触媒的環化反応 有機金属化学第10回oec.chembio.nagoya-u.ac.jp/PDFs/2017_OrgMet/10_handout.pdfScheme 6 Scheme 7. The efficient RCM-based synthesis shown is due to Fürstner

触媒的環化反応 2017年度 有機金属化学第10回

最初の例(量論反応)Pauson-Khand反応 ([2+2+1]付加環化反応)

Pauson, P. L.; Khand, I. U., Ann. N. Y. Acad. Sci. 1977, 295, 2-14.

Co Co

C CPh H

COOCOC

COCOCO

(OC)4Co Co(CO)4+

HPh–2CO

H2C CH2Ph

O

初期の触媒反応の例

Rautenstrauch, V.; Mégard, P.; Conesa, J.; Küster, W.Angew. Chem. Int. Ed. Engl. 1990, 29, 1413-1416.

Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.Foreman, M. I., J. Chem. Soc., Perkin Trans. 1 1973, 977-981.

ホスフィン添加で効率向上＆不斉化

Ts N

Co2(CO)8, 20 mol%(S)-BINAP, 20 mol%

80 °C, 1 atm CONTs O

H

54% yield94% ee

PPh2PPh2

(S)-BINAP

Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I.Tetrahedron Asym. 2000, 11, 797-808.

N

OAc

1) Co2(CO)82) NMO, H2O3) Pd/C, H2

OAc

N

H

HHO

O

NHH

O(–)-dendrobine

Cassayre, J.; Zard, S. Z., J. Am. Chem. Soc. 1999, 121, 6072-6073.

アルカロイド合成への応用

最初の例アルキン三量化反応 ([2+2+2]付加環化反応)

OH

OH

HO

Ni(CO)2(PPh3)2

HO

OH

OH +

HO

OH

OH

Reppe, W.; Schwecknediek, W. J.Justus Liebigs Ann. Chem. 1948, 560, 104-116.

nBu

MeOMeO

nBu

Ni(cod)2/PPh3 nBu

nBu

MeO

MeO

ヘリセン合成への応用

Teplý, F.; Stará, I. G.; Starý, I.;Kollárovič, A.; Šaman, D.;Rulíšek, L.;

Fiedler, P., J. Am. Chem. Soc. 2002, 124, 9175-9180.

NTs CO2MeNTs

[Rh(cod)]2BF4 (5 mol%)(S,S)-bdpp (5 mol%)

(S,S)-bdpp87%, 92% ee

Ph2P PPh2

軸不斉シクロファン合成への応用

Araki, T.; Noguchi, K.; Tanaka, K.Angew. Chem. Int. Ed. 2013, 52, 5617-5621.

カルベン錯体の反応最初の報告 Rh触媒シクロプロパン化の反応機構

触媒的不斉シクロプロパン化

Simmons, H. E.; Smith, R. D., J. Am. Chem. Soc. 1958, 80, 5323-5324.

CH2I2, Zn(Cu)

R

R’

ICH2

ZnI

R

R’H2CI ZnI

up to 70%

Fischer, E. O.; Dötz, K. H., Chem. Ber. 1970, 103, 1273-1278.

(OC)5Cr CO

Ph

Me+Me

CO2MeCO2Me

Me PhOMe

N

有機金属錯体を用いる最初の報告

O

OR

N2

CO2Me

Ph

+Rh cat. (1 mol%)

CO2Me

Ph84% yield84% ee

–78 °C

OO

N

H

O

O Rh

Rh

C12H25 4

O

OR

O

OR

O

OR

Rh

Rh

Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.;Fall, M. J., J. Am. Chem. Soc. 1996, 118, 6897-6907.

Nowlan, D. T.; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A.J. Am. Chem. Soc. 2003, 125, 15902-15911.

NEWG

RN N

EWG

RN

RhN

EWG

RN Rh

EWG

RRh

R’ EWG

RRhR’

R’EWGR

Rh

NN

Cl Cl

ClCl

CuOTf, 10 mol%

11 mol%

O

+N ITs Ph –78 °C

O

NTs75% yield

98% eeLi, Z.; Conser, K. R.; Jacobsen, E. N.J. Am. Chem. Soc. 1993, 115, 5326-5327.

nitrene transferによる触媒的アジリジン化

カルベン錯体の反応：オレフィンメタセシス

Banks, R. L.; Bailey, G. C.Ind. Eng. Chem. Prod. Res. Dev. 1964, 3, 170-173.

H.S. Eleuterio , Ger. Pat. 1960, 1072811.

MoO2/Al2O3/LiAlH4

AliBu3/MoO2/Al2O3

+

+

+ isomers

+ isomers

42% 55%

2%

++ isomers

1%

“unsaturated polymer”

最初の報告

G. Natta, G. Dall'Asta, I. W. Bassi, G. Carella, Makromol. Chem., 1966, 91, 87-106.

WCl6/EtAlCl2n

P. J. L. Hérisson, Y. Chauvin, Makromol. Chem., 1971, 141, 161-176. J.-P. Soufflet, D. Commereuc, Y. Chauvin, C. R. Hebd. Seances Acad. Sci. Série C, 1973, 276, 169-171.

RR1

R1

M

R1R1

M

R1 R1

M

R1

M

反応機構

Yves Chauvin Nobel Prize 2005

Schrock, R. R., J. Am. Chem. Soc. 1974, 96, 6796-6797.

TaCl

CltBu tBu

tBu Li tBu2

H tBu–Ta

tBu

tBu

tBu

CtBu

H

Cl tBuLi

Richard Schrock Nobel Prize 2005

構造の明確なアルキリデン錯体の合成

Murdzek, J. S.; Schrock, R. R., Organometallics 1987, 6, 1373-1374.

MoC

ClClO

O Cl

tBuNH

iPriPr

Me3Si

Mo

C

ClClO

O

tBu

N DipH OLi

CF3CF3

MoC

O

OtBu

NDip

H

F3C CF3

F3C CF3

Robert Grubbs Nobel Prize 2005

Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. Engl. 1995, 34, 2039-2041.

官能基許容性の高いRu錯体

Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.

(Ph3P)2RuCl2

CN2Ph

H

Ru

PCy3

PCy3

CCl

Cl H

Ph

1st generation

1)

2) PCy3

N N MesMesH OtBu

Ru

PCy3

CCl

Cl H

Ph

2nd generation

NN MesMes

カルベン錯体の反応：オレフィンメタセシスの応用反応形式の分類

R1R2+

R1

R2

+

+

n

n

R2R1

R1CR12R2

+R1 R2

R1 R2

cross metathesis (CM)

ring-closing metathesis (RCM)

acyclic dienemetathesispolymerization (ADMET)

ring-opening metathesispolymerization (ROMP)

eneyne metathesis(EYM)

ring-openingcross metathsis(ROCM)

7

Scheme 6

Scheme 7. The efficient RCM-based synthesis shown is due to Fürstner in his approach to balanol.10

Scheme 8. The example of the formation of a dicarba-analogue of a disulfide β-turn by RCM was disclosed by Grubbs.11

Fürstner, A.; Thiel, O. R., J. Org. Chem. 2000, 65, 1738-1742.

複雑天然物合成への応用

Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E., Nature 1997, 387, 268.

8

Scheme 9. Solid phase synthesis used by Nicolaou in the syntheses epothilone A and its various derivatives. A RCM cyclization/cleavage strategy is used.12

Scheme 10. An efficient CM with allylic stereocontrol observed with a substituted allylic amine.13

Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda, A. H., Nature 2011, 471, 461.

varying amounts of 6 (see Supplementary Information for details).The latter studies established that, although fewer equivalents of 6lead to reduced Z selectivity and competitive homocoupling, with5 equiv. of the inexpensive and commercially available enol ether,8a can be obtained in 93:7 Z:E selectivity and 71% yield (7% homo-coupled product). Excess enol ether 6 does not complicate productisolation, as this inexpensive reagent is volatile and can be easilyremoved in vacuo.

Z-Disubstituted enol ethers are obtained in 57–77% yield throughexceptionally stereoselective (94% to .98% Z) CM with Mo alkylidene1a (Fig. 2). Alkyl- (8) or aryl-substituted (10) Z enol ethers as well asthose that bear a carboxylic ester (8c), a secondary amine (8e), a brom-ide (10b) or an alkyne (10c) are readily accessed. Reactions with themore electron-deficient enol ether 9 and the relatively electron-richalkenes proceed with 2.0 equiv. of the aryl-substituted enol ether; incontrast, 10 equiv. of alkyl-substituted and easily removable 6 arerequired for similar efficiency. Such variations probably occur becausewhen 9 is used there is a better electronic match3 between the Mo-alkylidenes derived from the cross partners and either of the twoalkenes, favouring CM versus homocoupling. Only 1.2 mol% 1a and2.0 equiv. of the p-methoxyphenylenol ether (for example, 10a, 10b and10d, Fig. 3c) are sufficient for an effective and exceptionally Z-selectiveCM to take place.

Synthesis of natural product C18 (plasm)-16:0 (PC)Next, we set out to demonstrate the utility of the catalytic CM process bya diastereo- and enantioselective synthesis of an anti-oxidant plasmalo-gen phospholipid, C18 (plasm)-16:0 (PC) (Fig. 2)16,17, the correspond-ing E isomer of which has been shown to be less active17. This initiativerequired addressing a challenge that is of general concern in catalyticCM: the inefficiency associated with the use of excess of one crosspartner. The enol ether to be used (11) in the CM step is more valuablethan the commercially available and inexpensive 1-octadecene (12 ),rendering utilization of excess amounts of the former unfavourable.Reducing the enol ether concentration diminishes efficiency andZ-selectivity, as detailed above and substantiated by the data inTable 2 (85% and 47% conversion with 5:1 and 1:1 11:12 ; entries 1versus 2). Larger quantities of the less valuable 12 could improve yieldand selectivity, as Mo-methylidene concentration is probably loweredthrough its reaction with excess alkene. However, increased amounts ofan aliphatic alkene, unlike an enol ether, give rise to homocoupling andethylene generation. Ethylene, in addition to being detrimental to therate of CM (because it competes with the substrates for reaction with theavailable alkylidene), causes diminished stereoselectivity by increasingmethylidene concentration, which promotes Z alkene isomeriza-tion (see above). We thus surmised that, if the negative effects of thegenerated ethylene were to be attenuated by performing the reaction

11 (1.0 equiv.)

12 (2.0 equiv.)

H17C8 On-Bu

8b76% conv., 68% yield,

98% Z

On-Bu

8c76% conv., 73% yield,

98% Z

OPhO On-Bu( i-Pr)3SiO

8d86% conv., 77% yield,

94% Z

On-BuPhHN

8e57% conv., 51% yield,

>98% Z

OPMPBr

10a71% conv., 57% yield,

>98% Z

10b74% conv., 70% yield,

>98% Z

10c66% conv., 59% yield,

>98% Z

Cy OPMP

10d81% conv., 75% yield,

>98% Z

Bn OPMP OPMPMe3Si ( ) 6( ) 6

15

N

Ph Ph

SONO

O

i-Pr

i-Pr

i-Pr

a H33C16 O

1485% overall yield,

>98% ZH33C16

OSi( i-Pr)3

b

H33C16

O OHOH

1664% yield,

98:2 e.r., >98% Z

H33C16

O OO

C15H31

O

C18 (plasm)-16:0 (PC)

PO

O

O

NMe3

Four steps

86% overall yield(see ref. 12)

On-Bu

6(10 equiv.)

O

9 OMeor

1.2–5.0 mol% 1a

C6H6, 22 °C, 2 h

G G O On-Buor

G OMe

8 10(2.0 or 10 equiv.)

Figure 2 | Z-selective CM reactions of enol ethers with terminal alkenes andapplication to stereoselective synthesis of C18 (plasm)-16:0 (PC). Various Zenol ethers are synthesized with 1.2–5.0 mol% of Mo complex 1a, and typicallyrequire 2.0 equiv. (in the case of p-methoxyphenylvinyl ether) or 10.0 equiv.(with butylvinyl ether) of the terminal enol ether; excess butyl vinyl ether (6) iseasily removed in vacuo. The desired Z alkenes are obtained in 51–77% yieldand in 94% to .98% Z selectivity. Application to synthesis of C18 (plasm)-16:0(PC) demonstrates the utility of the Z-selective Mo-catalysed CM, which is usedin conjunction with a site- and enantioselective Cu-catalysed dihydroborationof the terminal alkyne in 14 (see Supplementary Information for details). Allreactions shown were performed under N2 atmosphere; catalysts were prepared

and used in situ. Conversions and Z selectivities were determined by analysis of400 MHz 1H NMR spectra of unpurified mixtures; the variance of selectivityvalues is estimated to be ,62%. Yields of isolated products are shown (65%).Reactions: for 8b–8e, we used 2.5 mol% 1a and 10 equiv. 6; for 10a, 10b, weused 1.2 mol% 1a and 2.0 equiv. 9 ; for 10c, 10d, we used 5.0 mol% 1a and 10equiv. (10c) or 2.0 equiv. 9 (10d). See Supplementary Information forexperimental details. Conditions for synthesis of 16. Route a, step 1; 2.5 mol%1a, C6H6, 22 uC, 2.0 h, decalin, 1.0 torr: step 2; 5.0 equiv. (n-Bu)4NF, THF,22 uC, 2 h. Route b; 2.5 mol% 15 , 2.5 mol% CuCl, 20 mol% NaOt-Bu, 2.1 equiv.bis(pinacolato)diboron, 3.0 equiv. MeOH, THF, 0 uC, 24 h; 30% H2O2, NaOHin aqueous THF, 1.0 h.

ARTICLE RESEARCH

2 4 M A R C H 2 0 1 1 | V O L 4 7 1 | N A T U R E | 4 6 3

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Z-Selective cross-metathesis of enol ethersWe began by evaluating the ability of stereogenic-at-Mo complexes topromote transformations of enol ethers, a class of substrates for whicha CM reaction has not been previously reported (E-or Z-selective); theresulting products have proven to be of utility in chemical synthesisand can be found in biologically active molecules (see below). In thepresence of 2.5 mol% 1a, CM between 6 and 7 (entry 1, Table 1)proceeds to 85% conversion to afford disubstituted enol ether 8a in98% Z selectivity and 73% yield. With 1b, which bears a more sizeable2,6-di-i-propyl-arylimido unit, the reaction is completely Z-selective(.98% Z) but 47% conversion is achieved within the same time span.When alkylidene 2 is used, CM proceeds to 37% conversion and

.98% Z-8a is generated; further transformation is not observed aftersix hours. Mo-based diolate 3 and Ru carbene 5 do not promote CM,and achiral Mo complex 4 catalyses a non-selective transformation(47.5% Z). Thus, stereogenic-at-Mo complexes prove to be effective inpromoting enol ether CM, and although 1b or the less hindered 2 alsoafford exceptional stereoselectivity, neither delivers the efficiency of1a. The 2,6-dimethylphenylimido 1a therefore offers the best balancebetween activity and stereoselectivity. Such performance variationsmay be observed because catalyst turnover is slower with the moresizeable 1b whereas the methylidene of the relatively unhindered 2(compare IV, Fig. 1) might suffer from a shorter life span. Consistentwith the above scheme, 82% 8a is formed when CM with 1b is allowedto continue for 16 hours; in contrast, conversion with 2 after 10 minutesor two hours is nearly identical (,38%).

There are several, mechanistically revealing, reasons for use of excessenol ether. CM generates a Mo-methylidene; this unhindered alkyli-dene can readily react with the Z-alkene product, reverse CM, causeequilibration and lower stereoselectivity. An enol ether reacts with amethylidene complex, circumventing diminution in Z selectivity. Themore stable alkoxy-substituted alkylidene, generated from reaction of amethylidene complex and an enol ether (I in Fig. 1 with R1 5 On -Bu),can undergo productive CM, giving rise to longer catalyst lifetime andimproved turnover numbers. Furthermore, generation of the afore-mentioned alkoxy- or aryloxy-containing alkylidene means less ofthe alkyl-substituted derivative is formed and homocoupling of thealiphatic alkene is minimized. Owing to electronic factors, productivereaction between an enol ether-derived alkylidene and anotherO-substituted alkene is disfavored2. However, as use of excess enolether is wasteful, we decided to examine the efficiency of the CM with

Z-Selective cross-metathesis of terminal alkenes

G1

G2

Catalyst

G1 G2

G1

G2

G1 G1

G1

G2

G2

G2

Cross-metathesisproducts

Homocouplingproducts

Z alkeneshigher in energy

than correspondingE alkenes

G2

G1

Catalyst-induced kinetic controlis required for

stereoselective Z-alkene synthesis(vs substrate-induced thermodynamic control)

Rotating and largemonodentate aryloxide

ligand generates a significant steric presence

Mo

O Br

TBSO

Br

NN

R1

R2

Mo

O

N

R1

R2BrTBSO Br

N

R1

1a R = Me 1b R = i-Pr

Mo

O Br

TBSO

Br

NPh

N

Mo

O Br

TBSO

Br

N Ph

2

Ru

Oi-Pr

NMesMesN

Cl

Cl

i-Pr i-Pr

CF3

F3 C

Mo

N

F3 C OO

F3 C

4 53

Mo

N

Br

TBSO

Br

NR2 R1

OR1 R2

N

Mo

OBr

OTBSBr

N

I II III IV

Mo

N

i-Pr i-Pr

OO

N

R R

Ph Ph

Rotationaround

Mo–O bond

R2

Figure 1 | A catalytic CM reaction can afford as many as six alkenes, so thechallenge is designing an efficient process that favours formation of thecross products. Particularly difficult is the development of a process thataffords the higher-energy Z alkene predominantly. To accomplish a Z-selectiveCM, a variety of catalysts were considered, such as stereogenic-at-Mocomplexes (1, 2 ) or other previously reported Mo- and Ru-based complexes

(3 –5 ). The structural flexibility of the stereogenic-at-metal complexes 1 and2 can give rise to exceptional reactivity, and free rotation around the Mo–Obond of these alkylidenes might serve as the basis for development of highlyZ-selective olefin metathesis reactions of terminal alkenes. The sphererepresents an appropriate size imido substituent.

Table 1 | Examination of various catalysts for CM with an enol ether

Entry no. Complex Time Conv. (%)* Yield (%){ Z:E*

1 1a 2 h 85 73 98:22 1b 2 h 47 ND .98:23 2 2 h 37 ND .98:24 3 2 h ,2 NA NA5 4 10 min 80 ND 47.5:52.56 5 24 h ,2 NA NA

The reactions were carried out in purified benzene under an atmosphere of nitrogen gas; 10 equiv. of 6was used (see Supplementary Information for details). NA, not available; ND, not determined.*Conversion (conv.) and Z:E ratios were measured by analysis of 400 MHz 1H NMR spectra ofunpurified mixtures; the variance of values is estimated to be ,62%.{Yield of isolated product after purification; the variance of values is estimated to be ,65%.

7Ph

2.5 mol%Mo or Ru complex

C6 H6 , 22 °C

Bn On-BuOn-Bu

6 8a

RESEARCH ARTICLE

4 6 2 | N A T U R E | V O L 4 7 1 | 2 4 M A R C H 2 0 1 1

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Z-選択的クロスメタセシス

触媒的C‒H結合官能基化触媒的C–H結合官能基化

C–H結合官能基化の熱力学

C–H結合切断メカニズム

C H C [M]

C CC OC NC BC halogen

C‒H 結合の活性化段階に金属 (M) が関与し， C‒M 結合を有する中間体を経由して進行する触媒反応．

∆G° (kcal/mol)in gas phase

–16

–30

+5

–11

+10

–10

H

H

:C OO

H

:C OO

+

H

SiMe3

H SiMe3+ H H

H

SiMe3+ H H

H SiMe3 +

O

O

C OO

H

+10

– HX

– HX

– HO2CR

[M] H

[M]H

[M]H

[M]H

[M]

X

[M]H

X

[M] O

OH

R

O[Ru] [Ru]

O

H[Ru]

O

HH

Oxidative Addition (OA)M = Ru0, RhI, IrI, Ni0

Concerted Metallation Deprotonation (CMD)M = PdII, RuII

Electrophilic Aromatic Substitution (SEAr)M = PdII; X = OC(O)R, halogen

Nucleophilic Aromatic Substitution (SNAr)M = Ru0

σ-Bond Metathesis (SBM)M = RhIII, IrIII; X = B

[M]

H3C[M]

H H3C[M]

H

H3C[M]

HX

– HX

H3C H

– HX

H3C[M]

HX

[M] O

OHH3C

R – HO2CRH3C

[M]

sp2炭素

sp3炭素Oxidative Addition (OA)M = Ru0, RhI, IrI

σ-Bond Metathesis (SBM)M = RhIII; X = B

Electrophilic Substitution (SE)M = PtII; X = solvent

Concerted Metallation Deprotonation (CMD)M = PdII

thanks to prof. Nakao@Kyoto

触媒的C‒H結合官能基化芳香族化合物の触媒的アルケニル化(SEAr経由)

+

90%

cat. Pd(0/II)

oxidant

Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166-7169.

[Pd+2]

[Pd+2]R1

[Pd+2]

EWG

R1

[Pd0]

EWGR1

EWG+ HX

[O]

R1 = (het)Ar, alkenyl, alkylX = halogen, OR3

[O] = oxidant

CMDor

SEAr

R1–H

H–X

XX

X

X

Pd(OAc)2 (2 mol %)BQ (1.0 equiv)TsOH (0.5 equiv)AcOH, 20 °C, 15 h

H

HN

91%

+ CO2BuO

Me

HN

O

Me

CO2BuBoele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M., J. Am. Chem. Soc. 2002, 124, 1586-1587.

応用例

RuH2(CO)(PPh3)3 (1 mol %)toluene, reflux, 0.5 h

+

H

O Si(OEt)3

Si(OEt)3

OH

100 mmol 110 mmol 92–96%

芳香族化合物の触媒的アルキル化(OA or SNAr経由)

Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N., Nature 1993, 366, 529-531.

H

Br PdCl2 (5 mol %)AgOTf (1.0 equiv)DMF, 90 °C, 2 h

+

56%CO2Me

HN

O

HN

O

CO2Me

求電子剤とのカップリング

Zaitsev, V. G.; Daugulis, O., J. Am. Chem. Soc. 2005, 127, 4156-4157.

H

I

Cl

Pd(OAc)2 (2.5 mol %)Cs2CO3 (2.0 equiv)DMF, MS4A, 110 °C, 21 h

+

72%

OH

Ar

OH

Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M., Angew. Chem. Int. Ed. Engl. 1997, 36, 1740-1742.

F

H

Br

Pd(OAc)2 (5 mol %)(t-Bu)2MeP•HBF4 (10 mol %)K2CO3 (1.3 equiv)

+98%DMA,120 °C, 12 hMe

FF

FF

F

Ar

FF

FF

Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K., J. Am. Chem. Soc. 2006, 128, 8754-8756.

反応機構

thanks to prof. Nakao@Kyoto

触媒的C‒H結合官能基化[Ir(OMe)(cod)]2 (1.5–5 mol %)dtbpy (3–10 mol %)alkane, rt–80 °C

+Ar H (nip)B B(pin)1/2 Ar B(pin) + 1/2 H2

ベンゼン環C–Hホウ素化

B(pin)

Cl

I82%

B(pin)

Cl

MeO2C80%

B(pin)

F

82%

SiMe2H

BF3K

Cl

100%

OH

B(pin)

Br

NC83%

B(pin)

ClO SiMe2H

via

B(pin)

Cl

82%

Cl

B(pin)

Cl

82%Cl

B(pin)(nip)B

97%

B(pin)(nip)B

(nip)B B(pin)83%

B(pin)95%, o/m = 98:2

with [3,5-(F3C)2–C6H3]3P

O

OMe

Ishiyama, Miyaura, Hartwig, et al. Angew. Chem. Int. Ed. 2002, 41, 3056;Marder, et al. Chem. Commun. 2005, 2172; Hartwig, et al. J. Am. Chem. Soc. 2008, 130, 7534.

Ishiyama, Miyaura, et al. Chem. Commun. 2010, 159.

IrN BBN

B

IrN BBN

B

Ar HIrN B

HN

B

B–Bor

H–B

H–Bor

H–H

OAor

SBM

B = B(pin)

Ar–H

Ar–BIshiyama, Miyaura, Hartwig, et al. J. Am. Chem. Soc. 2002, 124, 390;

J. Am. Chem. Soc. 2005, 127, 14263; Sakaki, et al. J. Am. Chem. Soc. 2003, 125, 16114.

Cp*Rh(η4-C6Me6)3 (2.4 mol %)150 °C

+ (nip)B B(pin)R H + H B(pin)R B(pin)

or [Cp*RuCl2]2, [Cp*RuCl4] (5 mol %Ru)

B(pin)

49%B(pin)

B(pin)+

73%, 5:1

O B(pin)

91%B(pin)

OO

74%

B(pin)F

83%

n-C8F17 B(pin)

90%

N B(pin)55%

Bu2N B(pin)

75%

C(sp3)–Hホウ素化

(70-85%) that were similar to those of the catalytic processand with comparable or faster rates. The reaction ofCp*Rh(H)2(Bpin)2 or Cp*Rh(H)(Bpin)3 with benzene oc-curred at 80 °C in 82-85% yield, while the reaction withoctane occurred at 125 °C, giving octylBpin in 70% and 72%yields, respectively. The reaction with octane formed 1-oc-tylBpin as the only alkylboronate ester product. Therefore,Cp*Rh(H)2(Bpin)2 and Cp*Rh(H)(Bpin)3 are chemically andkinetically competent to be intermediates in the borylationof arenes and alkanes.

After having identified likely reaction intermediates,the reactions of methane with CpRh(H)2(BO2C2H4)2 andCpRh(H)(BO2C2H4)3 were studied by Harwig, Hall, and co-workers as models for the reactions of alkanes withCp*Rh(H)2(Bpin)2 and Cp*Rh(H)(Bpin)3 (Scheme 12). Novelconclusions were drawn from these studies.8 The emptyp-orbital of the boryl ligand in the CpRh(BO2C2H4)2 inter-mediate was found to be involved in the C-H borylationprocess in several ways.

Reaction of the bisboryl intermediate with methane wascalculated to occur by coordination of the alkane, followedby conversion of the alkane complex to a borane complexthrough a single transition state. This process occurs withoutformation of a discrete Rh(V) intermediate, much like thepathway lacking a high-valent intermediate calculated forthe stoichiometric reactions of the iron and tungsten borylcomplexes. Coupling of the alkyl group with the second borylligand is calculated then to form the final products (part (a)of Scheme 12).

Reaction of the boryl hydride intermediate with methanewas calculated to occur by a related but distinct mechanism.After coordination of the alkane, simultaneous cleavage ofthe alkane C-H bond and formation of a borane B-H bondis calculated to form an alkyl complex containing a coor-dinated borane. Coupling of the boryl moiety with the alkylgroup would then form the final products (part (b) of Scheme12).

Miyamoto and co-workers69 performed computationalstudies on the reaction of BH3 with CH4 catalyzed by CpRh.This set of calculations, like those conducted by Hall,Hartwig, and co-workers, indicated that the rate-determiningstep in the functionalization of alkanes catalyzed by Cp*Rhis C-H bond cleavage and that the reductive elimination ofa C-B bond is rapid. However, these authors proposed thata pathway involving oxidative addition and reductive elimi-nation through a high-valent rhodium intermediate is fol-lowed (Scheme 13).

The difference between the two sets of computationalconclusions can be explained by some simplifications madeby Miyamoto and co-workers. For example, HBpin andB2pin2 are the only reagents, so far, that undergo the rhodium-

catalyzed borylation of alkanes and arenes. The alkoxygroups on HBpin modulate the strength of B-H interactions,which are critical to the catalytic process. Thus, BH3 mightbe a poor computational model for HBpin and B2pin2 in thesereactions. Second, the intermediates in the catalytic processare bisboryl dihydride and trisboryl monohydride complexes,not the monoboryl trihydride complexes studied by Miyamoto.

5.4. Rh-Catalyzed Borylation of Benzylic C-HBonds

Rhodium complexes also catalyze the borylation of ben-zylic C-H bonds. After the observation of benzylic bory-lation as a side product from the reaction of B2pin2 withm-xylene reported by Smith63 when using the Cp*Rh-basedcatalyst developed by Hartwig, Marder and co-workersdescribed, in 2001, the benzylic borylation of toluene,p-xylene, and mesitylene with HBpin catalyzed by[Rh(Cl)(N2)(PiPr3)2].65 [Rh(Cl)(N2)(PiPr3)2] (3 mol %) and1 M HBpin were allowed to react with toluene at 140 °C,and the major product was 2-benzyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Scheme 14). Products resulting fromthe borylation of arene C-H bonds or from diborylation ofthe benzylic position were produced in low yields. Thequantity of PhCH(Bpin)2 produced indicated that borylationof the benzylic C-H bonds in toluene further activated oneof the remaining benzylic hydrogens to C-H borylation.para-Xylene was borylated at the benzylic position inpreference to the aromatic position (98:2). The reaction ofmesitylene with HBpin catalyzed by [Rh(Cl)(N2)(PiPr3)2]yielded 2-(3,5-dimethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2]di-oxaborolane, resulting from the borylation of a benzylic C-Hbond, as the sole monoborylation product, along with smalleramounts of bisborylation products and traces of trisborylationproducts.

Scheme 12. Mechanism of C-H Bond Cleavage and C-B Bond Formation Supported by Density Functional Theory (DFT)Calculations for Hydridoboryl (a) and bis(Boryl) (b) CpRh Complexes

Scheme 13. Mechanism of the Borylation of AlkanesCatalyzed by Cp*Rh Proposed by Miyamoto andCo-workers

898 Chemical Reviews, 2010, Vol. 110, No. 2 Mkhalid et al.

(70-85%) that were similar to those of the catalytic processand with comparable or faster rates. The reaction ofCp*Rh(H)2(Bpin)2 or Cp*Rh(H)(Bpin)3 with benzene oc-curred at 80 °C in 82-85% yield, while the reaction withoctane occurred at 125 °C, giving octylBpin in 70% and 72%yields, respectively. The reaction with octane formed 1-oc-tylBpin as the only alkylboronate ester product. Therefore,Cp*Rh(H)2(Bpin)2 and Cp*Rh(H)(Bpin)3 are chemically andkinetically competent to be intermediates in the borylationof arenes and alkanes.

After having identified likely reaction intermediates,the reactions of methane with CpRh(H)2(BO2C2H4)2 andCpRh(H)(BO2C2H4)3 were studied by Harwig, Hall, and co-workers as models for the reactions of alkanes withCp*Rh(H)2(Bpin)2 and Cp*Rh(H)(Bpin)3 (Scheme 12). Novelconclusions were drawn from these studies.8 The emptyp-orbital of the boryl ligand in the CpRh(BO2C2H4)2 inter-mediate was found to be involved in the C-H borylationprocess in several ways.

Reaction of the bisboryl intermediate with methane wascalculated to occur by coordination of the alkane, followedby conversion of the alkane complex to a borane complexthrough a single transition state. This process occurs withoutformation of a discrete Rh(V) intermediate, much like thepathway lacking a high-valent intermediate calculated forthe stoichiometric reactions of the iron and tungsten borylcomplexes. Coupling of the alkyl group with the second borylligand is calculated then to form the final products (part (a)of Scheme 12).

Reaction of the boryl hydride intermediate with methanewas calculated to occur by a related but distinct mechanism.After coordination of the alkane, simultaneous cleavage ofthe alkane C-H bond and formation of a borane B-H bondis calculated to form an alkyl complex containing a coor-dinated borane. Coupling of the boryl moiety with the alkylgroup would then form the final products (part (b) of Scheme12).

Miyamoto and co-workers69 performed computationalstudies on the reaction of BH3 with CH4 catalyzed by CpRh.This set of calculations, like those conducted by Hall,Hartwig, and co-workers, indicated that the rate-determiningstep in the functionalization of alkanes catalyzed by Cp*Rhis C-H bond cleavage and that the reductive elimination ofa C-B bond is rapid. However, these authors proposed thata pathway involving oxidative addition and reductive elimi-nation through a high-valent rhodium intermediate is fol-lowed (Scheme 13).

The difference between the two sets of computationalconclusions can be explained by some simplifications madeby Miyamoto and co-workers. For example, HBpin andB2pin2 are the only reagents, so far, that undergo the rhodium-

catalyzed borylation of alkanes and arenes. The alkoxygroups on HBpin modulate the strength of B-H interactions,which are critical to the catalytic process. Thus, BH3 mightbe a poor computational model for HBpin and B2pin2 in thesereactions. Second, the intermediates in the catalytic processare bisboryl dihydride and trisboryl monohydride complexes,not the monoboryl trihydride complexes studied by Miyamoto.

5.4. Rh-Catalyzed Borylation of Benzylic C-HBonds

Rhodium complexes also catalyze the borylation of ben-zylic C-H bonds. After the observation of benzylic bory-lation as a side product from the reaction of B2pin2 withm-xylene reported by Smith63 when using the Cp*Rh-basedcatalyst developed by Hartwig, Marder and co-workersdescribed, in 2001, the benzylic borylation of toluene,p-xylene, and mesitylene with HBpin catalyzed by[Rh(Cl)(N2)(PiPr3)2].65 [Rh(Cl)(N2)(PiPr3)2] (3 mol %) and1 M HBpin were allowed to react with toluene at 140 °C,and the major product was 2-benzyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Scheme 14). Products resulting fromthe borylation of arene C-H bonds or from diborylation ofthe benzylic position were produced in low yields. Thequantity of PhCH(Bpin)2 produced indicated that borylationof the benzylic C-H bonds in toluene further activated oneof the remaining benzylic hydrogens to C-H borylation.para-Xylene was borylated at the benzylic position inpreference to the aromatic position (98:2). The reaction ofmesitylene with HBpin catalyzed by [Rh(Cl)(N2)(PiPr3)2]yielded 2-(3,5-dimethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2]di-oxaborolane, resulting from the borylation of a benzylic C-Hbond, as the sole monoborylation product, along with smalleramounts of bisborylation products and traces of trisborylationproducts.

Scheme 12. Mechanism of C-H Bond Cleavage and C-B Bond Formation Supported by Density Functional Theory (DFT)Calculations for Hydridoboryl (a) and bis(Boryl) (b) CpRh Complexes

Scheme 13. Mechanism of the Borylation of AlkanesCatalyzed by Cp*Rh Proposed by Miyamoto andCo-workers

898 Chemical Reviews, 2010, Vol. 110, No. 2 Mkhalid et al.

反応機構

反応機構

Hartwig, Hall, et al. J. Am. Chem. Soc. 2005, 127, 2538.Hartwig, et al. Science 2000, 287, 1995; J. Am. Chem. Soc. 2003, 125, 858; J. Am. Chem. Soc. 2004, 126, 15334; J. Am. Chem. Soc. 2006, 128, 13684.

thanks to prof. Nakao@Kyoto

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