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Home , Stille reaction

Stille, Suzuki, and Sonogashira Couplings Cross-Coupling reactions: catalyst R-X + R'-M 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: Pd(0)

H3C Br + SnBu3 H3C + Bu3SnBr

Stille Reaction Mechanism: Pd(II)

H3C Br Pd(0)L from cis complex n

H3C Pd(II)Ln––Br initially: H C Pd(II)L R' 3 n

L L Pd L transmetallation R L Pd R' trans Bu SnBr SnBu3 cis R 3 RDS General Cross-Coupling Reactions Oxidative addition initially gives rise to a cis complex that rapidly isomerizes to a trans complex L L PdL2 fast R-I L Pd I R Pd I

R L β-hydride elimination occurs for Csp3 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 leaving groups (Cl) are used; then oxidative addition is RDS.

Order of transfer from Sn: > > > > R benzyl

Stille-specific conditions:

Catalyst: Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3 Large rate enhancements are often observed with poorly electron donating : (furyl)3P, Ph3As CuI can dramatically increase the due to ’s free-ligand scavenging ability:

Pd2(dba)3 5mol% PPh (20mol%) I 3 JOC, 1994, 5905. + SnBu3

mol% CuI relative rate 0 1 10 114 Stille Cross-Coupling The use of aryl requires special conditions:

Pd2(dba)3 5mol% P(t-Bu) OEt Cl OEt 3 CsF + dioxane, 100°C SnBu3 H3CO H3CO

Sn->Cu transmetallation increases the rate of cross-: ACIEE, 1999, 2411 R OH

ONf R OH Pd(PPh3)4 (10mol%) + LiCl (6 eq), CuCl (5eq)

SnBu3 DMSO, 60°C

Nf=SO2(CF2)3CF3 92% JACS, 1999, 7600 Coupling of Acid Chlorides: O BnPdCl(PPh3)2 Bu3Sn O O O CuI, THF, 50°C + Cl H2N O H2N O

JOC, 1993, 343 Benzylic coupling:

Pd(PPh3)4 (10mol%) Br + Bu3Sn R R CHCl3, reflux O O OTHP OTHP 65% JOC, 1993, 165

Preparation of Aryl and Vinyl Stannanes

From Organolithium reagents via directed ortho-lithiation: 1. t-BuLi

Chem. Rev. 1990, 923. 2. Bu3SnCl SnBu3 OMOM OMOM

((CH3)3Sn)2 TL 1997, 4737. Pd(PPh3)4 Br N R Bu3Sn N R Prep of vinyl stannanes: SnBu3 Bu3SnH AIBN CH CH 3 + 3 CH3 Bu3Sn OTHP OTHP OTHP 85 : 15

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

Alternatively,

Bu3Sn CH3 OH CH3 OH SnBu3

Bu Sn O I O 3 PdCl2(CH3CN)2, 5mol% 69% Synlett, 1997, 771 Alternative Preparations of Vinyl Stannanes

OEt Bu3Sn(Bu)CuCnLi2 OEt TL, 1991, 6337. EtO THF; CH OH 3 EtO SnBu H 3

CH3 Cp2Zr(H)Cl CH3 CH3 SnBu3 H O CH SnBu BuLi; Bu3SnCl 2 3 3

EtO EtO EtO Zr(Cl)Cp2 EtO H SnBu3 H Z-vinyl stannane syn hydrozirconation

OEt OEt TL, 1992, 5861 Bu3Sn(Bu)CuCnLi2 TL, 1991, 6337 EtO SnBu3 EtO THF; Br H

t-BuLi (3 eq) JACS, 1999, 7600 R Bu SnCl R Br 3 Bu3Sn

OH OH Vinyl stannanes react cleanly with to form vinyl with retention of :

R R R Pd(PPh ) Cl 3 2 2 I2, DCM JACS, 1998, 3935 TBSO Bu3SnH TBSO TBSO CH Cl , 0°C 2 2 SnBu TBSO TBSO 3 TBSO I Suzuki Coupling

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

Pd(OAc)2 (0.3 mol%)

PPh3 (0.9 mol%)

B(OH)2 + Br CHO OHC Na2CO3,(1.2 eq) iPrOH, H2O heat

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

HO- ArB(OH)2 O OH RL2Pd–X RL2Pd–OH RL2Pd B Ar OH

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

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 Transfer of primary alkyl groups utilizing the Suzuki coupling: O

O 9-BBN Br B JACS, 1989, 314 CN CN PdCl2(dppf) CN K2CO3 DMF, THF, 50°C

PPh2 Cl Cl large "bite" angle of dppf is believed to furnish a catalyst with a more Pd Fe favorable ratio of rate constants for reductive elimination vs. !-hydride eliminiation

Ph2P 99° PPh2 PPh2 JACS, 1984, 249

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

O (HO)2B

O O ACIEE, 1999, 2413 Cl MeO MeO Pd(OAc)2 1mol% KF (3 eq), THF P(t-Bu) 2 91% O

2 mol%

Synthesis of Boronic Acids

1. B(Oi-Pr)3

Li B(OiPr)2 Organometallics, 1983, 1316 2. HCl/Et2O

O O B B O O O O2N OTf O2N B JOC, 1995, 7508 PdCl2(dppf) 3 mol% O KOAc, DMSO, 80°C 86%

1. n-BuLi H2, Lindlar H B(OiPr)2 B(OiPr) 2. B(OiPr)3 2 TL 1988, 2631, 2635. O H B H O O B O JACS, 1972, 4370 THF, 70°C syn-hydroboration 80%

HO H H O (iPc) BH I 2 B(OEt)2 HO B O CH CH OH 3 2 I I syn- hydroboration H O EtZnI B O Chem. Lett, 1993, 1429. PdCl2(dppf) 1mol% Comparison of the Stille and Suzuki couplings The two methods are comparable, but the higher cost and toxicity of stannanes makes the Suzuki preferable.

OMe Sn(Me)3 B(OH)2 OMe

OMe

NO2 NO2 Pd(PPh ) Pd (dba) 3 4 NO2 2 3 K3PO4 OTf P(o-tol)3 80% 82% DMA, 85°C LiCl Heterocycles, 1998, 1513

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

B SnMe3 O O 88% Synlett, 1991, 687

PdCl2(dppf) SnMe3 Br K3PO4, DMF

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

Br 1 mol% Pd(0)

+ 1/3 eq. In THF, 60°C

CO2Et CO2Et 92% JACS, 2001, 4155

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

PdCl2(PPh3)2 X + R R CuI, Et2NH

R PdCl (PPh ) R X 2 3 2 R''' R' + R''' CuI, Et2NH R' R'' R''

R R' R––X Pd(0)L reductive elimination n from cis complex oxidative addition L L R Pd(II)––X

L Pd R' L R' R cis transmetallation

trans Cu R' L Pd L CuX RDS

R copper(I) coordination to CuI enhances acidity: H R'

R2NH Examples of Sonogashira Coupling

CH3

PdCl (PPh ) CH3 2 3 2 CO H CuI, DMF 2 + I

CO2H TL, 2002, 4703

PdCl2(PPh3)2 HO HO OCH3 CuI, DMF I + H CO 87% 3

JOC, 2001, 6037