(−)-104 was prepared by boiling the mixture in benzene (or toluene). We tried
various solvent for the separation of the addition complex (Table 5, entry 1). For
example, in the case of benzene and cyclohexane, the complex did not crystallize /
precipitate. In petroleum ether formation of gummy mass was observed. We then
tried mixture of pet ether:diethyl ether as the solvent. In this case the complex
became soluble and did not crystallize / precipitate at all. We could not isolate the
addition compound in any of the case. Changing the ratio of diol and (−)-104 from
153
1:1 to 2:1 did not help, racemic diol was recovered (entry 2). Similar kind of results
were obtained in the case of other resolving agents such as (1S,2S)-(−)-1,2-
diphenylethane-1,2-diamine 110 (Figure 11), (−)-cinchonidine 97 and (+)-cinchonine
111.
Table 5. Attempted resolution of 94 using various resolving agents
dl-94
MePh
PhMe
OH
OH(+)-94 + (−)-94
Resolving agent x
Entry Resolving agent
Ratio Solvent Result
1 (−)-104 1:1 Benzene or cyclohexane Pet ether Per ether:Et2O
Complex was highly soluble. Gummy mass formation which does not crystallizes. Complex was soluble at RT, no crystallization at −10 oC.
2 (−)-104 2:1 Toluene Pet ether
Complex was highly soluble. Racemic diol was obtained.
3 (−)-110 1:1 Toluene Pet ether or Et2O or PE:Et2O
Complex was highly soluble. Racemic diol crystallize out.
4 (−)-110 2:1 Toluene Toluene:PE
Complex was highly soluble. Racemic diol precipitates out.
5 (−)-97 1:1 Toluene or THF or CHCl3:PE or CHCl3:CH3CN
Cinchonidine precipitates out.
6 (+)-111 1:1 Toluene or THF or CHCl3 EtOH
Mixture was not soluble even at boiling condition Cinchonine precipitates out.
a Ratio of (±)-94 with resolving agent.
154
N
HO NH
cinchonine
(+)-111
Ph NH2
NH2Ph
(−)-110
Figure 11
The reason for the unexpected results was attributed to the formation of weak
hydrogen bonding between diol and the resolving agents. We thought that formation
well defined covalent complex between diol and the resolving agent would provide
the resolution. For this purpose we planned the resolution through formation of
borate complex.
2. Resolution of dl-94 through chiral borate complex
The resolution through borate ester is an attractive method for the preparation
of enantiomerically pure diols due to easy formation or cleavage of boron-oxygen
bond.
In 1996 Shan et al.45a reported the resolution of 98 using quinine 113 as the
resolving agent. In this method, the reaction of racemic 98 with borane-dimethyl
sulfide complex in diethyl ether gave binaphthol borane 112 which upon treatment
with 113 gave diastereomeric borate esters. Hydrolysis of these esters furnished (−)-
98 and (+)-98 in good yield with high enantiomeric purity (Scheme 36).
155
(±)-98H3B.SMe2
aq. HCl(−)-98
41% yield100% ee
filtrate aq. HCl
(+)-98
39% yield100% ee
precipitate
Et2O
O
OB H
N
HO N
MeO
Quinine 113
113
THF
112
Scheme 36. Resolution of 98 through borate ester using 113
The same author45b in 1998 described resolution of 98 using boric acid and
(S)-proline (Scheme 37). In this protocol, the mixture of racemic 98 and boric acid
was refluxed for several hours with simultaneous azeotropic removal of water to
obtain binaphthol boric anhydride 114. It was then treated with excess (S)-proline in
THF under reflux to give binaphtholboric acid-(S)-proline complex 115a and 115b,
which upon treatment with sodium hydroxide followed by aqueous hydrochloric acid
provided (+)-98 and (−)-98 respectively in good yield with high enantiomeric purity.
O
OB O2 (±)-98 + 2 B(OH)3
O
OB
Toluene
azeotropic distillation
(S)-prolineTHF, reflux
O
OB
O
N
O
HO
OB
O
N
O
H
+
i) aq. NaOHii) aq. HCl
(−)-98
39.5% yield100% ee
(+)-98
37% yield100% ee
i) aq. NaOHii) aq. HCl
115a 115b
114
Scheme 37. Resolution of 98 using boric acid and (S)-proline
156
In 1999 Periasamy et al.46a described the resolution of 98 using boric acid and
(+)-1-phenylethyl amine 116 (Scheme 38). In this method, the mixture of diol 98,
boric acid and amine (+)-116 was refluxed in acetonitrile to give diastereomeric
borate complex. Author observed that the precipitated and mother liquor borate
complex have different solubilities in acetonitrile and THF, which helped in the
separation of both the enantiomers of 98 with high optical purity.
(±)-98 + B(OH)3 Ph NH2
Me
(R)-(+)-116
+
i) CH3CN, reflux
(−)-98
35% yield>99% ee
filtrate
i) THF, reflux
(+)-9826% yield>99% ee
precipitate
Reflux
CH3CNii) aq. HCl
ii) aq. HCl
(1 equiv) (0.5 equiv) (1.5 equiv)
Scheme 38. Resolution of 98 using boric acid and (+)-116
X-ray crystallographic analysis of the borate complex obtained from mother liquor
revealed that it was a Bronsted acid-amine complex 117 (Figure 12).
O
OB
O
O
Ph NH3
Me
117
Figure 12
Later in 2001 the same author46b described the resolution of aliphatic diol
using boric acid and (S)-proline (Scheme 39). In this protocol, first mixture of (S)-
proline and boric acid was refluxed in benzene (or toluene) for 12 h to give complex,
which on treatment with racemic 2,3-diphenylbutane-1,4-diol 118 under reflux for 12
h furnished diastereomeric borate esters. Precipitated borate complex gave (+)-118 in
157
moderate yield with excellent enantiomeric purity. While borate ester obtained from
filtrate gave (−)-118 with moderate ee.
N COOH
H
i) toluene or benzene reflux, 12 h
Ph OH
OHPh
reflux, 12 h
ii) then,
B(OH)3
+
i) THF, aq. HCl
(−)-118
12-18% yieldUp to 98% ee
filtrate
(+)-118
26-30% yieldUp to 57% ee
precipitate
i) THF, aq. HCl
(±)-118
ii) crystallization
ii) column chromatography
Scheme 39. Resolution of 118 using boric acid and (S)-proline
Present work
Results and discussion
Initially we tried the resolution of dl-94 by using chiral amine (+)-116 and
boric acid. In this experiment, the mixture of dl-94 (2 equiv), boric acid (1 equiv) and
(+)-116 (3 equiv) in acetonitrile was refluxed for 12 h with simultaneous removal of
water by azeotropic distillation (Table 6, entry 1). But the complex formed was
highly soluble
Table 6. Resolution of dl-94 through borate complex
Entry Resolving agent Solvent Result
1 (+)-116 Acetonitrile no resolution
2 (−)-phenyl glycinol Toluene no resolution
3 (S)-proline Toluene (−)-94, 29% yield
30% ee
in acetonitrile and did not precipitated / crystallized at all. We then examined (−)-
phenyl glycinol as the resolving agent. In this case first mixture of diol and boric acid
in toluene was refluxed for 3 h with simultaneous azeotropic removal of water.
Complete dissolution of boric acid indicated the formation of borate complex. The
158
resulting complex was then treated with phenyl glycinol under reflux for 3 h to give
diastereomeric borate complex. We tried various solvent for the separation of this
mixture. For example, in toluene and THF or mixture of solvents like THF:hexane or
hexane:ethyl acetate, the diastereomeric mixture was highly soluble. In the case of
hexane, formation of gummy mass was observed, which does not crystallized.
Finally, we could achieve partial resolution of dl-94 by using (S)-proline as the
resolving agent (Scheme 40).
(S)-Proline
+ B(OH)3(i) Toluene, Reflux, 12 h
(ii) dl-94, toluene reflux, 12 h
precipitate-1+ filtrate
precipitate-1
precipitate-2
filtrate
THF, RT, 24h
3N aq. HCl:THF(−)-94
29%, 30% eeRT, 4 h
N COOH
H
Scheme 40. Resolution of 94 using (S)-Proline and boric acid
First, the mixture of boric acid and (S)-proline was refluxed in anhydrous toluene for
12 h with simultaneous azeotropic removal of water. TLC of the reaction mixture
showed that proline has reacted completely. The resulting complex was then treated
with dl-94 under reflux for 12 h. Filtration of the reaction mixture gave precipitate-1,
which was washed with THF to obtain borate ester (precipitate-2) in 37% yield [mp
263−268 oC (dec.), [α]26 D −8 (c 0.5, EtOH)]. Treatment of precipitate-2 with 3N
hydrochloric acid followed by column chromatographic purification provided (−)-94
in 29% yield with 30% ee.
159
Summary:
We have synthesized and resolved all the four stereoisomers of 2,3-diphenyl
morpholine in good yields and high optical purity using tartaric acid and
mandelic acid.
These ligands were examined for enantioselective addition of diethylzinc to
aldehyde and moderate enantioselectivity was realized.
Partial resolution of 2,3-diphenylbutane-2,3-diol could be accomplished
through a chiral borate complex.
160
Experimental Section General
All the solvents and reagents were purified and dried according to procedures
given in D. D. Perrin’s purification of Laboratory chemicals.47 Diethylzinc was
purchased from Sigma-Aldrich chemical company. Benzaldehyde was freshly
distilled before use. All the reactions were performed in oven dried (120 oC)
glasswares. The reactions were monitored by TLC using silica gel 60 F254 pre-coated
plates. The products were purified by column chromatography on silica gel (100−200
or 230−400 mesh). All melting points were recorded on a Büchi B-540 electro
thermal melting point apparatus and are uncorrected. Optical rotations were
measured on Bellimheam+Standley ADP220 digital polarimeter. IR spectra were
recorded on a Shimadzu FTIR-8400 spectrophotometer. 1H spectra were recorded at
200 MHz with TMS as internal standard. 13C NMR spectra were recorded at 50 MHz
with CDCl3 (δ = 77) as the reference. Micro analytical data were obtained using a
Carlo-Erba CHNS-0 EA 1108 elemental analyzer. Ligand (−)-10448a and (−)-phenyl
glycinol48b were prepared according to the literature procedures. GC analysis was
carried using HP-5 (30m x 0.25 m x 0.25 μ) column. Chiral HPLC was performed
using Kromasil-5-Amycoat column (250 x 4.6 mm).
(±)-Erythro-2-amino-1,2-diphenylethanol (81)
Ph OH
NH2Ph
(±)-81
A solution of racemic α-benzoin oxime 87 (11.36 g, 50 mmol) in methanol
(130 mL) was hydrogenated at room temperature and at 50 psi pressure using 10%
Pd/C (0.5 g) for 6 h. Usual work-up28b provided crude solid 10.13 g (95%).
Recrystallization of the solid from methanol gave racemic erythro-2-amino-1,2-
Determination of enantiomeric excess for chiral 2,3-diphenyl
morpholines
(±)-79
N
OPh
PhH
(−)-79
N
OPh
PhH
>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; major isomer: tR = 7.76 min; minor isomer tR = 9.34 min.
189
(+)-79
N
OPh
PhH
>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; minor isomer: tR = 8.10 min; major isomer tR = 9.04 min.
(±)-80
N
OPh
PhH
190
(−)-80
N
OPh
PhH
92% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; minor isomer: tR = 9.06 min.; major isomer tR = 10.32 min.
(+)-80
N
OPh
PhH
>99% ee Kromasil-5-Amycoat column; i-PrOH:PE:TFA (20:80:0.1); 0.5 mL/min.;
220 nm; major isomer: tR = 8.68 min; minor isomer tR = 10.77 min.
191
X-ray Data (Collection, Structure Solution and Refinement)
Single crystal X-ray studies were carried out on a Bruker SMART APEX
single crystal X-ray CCD diffractometer with graphite-monochromatized (Mo
Kα?= 0.71073Å) radiation. The X-ray generator was operated at 50 kV and 30
mA. Diffraction data were collected with ω scan width of 0.3° at different
settings of ϕ (0°, 90°, 180° and 270°) keeping the sample-to-detector distance
fixed at 6.145 cm and the detector position (2θ) fixed at -28°. The X-ray data
acquisition was monitored by SMART program (Bruker, 2003). All the data
were corrected for Lorentzian and polarization effects using SAINT programs
(Bruker, 2003). A semi-empirical absorption correction based on symmetry
equivalent reflections was applied by using the SADABS program (Bruker,
2003). Lattice parameters were determined from least squares analysis of all
reflections. The structure was solved by direct method and refined by full
matrix least-squares, based on F2, using SHELX-97 software package.
(Sheldrick, G. M. Acta Cryst. 2008, A64, 112). Molecular diagrams were
generated using ORTEP-32 (Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565).
192
cis-5,6-diphenylmorpholin-3-one (85)
ORTEP diagram for 85
Crystal data table for compound 85
Empirical formula C16 H15 NO2 Formula weight 253.29 Temperature (K) 293(2) Wavelength (Å) 0.71073 Crystal system, Space group monoclinic, P21/c Unit cell dimensions a = 9.346(12) Å, α = 90°.
b = 5.483(7) Å, β = 104.64(4)°. c = 26.74(3) Å, γ = 90°.
Volume 1326(3) Å3 Z, Calculated density 4, 1.269 Mg/m3 Absorption coefficient 0.084 mm-1 F(000) 536 Crystal size 0.94 x 0.05 x 0.04 mm Theta range for data collection 2.25 to 25.00°. Limiting indices -10<=h<=11, -6<=k<=6, -31<=l<=31 Reflections collected / unique 11825 / 2330 [R(int) = 0.1109] Completeness to theta = 25.00° 99.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9967 and 0.9253
Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2330 / 0 / 176 Goodness-of-fit on F2 0.982 Final R indices[I>2sigma(I)] R1 = 0.0556, wR2 = 0.0990 R indices (all data) R1 = 0.1338, wR2 = 0.1179 Largest diff. peak and hole 0.141 and -0.161 e.Å-3
193
cis-1-(2,3-diphenylmorpholino)ethanone (89)
ORTEP diagram for 89
Crystal data table for compound 89
Empirical formula C18 H19 NO2 Formula weight 281.34 Temperature (K) 297(2) Wavelength (Å) 0.71073 Crystal system, Space group Triclinic, P-1 Unit cell dimensions a = 8.950(4) Å, α = 84.580(7)°.
b = 12.098(5) Å, β = 82.993(7)°. c = 14.211(6) Å , γ= 81.209(7)°.
Volume 1504.9(10) Å3 Z, Calculated density 4, 1.242 Mg/m3 Absorption coefficient 0.081 mm-1 F(000) 600 Crystal size 0.66 x 0.37 x 0.06 mm Theta range for data collection 2.85 to 25.00°. Limiting indices -10<=h<=10, -14<=k<=14, -16<=l<=16 Reflections collected / unique 14533 / 5282 [R(int) = 0.0290] Completeness to theta = 25.00° 99.5 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9952 and 0.9487 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5282 / 0 / 381 Goodness-of-fit on F2 1.046 Final R indices[I>2sigma(I)] R1 = 0.0437, wR2 = 0.0973 R indices (all data) R1 = 0.0580, wR2 = 0.1058 Largest diff. peak and hole 0.148 and -0.131 e.Å-3