Stille, Suzuki, and Sonogashira CouplingsCross-Coupling reactions:

R-X + R'-M

catalyst

R-R' + M-X

R, R' are usually sp2 hybridized

X= I (best), OTf, Br, Cl

M=Sn, B, Zn, Zr, In

Catalyst= Pd, sometimes Ni

Example:

BrH3C + SnBu3

Pd(0)

H3C + Bu3SnBr

Mechanism:Pd(II)

Pd(0)Ln

BrH3C

Pd(II)Ln––BrH3C

oxidative addition

SnBu3

transmetallation

RDS

Pd(II)LnH3C

PdL L

R'

R

trans

PdL R'

L

Rcis

initially:

reductive eliminationfrom cis complex

Bu3SnBr

Stille Reaction

General Cross-Coupling Reactions

Oxidative addition initially gives rise to a cis complex that rapidly isomerizes to a trans complex

PdL I

L

R

R-I

PdL2 fast

PdR I

L

L

β-hydride elimination occurs for Csp3 halides other than methyl:

H Pd(II)LnX + HPd(II)L2X

Both oxidative addition and reductive elimination occur with retention of double bond configuration

Transmetallation is usually the rate-determining step, except where poor halide leaving groups (Cl) are used; thenoxidative addition is RDS.

Order of ligand transfer from Sn:

> >R

>benzyl

> alkyl

Stille-specific conditions:Catalyst: Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3Large rate enhancements are often observed with poorly electron donating ligands: (furyl)3P, Ph3AsCuI can dramatically increase the reaction rate due to copper’s free-ligand scavenging ability:

I

+SnBu3

Pd2(dba)3 5mol%

PPh3 (20mol%)

mol% CuI relative rate 0 1 10 114

JOC, 1994, 5905.

Stille Cross-CouplingThe use of aryl chlorides requires special conditions:

Cl

+SnBu3

Pd2(dba)3 5mol%

P(t-Bu)3

CsF

dioxane, 100°C

H3CO

OEtOEt

H3CO

ACIEE, 1999, 2411Sn->Cu transmetallation increases the rate of cross-coupling reaction:

ONf

SnBu3

Nf=SO2(CF2)3CF3

+OHR Pd(PPh3)4 (10mol%)

LiCl (6 eq), CuCl (5eq)

DMSO, 60°C

OHR

92%

JACS, 1999, 7600

Coupling of Acid Chlorides:

O

Cl

+

H2N

Bu3Sn O

O

BnPdCl(PPh3)2

CuI, THF, 50°C

H2N

O

O

O

JOC, 1993, 343

Benzylic coupling:

O

Br

R

OTHP

Bu3Sn+

Pd(PPh3)4 (10mol%)

CHCl3, reflux OR

OTHP65%

JOC, 1993, 165

Preparation of Aryl and Vinyl Stannanes

From Organolithium reagents via directed ortho-lithiation:

OMOM

1. t-BuLi

2. Bu3SnCl

OMOM

SnBu3

Chem. Rev. 1990, 923.

NBr R

((CH3)3Sn)2

Pd(PPh3)4NBu3Sn R

TL 1997, 4737.

Prep of vinyl stannanes:

OTHP

CH3

Bu3SnH

AIBN

OTHP

CH3Bu3Sn

OTHP

CH3

SnBu3

+

85 : 15

•a radical reaction, reversible, giving a thermodynamic ratio of productsJACS, 1976, 222.

Alternatively,

O

OH

I

CH3

Bu3Sn

SnBu3

PdCl2(CH3CN)2, 5mol%O

OHCH3

Bu3Sn

69% Synlett, 1997, 771

Alternative Preparations of Vinyl Stannanes

OEt

EtO

H

Bu3Sn(Bu)CuCnLi2

THF; CH3OH

OEt

EtO SnBu3

TL, 1991, 6337.

CH3

EtO

H

BuLi; Bu3SnCl CH3

EtO

SnBu3

Cp2Zr(H)ClCH3

EtO

SnBu3

Zr(Cl)Cp2

H2O CH3

EtO

SnBu3

syn hydrozirconation

HZ-vinyl stannane

TL, 1992, 5861OEt

EtO

H

Bu3Sn(Bu)CuCnLi2

THF;Br

OEt

EtO SnBu3

TL, 1991, 6337

BrR

OH

t-BuLi (3 eq)

Bu3SnCl Bu3SnR

OH

JACS, 1999, 7600

Vinyl stannanes react cleanly with iodine to form vinyl iodides with retention of stereochemistry:

R

TBSO

TBSO

Pd(PPh3)2Cl2Bu3SnH

CH2Cl2, 0°C

R

TBSO

TBSO

SnBu3

I2, DCM

R

TBSO

TBSO

I

JACS, 1998, 3935

Suzuki Coupling

Suzuki Coupling is the reaction of vinyl or aryl boronic acids with aryl and vinyl halides or triflatesusing a palladium catalyst. Example:

B(OH)2 + CHO OHCBr

Pd(OAc)2 (0.3 mol%)

PPh3 (0.9 mol%)

Na2CO3,(1.2 eq)

iPrOH, H2O

heat

Mechanistic difference with Stille Coupling: Boron “ate” complexes are involved in transmetallation:

RL2Pd

O

Ar

B

OH

OH

H

RL2Pd–X

HO-

RL2Pd–OH

ArB(OH)2

Again Oxidative Addition and Reductive Elimination occur with retention of configuration

Reactivity of Leaving Groups: I> OTf > Br >>Cl

Rates of reductive elimination: aryl-aryl> alkyl-aryl > alkyl-alkyl

The additive thallium hydroxide (TlOH) accelerates the rate of coupling by facilitating hydroxyl-halogen exchangeat Pd: JACS, 1987, 4756.

Transfer of primary alkyl groups utilizing the Suzuki coupling:

Fe

CN

9-BBNB

CN

O

Br

PdCl2(dppf)

K2CO3

DMF, THF, 50°C

O

CN

JACS, 1989, 314

PPh2

PPh2

Pd

Cl Cl

Ph2PPPh299°

large "bite" angle of dppf is believed to furnish a catalyst with a morefavorable ratio of rate constants for reductive elimination vs. !-hydride eliminiation

dppf

JACS, 1984, 249

Buchwald’s room temperature cross-coupling of Aryl chlorides:

Cl

O

MeO

(HO)2B

O

Pd(OAc)2 1mol%

KF (3 eq), THF

P(t-Bu)2

O

MeO

O

ACIEE, 1999, 2413

91%

2 mol%

Synthesis of Boronic Acids

Li

1. B(Oi-Pr)3

2. HCl/Et2OB(OiPr)2

OTfO2N

B B

O

OO

O

PdCl2(dppf) 3 mol%

KOAc, DMSO, 80°C

BO2N

O

O

86%

JOC, 1995, 7508

Organometallics, 1983, 1316

H1. n-BuLi

2. B(OiPr)3

B(OiPr)2

H2, Lindlar

B(OiPr)2

H

OBO

H

THF, 70°C

B O

O

80%

JACS, 1972, 4370

TL 1988, 2631, 2635.

I(iPc)2BH

CH3CH2OH

B(OEt)2

I

H

syn-hydroboration

syn- hydroboration

HO

HO

B

I

H

O

O

B

H

O

OEtZnI

PdCl2(dppf)

1mol%

Chem. Lett, 1993, 1429.

Comparison of the Stille and Suzuki couplingsThe two methods are comparable, but the higher cost and toxicity of stannanes makes the Suzuki preferable.

OMe

NO2

OTf

Sn(Me)3

Pd2(dba)3

P(o-tol)3

LiCl

OMe

NO2

OMe

NO2

80%82%

B(OH)2

Pd(PPh3)4

K3PO4

DMA, 85°C

When alkyl boranes and stannanes are in the same molecule, the organoboron group reacts preferentially under basic conditions

O

Br

B SnMe3

PdCl2(dppf)

K3PO4, DMF

O

SnMe3

88% Synlett, 1991, 687

Heterocycles, 1998, 1513

Recently, triorganoindium reagents have been found to cross-couple with aryl and vinyl halides in anAtom-efficient manner, transferring all three organic ligands from indium. Indium is environmentally benign.

CO2Et

Br

In

CO2Et

+ 1/3 eq.

1 mol% Pd(0)

THF, 60°C

92%JACS, 2001, 4155

Sonogashira Coupling

Sonogashira Coupling is the coupling of terminal alkynes with aryl and vinyl halides in the presence of A palladium (0) catalyst, a Cu(I) co-catalyst, and an amine

X + R

PdCl2(PPh3)2

CuI, Et2NHR

XR

R'

R''

+ R'''

PdCl2(PPh3)2

CuI, Et2NH

R

R'

R''

R'''

Pd(0)Ln

Pd(II)––X

oxidative addition

transmetallation

RDSPdL L

R

trans

PdL

L

R cis

reductive eliminationfrom cis complex

CuX

R––X

R

L

L

Cu R'

H R'

CuI

R2NH

R'

R'

R R'

copper(I)coordination toalkyne enhancesacidity:

Examples of Sonogashira Coupling

CO2H

CH3

I+

PdCl2(PPh3)2CuI, DMF

CH3

CO2H

HO

+I

OCH3

PdCl2(PPh3)2CuI, DMF HO

H3CO87%

JOC, 2001, 6037

TL, 2002, 4703