Myers

Reviews:

The Suzuki Reaction

Analysis of Elementary Steps in the Reaction Mechanism

Chem 215

Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F., and Stang, P. J., Eds.; Wiley-VCH: New York, 1998, pp. 49-97. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483. Suzuki, A. J. Organometallic Chem. 1999, 576, 147168.
B-Alkyl Suzuki reaction:
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 2001, 40, 45444568.

Oxidative Addition
Br Pd0Ln Br Pd L isomerization L Pd Br L trans
II

L cis Relative reactivity of leaving groups: I > OTf > Br >> Cl .

Solid phase: Franzn, R. Can. J. Chem. 2000, 78, 957962.

Oxidative addition is known to proceed with retention of stereochemistry with vinyl halides and with inversion with allylic and benzylic halides. Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434442. Oxidative addition intially gives a cis complex that rapidly isomerizes to its trans isomer.

The Suzuki reaction is the coupling of an aryl or vinyl boronic acid with an aryl or vinyl halide or triflate using a palladium catalyst. It is a powerful cross coupling method that allows for the synthesis of conjugated olefins, styrenes, and biphenyls:

Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954959.

Transmetallation
L Pd Br
II

n-Bu

B O O

benzene/NaOEt Br 80 C, 4 h 98%

n-Bu
+

NaOEt

Et O PhL2Pd B

O O

L Pd L
II

n-Bu
+ O

n-Bu
Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866867. Mechanism:

B O O

n-Bu
EtO B

O
Organoboron compounds are highly covalent in character, and do not undergo transmetallation readily in the absence of base. The role of the base during transmetalation is unresolved. Boron "ate" complexes, formed via quaternization of the boron with a negatively charged base, are frequently invoked.

n-Bu
Pd0Ln

Ph Br Oxidative Addition

Reductive Elimination Ph Ph Br

Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461470.

Reductive Elimination n-Bu

EtO B O O
PdIILn PdIILn

L NaOEt Pd L trans
II

n-Bu
L cis

L Pd

II

n-Bu

n-Bu +

Pd0Ln

Ph

n-Bu

B O O

EtO

PdIILn

NaBr

Isomerization to the cis complex is required before reductive elimination can occur.

Transmetallation

Relative rates of reductive elimination from palladium(II) complexes: arylaryl > alkylaryl > n-propyln-propyl > ethylethyl Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.

>

methylmethyl

Suzuki, A. Pure & Appl. Chem. 1985, 57, 17491758.

Andrew Haidle/Chris Coletta

Conditions R BY2 + X R' P(PPh3)4 benzene, 80 C base time (h) 2 R R'

Catalyst and Ligands: The most commonly used system is Pd(PPh3)4, but other palladium sources have been used including PdII pre-catalysts that are reduced to the active Pd0 in situ:
- Pd2(dba)3 + PPh3 - Pd(OAc)2 + PPh3 - PdCl2(dppf) (for sp3-sp2 couplings-see section on B-alkyl Suzuki reaction)

yield (%) 80a

n-Bu

B O O

Br Ph

Ph

NaOEt

"Ligand-free" conditions, using Pd(OAc)2, have also been developed. Side reactions often associated with the use of phosphine ligands (phosphonium salt formation and aryl-aryl exchange between substrate and phosphine) are thus avoided. Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1997, 75, 6168. Use of N-heterocyclic carbenes as an alternative to phosphine ligands:
CH3 H3C N N CH3 H3C CH3 N + N Cl CH3 H3C 2
Pd2(dba)3 (1.5 mol%), 2 (3 mol%), Cs2CO3

NaOEt Br Br CH3 CH3 I Ph Br Ph NaOEt NaOEt NaOEt NaOEt

80a

H3C

NaOEt

2 2 2 4 2

81a 100b 63b 98b 3b

H3C

CH3 H3C 1 + Cl (HO)2B

CH3

H3C

dioxane, 80 C, 1.5h 96%

H3C

Cl Ph H3CO Br

The nucleophilic N-heterocyclic carbene 1 is the active ligand, and is formed in situ from 2. The use of ligand 1 allows for utilization of aryl chlorides in the Suzuki reaction (see the section on bulky, electron rich phosphines as ligands for use of aryl chlorides as coupling partners as well).

NaOEt

93b

Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804-3805.

B(OH)2

I Ph Br Ph Cl Ph Br

2M NaOH 2M Na2CO3 NaOEt 2M NaOH

6 6 6 2

62c 88c 0c 87d

Organoboranes: A variety of organoboranes may be used to effect the transfer of the organic coupling partner to the reactive palladium center via transmetallation. Choice of the appropriate organoborane will depend upon the compatability with the coupling partners and availability (see section on synthesis of organoboranes). Some of the more common organoboranes used in the Suzuki reaction are shown below:
O R B(OH)2 R B R B(OiPr)2 R B R B O R B O O CH3 CH3 CH3 CH3

n-Bu

B Br 2M NaOH 2 99d
Use of Aryltrifluoroborates as Organoboranes for the Suzuki Reaction:

The conditions shown above are the original conditions developed for the cross coupling by Suzuki and Miyaura. The reaction is stereo- and regiospecific, providing a convenient method for the synthesis of conjugated alkadienes, arylated alkenes, and biaryls. Note that under the conditions shown above, aryl chlorides are not acceptable substrates for the reaction, likely due to their reluctance to participate in oxidative addition.
a Miyaura, b Miyaura, c Miyaura, d Miyaura,

OCH3 CH3OH, reflux 2h, 95% The aryltrifluoroborates are prepared by treatment of the corresponding arylboronic acid with excess KHF2. According to the authors, aryltrifluoroborates are more robust, more easily purified, and less prone to protodeboronation compared to aryl boronic acids. Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 43024314.

BF3K

Br

OCH3

Pd(OAc)2, K2CO3

N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 34373440. N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866867. N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513519.

Solvent: The Suzuki reaction is unique among metal-catalyzed cross-coupling reactions in that it can be run in biphasic (organic/aqueous) or aqueous environments in addition to organic solvents. Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112, 43244330.

N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21, 28652868.

Andrew Haidle/Chris Coletta

TlOH and TlOEt as Rate-Enhancing Additives for the Suzuki Reaction

TBSO I TBSO OTBS OTBS + OTBS OTBS OTBS O OTBS OCH3 OTBS OTBS

Bulky, Electron-Rich Phosphines as Ligands for the Suzuki Reaction

R R

TBSO (H3C)2N OTBS OTBS OTBS O OTBS OCH3 R R = PCy2 (1) R = P(t-Bu)2 (2) Cl + (HO)2B R CH3 CH3 ligand PPh3 Pt-Bu3 4 Pt-Bu3 4 Pt-Bu3 Pt-Bu3 Pd source Pd2(dba)3 Pd2(dba)3 Pd(OAc)2 Pd2(dba)3 Pd(OAc)2 Pd2(dba)3 Pd2(dba)3 base Cs2CO3 Cs2CO3 KF Cs2CO3 KF Cs2CO3 Cs2CO3 solvent dioxane dioxane THF dioxane THF dioxane temp (C) time (h) yield (%) 80 80 23 80 45 80 5 5 6 5 6 5 0a 86a 95b 89a 93b 92a 91a R = PCy2 (3) R = P(t-Bu)2 (4)

TBSO (HO)2B

base KOH TlOH

temp (C) 23 23

time 2h <<30 sec

yield 86 92

relative rate 1 1000

TlOH greatly increases the rate of coupling, which the authors attribute to acceleration of the hydroxylhalogen exchange at palladium. Uenishi, J.; Beau, J.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 47564658.

CH3O

NH2 O

dioxane

80

TlOH vs. TlOEt

H3C Previous to the introduction of the bulky, electron-rich phosphine ligands shown above, most aryl chlorides were not suitable substrates for the Suzuki reaction.

t-BuO2C CO2t-Bu

(HO)2B (5 equiv)

OH

t-BuO2C CO2t-Bu

These ligands are either commercially available (Pt-Bu3) or readily synthesized from commercial starting materials (1-4). The increased activity of the ligands shown above allows for the Suzuki reaction of aryl bromides at room temperature.
a Littke,

Pd(PPh3)4 (10 mol %) I CO2Me TlOEt (1.8 equiv) 3:1 THF:H2O 97% HO CO2Me

A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 40204028.
J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 95509561.

b Wolfe,

THF (anhydrous) 93%

Alkyl Di-tert-butylphosphane-Ligated Palladium(I) dimers as catalyst for the Suzuki Reaction

Roush has found that TlOEt is a generally superior source of Tl for Suzuki couplings. Pure TlOH is available from only a single source, aqueous solutions of TlOH have a poor shelf life, and the aqueous solutions are both air- and light-sensitive. The largest problem with using TlOEt is that some boronic acidTlOEt adducts are not very soluble. Using water as a cosolvent helps to alleviate this problem in many cases.

PdI[P(1-Ad)t-Bu2] Br KOH, THF, 15 min, RT 95% As a solid, the catalytic complex is stable indefinitely in the air. it is believed that the catalyst fragments to form the monomeric subunits under the reaction conditions.
[t-Bu2(1-Ad)P]PdI

Br

Br + (HO)2B

Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 26912694.

Reactions of phenyl boronic acids with (deactivated) aryl chlorides occurred rapidly at room temperature, but conversion did not exceed 70%.

Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem. Int. Ed. 2002, 41, 4746-4748.

Chris Coletta

B-Alkyl Suzuki Reaction

sp3-sp3 Suzuki Coupling

R' Br

B R

PdCl2(dppf) (3 mol%) THF, NaOH, reflux

R R'

By employing a bulky, electron-rich ligand (similar to the ligands used in aryl chloride Suzuki couplings) Fu and coworkers are able to effect the Suzuki coupling of primary alkyl bromides or chlorides and 9-alkyl-9BBN:

vinyl bromide Br CH3 THPO CH3 Br CH3 O Br

9-alkyl-9-BBN 9-BBN 9-BBN

2

product CH3
6

yield (%) + 85 B Br CH3

9

4% Pd(OAc)2 8% PCy3 K2PO4H2O 85%

Ph

CH3
7

Ph OCH3 OCH3 CH3 THPO CH3

CH3
9

OCH3 80 OCH3 CH3 CH3 O

6

Netherton, M. R.; Dai, C.; Klaus, N.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099-10100.

9-BBN

CH3
7

98

+ Cl B
4

OTBS

5% Pd2(dba)3 20% PCy3 CsOHH2O dioxane, 90 C 72%

OTBS
4

9-BBN CH3 CH3 Br

CN
8

CH3 CH3

81 (CH2)8CN

Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 2002, 41, 1945-1947.

With the advent of the PdCl2(dppf) catalyst, primary alkyl groups can be transferred by Suzuki coupling, typically using 9-BBN reagents.
Other suitable coupling partners include aryl or vinyl triflates and aryl iodides. Secondary alkyl boron compounds are not suitable coupling partners for this reaction.

Suzuki Cross-Coupling of Unactivated Secondary Alkyl Halides

Recently, Fu and coworkers have developed a Ni0-catalyzed Suzuki coupling of unactivated alkyl bromides and iodides:

Alkyl boronic esters are also be viable substrates in the B-alkyl Suzuki reaction when thallium salts such as TlOH or Tl2CO3 are used as the base. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314321. Sato, M.; Miyaura, Suzuki, A. Chem. Lett. 1989, 1405-1408. The large bite angle of the dppf ligand has been noted and is believed to provide a catalyst with a more favorable ratio of rate constants for reductive elimination versus -hydride elimination. 88 Pd PPh2 Ph2P 99 PPh2 I + (HO)2B Br + (HO)2B

Ph

Ph

N 1

4% Ni(cod)2 8% 1 KOt-Bu, s-butanol 60 C, 5h 91 %

PPh2 dppf = Fe

Cl

Cl 4% Ni(cod)2 8% 1 O O KOt-Bu, s-butanol 60 C, 5h 62 %

Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158163. Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta. 1994, 220, 249259.

Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.

Chris Coletta

(+)-Discodermolide (B-Alkyl Suzuki Reaction)

Rutamycin B
I Ph3P CH3

CH3 CH3 O O TBSO MOMO PMP CH3

tBuO
CH3 CH3 OTBS O O H CH3 CH3 B(OH)2 I CH3 OTES 1. TlOH (2.6 equiv) 2. B (0.36 equiv) 3. Pd(PPh3)4 (20 mol %) THF, 23 C, 45 min 77% B = CH3

CH3 (2 equiv)

CHO OMOM

78 C 23 C, THF, 2.5 h 40 %

OTBS O OTBS CH3 CH3 CH3

CH3 CH3 O TBSO

CH3 CH3 CH3 I

E:Z

15:85

O TBSO MOMO PMP A CH3 OMOM

1. tBuLi (2 eq) CH3 CH3 CH3 I 2. PMBO OTES THF 1. K3PO4 (2.3 equiv), 23 C 2. A, DMF 3. PdCl2(dppf) (10 mol %), 16 h 74% CH3 CH3 CH3 O O TBSO MOMO PMP CH3 OMOM CH3 OPMB OTES CH3 CH3 CH3 CH3 BOCH3 Et2O, 78 C CH3O B PMBO OTES CH3 CH3 CH3 Li CH3 OTBS CH3 O O H

tBuO

CH3 OTES CH CH3

3

OTBS O OTBS CH3 CH3 CH3

CH3 O

TBSO

CH3 CH3 CH3 HO CH3 O O OH CH3 OH (+)-Discodermolide Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 78857892. CH3 OH O CH3 O NH2 CH3 Rutamycin B CH3 CH3 CH3 OH O O H

CH3 O O CH3 CH3 CH3 O HO OH O OH CH3 CH3 CH3

Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115, 1144611459.

Andrew Haidle

Palytoxin Amide: O TEOCN H

O O OTBS H TBSO O O O OTBS OTBS A CH3 CH3 TBSO CH TBSO

3

OTBS

OTBS 1. (COCl)2, DMSO, Et3N, 78 0 C OTBS O O TBSO TMEDA, THF, 0 C; 2. B B O O OH Li EtOAc; NaCl, HCl

OTBS OTBS TBSO (HO)2B

3. TlOH (10% aq); B, Pd(PPh3)4, 23 C 4. LiCH2P(O)(OCH3)2 (30 eq.)/THF, 78 C 7580%

I OAc OTBS OTBS OTBS OTBS TBSO O TBSO CH3O O B H2N O OH H HO OH OH O H2N OH CH3 O O OH CH3 OH CH3 HO OH O H HO OH OH OH OH CH3 OH O HO HO OH Kishi, Y., et al. J. Am. Chem. Soc. 1989, 111, 75257530. Kishi, Y., et al. J. Am. Chem. Soc. 1989, 111, 75307533. Palytoxin amide OH CH3 OH HO H OH HO O OH OH H OTBS OTBS OTBS O O OH OH O CH OH 3 OH OH OH OH OH HO OH HO HO OH OH O TEOCN H OTBS H TBSO

O O O O O CH3 OTBS OTBS TBSO CH3 CH3TBSO OTBS TBSO OTBS OTBS

OAc OTBS OTBS OTBS OTBS TBSO O TBSO (CH3O)2 P O H OTBS O OTBS OTBS

CH3

OH OH

Andrew Haidle

Epothilone A:

Synthesis of organoboron compounds:

S CH3 N CH3 (CH3)3Si CH3 1. N-iodosuccinimide AgNO3, acetone 0 23 C, 1.5 h CH3 3. PhSH, BF3OEt2 CH2Cl2, 23 C 4. Ac2O, Py, 4-DMAP CH2Cl2, 23 C 35% CH3 S CH3 N CH3 H PdCl2(dppf)2 (10 mol %) OAc Ph3As (10 mol %) CsCO3, H2O, DMF 4 h, 23 C; I Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 34473450. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 75087510. S CH3 CH3 N CH3 O H O O OH CH3 Epothilone A CH3 O OH CH3 CH3 CH3 S N CH3 H CH3 2 h, 23 C, 75% Aryl bromides and chlorides can also be used. B CH3 CH3 OCH3 OCH3 OTIPS OTBS O2N OTf 2. (c-Hex)2BH Et2O, AcOH, 23 C CH3 CH3 OCH3 OCH3 OTIPS OTBS Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 13161319. Li H R BX2

OMOM

1. B(Oi-Pr)3 (1 equiv) Et2O, 78 C 23 C, 4 h 2. HCl/Et2O, 0 C, 30 min 84% B(Oi-Pr)2

9-BBN THF, 23 C CH3 CH3 CH3 CH3

CH3 CH3 CH3 CH3 O O2N B O CH3 CH3 CH3 CH3

O B O B

O O

PdCl2(dppf) (3 mol %) KOAc, DMSO, 80 C 86%

OAc CH3 CH3 CH3

OCH3 OCH3 OTIPS OTBS

BX2 R

n-Bu

Br

1. HBBr2S(CH3)2 2. i-PrOH 87%

Br

n-Bu

KHB(Oi-Pr)3 n-Bu B(Oi-Pr)2 Et2O

89%

B(Oi-Pr)2

Meng, D.; Bertinato, P.; Balog, A.; Su, D.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S., J.

J. Am. Chem. Soc. 1997, 119, 1007310092.

Brown, H. C.; Imai, T. Organometallics 1984, 3, 13921395.

Andrew Haidle

1. n-BuLi,

n-Hex

Et2O, 78 C H 2. B(Oi-Pr)3 3. HCl/Et2O 95%

H2

B(Oi-Pr)2

R' R BX2

n-Hex

B(Oi-Pr)2

n-Hex
Lindlar cat. 82% 95:5 E:Z

Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 26312634. Srebnik, M.; Bhat, N. G.; Brown, H. C. Tetrahedron Lett. 1988, 29, 26352638. [Rh(cod)Cl]2 (1.5 mol %) P(i-Pr)3 (6 mol %) O TBSO (1.2 equiv) Et3N (1.0 equiv) cyclohexane, 20 C, 2 h HB O O (1.0 equiv)

n-Bu

1. (Ipc)2BH 2. CH3CHO

n-Bu

pinacol B(OEt)2

n-Bu

B O

CH3 CH3

CH3 CH3 CH3 HO OH CH3 = pinacol CH3

TBSO B O

n-Bu

CH3 CH3

B O

CH3 CH3

EtZnI PdCl2(dppf) (1 mol%) Et2O, 25 C, 2 h 67%

CH3 CH3

Moriya, T.; Miyaura, N.; Suzuki, A. Chemistry Lett. 1993, 14291432. 72 %, 98 % Z

Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122, 49904991.

BX2 R R'

BX2 Br O B O O

n-Hex
O HB O

n-BuLi
Et2O, 78 C 83%

O CH3

n-Hex

n-Pr

H THF, 70 C 80%

n-Pr

B O

O Grignard reagents can also be used. Brown, H. C.; Imai, T.; Bhat, N. G. J. Org. Chem. 1986, 51, 52775282.

Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 43704371.

n-Bu n-Bu
H 1. Et3SiH, 78 C 2. BCl3

Br

n-HexBHBrS(CH3)2
Et2O, 0 C

Br

n-Bu

B Br

n-Hex

NaOCH3 CH3OH

B(OCH3)2

n-Bu

n-Hex
> 75%

n-Bu

HO BCl2 83%

OH

n-Bu

B O

Exact yield not specified because the vinyl borane shown was oxidized to a ketone. Soundararajan, R.; Matteson, D. S. J. Org. Chem. 1990, 55, 22742275. Brown, H. C.; Basavaiah, D.; Kulkarni, S. U. J. Org. Chem. 1982, 47, 38083810.

Andrew Haidle

Comparison of the Stille and Suzuki cross-coupling methods: B(OH)2 The yields are often comparable: OCH3 OCH3 O MenO TfO OCH3 Pd(PPh3)4 (5 mol %) CuI (4 mol %) LiCl (4.4 equiv) BHT (1.8 mol %) OtBu O MenO CH3O NH O OtBu Holzapfel, C. W.; Dwyer, C. Heterocycles 1998, 48, 15131518. CH3 O CH3 NO2 Pd(PPh3)4 (10 mol %) K3PO4 DME, 85 C OCH3 82% OTf NO2 Pd2dba3 (5 mol %) P(o-tol)3 (40 mol %) LiCl, dioxane, 85 C 80% NO2 Sn(CH3)3 OCH3

(CH3)3Sn

H N

pdioxane, reflux, 1 h
81%

CH3O

Some highly sensitive compounds do not tolerate the basic conditions of the Suzuki reaction. Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1652.

O MenO TfO

CH3 O OCH3 Pd(PPh3)4 (4 mol %) Na2CO3 MenO CH3O NH O OtBu CH3

When alkylboron and alkylstannane groups are present in the same molecule, the organoboron groups react preferentially under basic conditions. O OCH3 CH3 PdCl2(dppf) (3 mo l%) Br B Sn(CH3)3 K3PO4, DMF 5060 C, 88% O CH3 Sn(CH3)3

pdioxane, reflux, 45 min

(HO)2B H N O OtBu 90%

CH3O

Ishiyama, T.; Miyaura, N.; Suzuki, A. Synlett 1991, 687688. The cross-coupling reaction of primary organoboranes is possible, while primary organo OH O = Men CH3 OH O HO (+)-Dynemicin A H HN CH3 COOH O OCH3 H S S CH3 H 1. 9-BBN, THF, 0 C 2. Br OAc CH3 CH3 CO2CH3 S S CH3 H stannanes are not typically used. CH3O2C CH3

CH3

CH3

PdCl2(dppf) (15 mol %) K2CO3, DMF, 50 C The higher cost and toxicity of organostannanes makes the Suzuki coupling the preferred method. 77% Myers, A. G.; Tom., N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc. 1997, 119, 60726094.

OAc CH3

Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, Y. J. Am. Chem. Soc. 1991, 113, 54025410.

Andrew Haidle

 Stille couplings with primary organostannanes typically involve special structural features, such as an -heteroatom, and typically cannot undergo -hydride elimination.

In the following examples, the Suzuki coupling was successful but the corresponding Stille reaction failed. This was attributed to a proposed slower rate of transmetalltion in the Stille reaction. CH3O O CH3O I CH3O O OCH3 O

Bu3Sn Br

OCH3 (1.3 equiv) OCH3

CH3O

H3C CH 3 O CH3 B O CH3 OCH3

PdCl2(PPh3)2 (1 mol %) HMPA, 80 C, 20 h 73%

PdCl2(dppf) (3 mol %) K3PO4, DMF, 5060 C 88%

Kosugi, M.; Sumiya, T.; Ogata, T.; Sano, H.; Migita, T. Chemistry Lett. 1984, 12251226.

OCH3 The Stille coupling has been used for the introduction of glycosylmethyl groups. CH3O O CH3O CH3O H3C O O CH3 H OTBS CH3 O H CH3 CH3 OCH3 OTf Pd(PPh3)4 (20 mol %) LiCl (40 equiv) THF, 130 C 52% CH3 H CH3 O AcO O Bu3Sn O O OAc (7.6 equiv) CH3 CH3 H OTBS CH3 O OCH3 O CH3O O CH3 CH3 CH3O I CH3O O OCH3 O O CH3O O O OCH3 OCH3 O O

versus CH3O Sn(CH3)3 OCH3 various conditions CH3O H CH3O O O

CH3O

Sn(CH3)3 OCH3

Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J.

J. Am. Chem. Soc. 1999, 121, 65636579.

O OCH3

Zembower, D.E.; Zhang, H. J. Org. Chem. 1998, 93009305.

Andrew Haidle