carbometallation reactions in organic...

Carbometallation Reactions in Organic Synthesis

Topic Review

September 24th , 2015

Presented by Sankar Rao Suravarapu

Prof. Dr. Philippe Renaud

University of Bern, Department of Chemistry and Biochemistry

1

Carbometallation : A chemical process involving a net addition of carbon-metal bond

to an unsaturated carbon-carbon multiple bonds.

Definition

HOMO

HOMO

LUMO

LUMO

Carbometallation reactions that are proceeding via pericyclic reactions

are stereoselective (4-centered syn addition mechanism)

Structural requirement for organometallic species is the presence of a low-lying

empty metal orbital

Activation energy for the carbometallation would be more than that of corresponding

hydrometalltion

2 Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427

transmeatllation

Dynamic

polarization

1M 1L 2M2L

1M

1L2M

2L

1M

1L2M

2L

-+

1M 2L 2M1L

1M

1L2M

2L+

ate

complexatio

n

3

Negishi, E. et al., Pure Appl. Chem. 1981, 53, 2333

Interaction between two metal containing Lewis acids

PhPh

2 Me3Al

Cp2TiCl

2

Ph Ph

Me TiCp2Cl.AlMenCl3-n

Ph Ph

Me I

Ph Ph

Me H/D

84 %75 %

IodineH3O+/D3O+

Stoichiometric carbotitanation of alkynes

4

Negishi, E. et al., Organomet. Chem. 1978, 156, C20

Cp2TiCl2

2Me3AlMe2Al

Cl

TiCp2

LBCH2=TiCp2

PhPh

TiCp2

PhPhI2

PhPh

II

H3O+ PhPh

H/DD/HD3O+

Tebbe et al., J. Am. Chem. Soc, 1978, 100, 3611

Different sequence and time intervals of addition in same molar ratio

5

Zirconium-catalyzed carboalumination of alkynes

HPh

1. n-BuLi2. D2O

DPhMe3Al

cat. Cp2ZrCl2 AlMe2

DPh

Me H

DPh

Me

H2O

Z-isomer

Me3Al

cat. Cp2ZrCl2 AlMe2

HPh

Me

D2O

D

HPh

Me

I2

I

HPh

Me Li

HPh

Me

n-BuLi

D2O

6 Negishi, E. et al., J. Am. Chem. Soc. 1985, 107, 6639

Mechanistic investigations

Me3Al Cp2ZrCl2 Me2AlCl

ZrCp2MeCl

RR

ZrCp2 Cl AlMe2ClMe

RR

+ -

R

Me

R

ZrCp2

Cl Cl

Me2Al

R

Me

R

AlMe2

Cp2ZrCl2






MenAlCl3-nCp2ZrCl2 Me(X)Al

ClZrCp2Y

Cl

RR

Cl ZrCp2YMe

RR

+ -

R

Me

R

Al

Cl ZrCp2Y

Cl

R

Me

R

AlXYCp2ZrCl2

Al

X Cl X


Two other possible six- centered mechanisms

RR

Cp2Zr

Cl AlHX2

R1

X

RR

Cp2Zr Cl

AlX2R1



10

Zirconium-catalyzed carboalumination of alkenes

n-Hex

AlMe3

cat. ZrCp2Cl2n-Hex

Me

H

H3O+

traces

Negishi, E. et al., J. Am. Chem. Soc. 1995, 117, 10771

Negishi, E. et al., Chem. Soc. Rev. 1996, 25, 427

11

AlMe3

cat. Cl2ZrCp2*

O2

R R

Me

OH

Me

OHMe

OH

Me

OH

Me

OHEt2NHO

68%, 71% ee88%, 72% ee 79%, 75% ee 30%, 80%ee

Negishi, E. et al., J. Am. Chem. Soc. 1995, 117, 10771

Zirconium-catalyzed enantioselective methylalumination of alkenes

12

C6H13

1. Me3Al (2.0 eq)Cp2ZrCl2 (0.2 eq)H2O (1.2 eq)

CH2Cl2, -70 oC

2. 3 N HClMe

C6H13 C6H13

Me

97:3

Water accelerated carboalumination

Just 10 mins

AlR3

Cp2ZrCl2

- Cl

ZrCp

Cp

R

ClAl

R

R

H2O

T< 0 oC

ZrCp

Cp

R

OAl

R

R

R1 Hslow fast

R

R1 H

AlR2

AlO

AlR

RR

R

AlR3

Wipf, P. et al., Angew. Chem. Int. Ed. 1993, 32, 1068

13 Wipf, P. et al., Org. Lett 2000, 2, 1713

Asymmetric methylalumination

Limitation: carboalumination of alkynes and alkenes

i-Bu3Al-Cp2ZrCl2

System do not undergo carboalumination of alkenes or alkynes, rather

it would undergo hydroalumination

14

Zirconium catalyzed- Ethylmagnesiation of alkenes

ZrCp2

R

ZrCp2

R

EtMgBr

R

ZrCp2

MgBr

H

R

Et

MgBr

R

EtMgXcat. Cp2ZrCl2

R

Et

MgX

Dzhemilev ethylmagnesiation

Catalytic cycle

Limitation:

this reaction only works

with ethyl Grignard


16

Carbocupration reactions

17

Regioselectivity in the carbocupration reaction

Alkoxy-substituted terminal alkynes

Nakamura, E. et al., J. Am. Chem. Soc. 1992, 114, 6686

J. Am. Chem. Soc. 1997, 119, 4887

18

OBn

OOMe H

H H

OBn

OOMe H

H H

OPMB

O O

1. PMBO(CH2)3MgBr, CuBr

LiBr, THF, -95 oC to -78 oC

85 %

2. (OCH2CH2O)CH(CH2)2MgBr

CuCN, LiCl, -78 oC

84%

Gambieric acid fragment

Alkoxy-substituted alkynes

Sequential carbocupration reaction

Clark, J. S. et al., Angew. Chem. Int. Ed. 2005, 44, 6157

19 Marek, I. et al., Synlett.. 2010, 329

20

b-isomer

a-isomer

Solving the regioselectivity problem in di-substituted alkynes

Marek, I. et al., Synlett.. 2010, 329

21

carbocupration of O- alkynyl carbamates

Marek, I. et al., Org. Lett. 2003, 5, 5087.

22

N-substituted alkynes

15 is more stable than corresponding b- metalated enol ether

23

Tandem carbocupration sigmatropic reaarangement

Oshima, K. et al., Chem. Lett. 2007, 36, 32.

Carbometallation-Oxidation-Ring opening: formation of quaternary centers

Marek, I. et al., Angew. Chem. Int. Ed. 2013, 52, 5333 –5337 24

R1

EtO O

1. R2MgBr

CuI (10 mol%)

Et2O, -35 oC

2. O2, -35 oC, 30 min

3. H3O+

H

O

EtO2CR1 R2H

O

EtO2CR2 R1

1. R2CuCNLi

Et2O, -35 oC

3. H3O+

2. t-BuOOLi, -78 oC

to -30 oC, 30 min

H

O

EtO2CMe Bn

51 %

H

O

EtO2CMe Bn

52 %

H

O

EtO2CBu Me

H

O

EtO2CBn Me

55 %

64 %

ON

O

R

R1

MeCu.SMe2

Et2O, -40 oC

N

Me

R

[Cu]

O

R1

O

MeLi + Me2S.CuBr

ON

O

R

R1

Me2CuLi.LiBr.SMe2

Et2O, -40 oCN

Me

R

Cu

O

R1

O

2 MeLi + Me2S.CuBr

Me Li+

t-BuOOLi

t-BuOOH+ n-BuLi

THF, -80 oC

t -BuOOH

Me-H

N

Me

R

Cu

O

R1

O

O

O

t-Bu-80 oC

N

Me

R

O

O

R1

O

Cu

O

t-Bu

-80 oC

protic source

-80 oC

N

O

OO

R1

R

H Me

Carbocupration-Oxidation

25 Marek, I. et al., Nature. 2012, 490, 522

26 Marek, I. et al., Nature. 2012, 490, 522

Application to the aldol and Mannich reactions

27

Carbosilylation reactions

R1 R2 SiMe3EtAlCl2

TMSCl (20.0 equiv)

SiMe3

R2

R1

Lewis acid-catalyzed trans- carbosilylation of simple alkynes

Yamamoto et al., J. Org. Chem. 1996, 61, 4874

SiMe3

H

SiMe3

H

SiMe3

Me

93 %

MeO

95 % 88 %

R

H H

Bi product in this reaction although, traces

28

R H

SiMe3

Me3Si H

R

EtAlCl2

R H

EtAlCl2

R

HCl2EtAl

SiMe3

TMSCl

R

HClEtAlH2O

R

HH

Yamamoto et al., J. Org. Chem. 1996, 61, 4874

Mechanism carbosilylation of simple alkynes

29

HfCl4 -catalyzed carbosilylation reaction

H

SiMe3Ph

H

Me

HH

SiMe3Ph

H

Me

Me

H

SiMe3Ph

Me

H

H

96 % 97 % 92 %

Yamamoto et al., J. Am. Chem. Soc. 1997, 119, 6781. 30

Ph HSiMe3

HfCl4

CH2Cl2H

SiMe3Ph

R3

R3

R1

R2

R1

R2

0 oC, 20 min

R

SiMe3

n

10 mol% HfCl4

50 mol% Me3SiCl

CH2Cl2 0 oC

Me3Si R

n

Me3Si R

n

HfCl4 –catalyzed intramolecular carbosilylation reaction

Me3Si Me3Si

2

Me3Si

61 %99 %76 %


Mechanism for the exclusive endo-dig carbosilylation reaction


33

SiMe3

SiMe3

HfCl4

SiMe3

SiMe3

HfCl4 Me3Si SiMe3exo-mode

87%

SiMe3

SiMe3

SiMe3Me3SiSiMe3Me3Si

exo-mode endo-mode

64%

not observed

• exo-mode is favorable because of b-silicon effect

Mechanistic insights

• Controversial result

• Electronic factor is not dictating the reaction

• Computational studies showed that the endo product is favored by 18.3 kcal/mol

Yamamoto et al., J. Am. Chem. Soc. 1998, 120, 5339.

Hcat. EtAlCl2

CH2Cl2 0 oC

SiMe3

SiMe3

R

n

R

n

Lewis acid-catalyzed intramolecular vinylsilylation reaction


SiMe3

H

SiMe3 SiMe3

2

0 % 90 % 35 %

34

H

n

SiMe3

R

b a

SiMe3

R

AlEtCl2

n

r oute a

SiMe3

H

n

r oute b AlEtCl2

R

SiMe3endo exo

n

SiMe3

R

not observed


endo exo

Lewis acid-catalyzed intramolecular trans vinylsilylation and

arylsylilation of alkynes


36

SiMe3

cat. HfCl4n

SiMe3

n

CH2Cl2

n=1, 74%n=2, 45%

Arylsilylation of alkynes

37

SiMeMe

SiMeMe

SiMeMe

Me

Me71% 57% 20%

SiAr

Si

Ar

HfCl4 (0.5 eq)

CH2Cl2, rt

Arylsilylation of alkynes


38

SiR2

R1

Si

R1

R2cat. EtAlCl2

CH2Cl2, 0 oC to rt

Vinylsilylation of alkynes

Si

Me Me

H

H Si

Me Me

Ph

HSi

Me Me

H

Me

0% 92% 83%


39

R1 R2

R3Sn R3

car bosr anny lat ionR2R1

R3Sn R3

Corrostannylation reactions

SnBu3R1 R3R2

[PdCl(-C3H5)]2

(5 mol % of Pd, Pd/1=1)

SnBu3

R2 R3

R1

R2 R3

Bu3Sn

R1

5

6

NPh

PPh21

Carbostannylation of alkynes catalyzed by an

iminophosphine-palladium complex

E. Shirakawa et al., J. Am. Chem. Soc. 1998, 120, 2975.

• Regioselectivity of the products depend on sterics and electronics of substituents

40

E. Shirakawa et al., J. Am. Chem. Soc. 1998, 120, 2975. 41

Br SnCl2

PdCl2(PhCN)2 (5 mol%)

EtMgBr, rt, 1h

SnEt3

toluene

• Allylstannylation

• Mechanism

Pd-catalyzed ally and arylstannylation of norbornenes

K. Fugami et al., J. Orgmet. Chem. 2000, 611, 433 42

PdCl2(PhCN)2 (5 mol%)

MeMgI, rt, 1h

ArSnCl3

Ar

SnMe3

Ar

Me3Sn

• Arylstannylation

3 SnCl4SnAr44 ArSnCl3

150 oC

• Preparation of aryltintrichloride

Pd-catalyzed ally and arylstannylation of norbornenes


• This reaction does not proceed with tributytin chloride reagent

• Question why???

• Mechanism


R1

Z R2

SnBu3

[AgOTf(PPh3)]3

toluene 70 oC

ZR1

SnBu3

R2

ZR1

R2

little amount

dsp: destannylated product*

A, M. Echavarren et al., Angew. Chem. 2007, 119, 2726.

Ag-catalyzed intramolecular carbostannylation

45

H

SnBu3

Me

H

SnBu3

Me

H

SnBu3

H

MeO2C

MeO2C

PhO2S

PhO2S

TBDPSOH2C

TBDPSOH2C

87 % 91 % 93 %

dsp: 3 % dsp: 0 % dsp: 0 %

H

H

SnBu3

[AgOTf(PPh3)]3

toluene 70 oC

H

SnBu3

H

H

H

HOH2C

HOH2C

HOH2C

HOH2C

31 %

HOH2C

HOH2C

11 %

• The major byproduct in this reaction is bicyclic acetal O

OMe

SnBu3

30 %


A, M. Echavarren et al., Angew. Chem. 2007, 119, 2726. 46

•Small application in six-and seven- membered-ring systems



PCy

Ag-thf

Cy SbF6

[AgILx] =

47

H

toluene 70 oCPhO2S

PhO2S

[AgILx] (10 mol%)

4 h

SnBu3PhO2S

PhO2S

HPhO2S

PhO2S

51 % 32 %

SnBu3

TsN toluene 70 oC

[AgILx] (10 mol%)

0.5 h, I2

NTs

27 %

SnBu3TsN

I

I

43 %

toluene 110 oC

[AgILx] (10 mol%)

1.5 hSnBu3

MeO2C

MeO2C MeO2C

MeO2C

Bu3Sn

MeO2C

MeO2C

H

90 % 8 %


Small application in six-and seven- membered-ring systems

48

PCy

Ag-thf

Cy SbF6

[AgILx] =

49

H

Me

Me

Me

MeMe

H

Me

[AgILx]

DCE, 50 oC.

24 h, 66 %

MeO2C

MeO2C

MeO2C

MeO2C

PCy

Ag-thf

Cy SbF6

[AgILx] =

Cyclopropanation reaction

50

R1 R2

BX

XR3

car bobor ationR2R1

B R3

XX

Cabroboration reactions

51

OH

n-Pr

Me

(i-Pr2N)BCN

Pd2(dba)3

toluene, reflux, 3 h

BO

CN

n-PrMe

NiPr2

94 %

BO

CNNiPr2

88 %

BO

CNNiPr2

84 %

BO

CN

MeMe

NiPr2

92 %

Et Ph

M. Murakami et al., J. Am. Chem. Soc. 2003, 125, 6358

Palladium- and Nickel-Catalyzed Intramolecular

Cyanoboration of Alkynes

Ni(COD)2 also works as efficiently as Pd catalyst

52

S

N

MeO

OH RB(OH)2 (2.0 equiv)

tartaric acid (1.0 equiv)

CH2Cl2, 60 oC, 2 h.

OB

RN

S

MeO

HO

Transition-Metal-Free Direct anti- Carboboration of Alkynes with

Boronic Acids

Org. Lett. 2015, 17, 1605

OB

N

S

MeO

HO OB

N

S

MeO

HOO

B

N

S

MeO

HO

Ph C6H10

58 %75 % 73 %

53 Org. Lett. 2015, 17, 1605

54

R1

(9-BBN-H)2

THF, 60 oC , 1 h

R1 B PhEtO2Ccat. PBu3

B

Ph

R1

O

EtO

THF, 80 oC

8 h

Phosphine-Catalyzed Anti-Carboboration of Alkynoates

B

Ph

O

EtOB

R1

O

EtO B

R1

O

EtO

OMe

89 %

S

87 % 62 %

B

R1

O

EtO

34 %

M. Sawamura et al., J. Am. Chem. Soc. 2014, 136, 10605

55

Mechanism

M. Sawamura et al., J. Am. Chem. Soc. 2014, 136, 10605

56

Corrolithiation reactions

57

Me

OMe

MeO

Me

MeLi, DME

I Br I Me

OMe Me Zn, cat. PbCl2

CH2Br2, TiCl4

THF I Me

Me Me

I Me

Me Me

t -BuLi, TMEDA

-78 oC to rt

1 h

Li Me

Me Me

MeMeMe

Li(CH2O)n

-78 oC to rt

H3O+

MeMeMe

OH

65%

CH3COCl, Py

Et2OMe

MeMe

O

O

86%

car boli thiation

Carbolithiation reaction

Starting material synthesis

long tailed Mealybug Pheromone

58

Still, Many More Reactions…………………

carbometallation reactions in organic...

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