The Suzuki Reaction Chem 115 Reviews: Analysis of Elementary Steps in the Reaction Mechanism Suzuki, A

Home , Coupling reaction, Stille reaction, Suzuki reaction

Myers The Suzuki Reaction Chem 115 Reviews: Analysis of Elementary Steps in the Reaction Mechanism Suzuki, A. J. Organometallic Chem. 1999, 576, 147–168. Oxidative Addition Br L Suzuki, A. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Stang, P. J., Eds.; Wiley- Br 0 Pd Ln isomerization VCH: New York, 1998, pp. 49-97. Pd L PdII Br L L Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. cis trans

B-Alkyl Suzuki reaction: • Relative reactivity of leaving groups: I – > OTf – > Br – >> Cl –. Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 2001, 40, 4544–4568. • Oxidative addition is known to proceed with retention of stereochemistry with vinyl halides and with Solid phase: inversion with allylic or benzylic halides. Franzén, R. Can. J. Chem. 2000, 78, 957–962. Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434–442. • The Suzuki reaction is the coupling of an aryl or vinyl boronic acid with an aryl or vinyl halide • Oxidative addition intially gives a cis complex that rapidly isomerizes to its trans isomer. 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, 954–959.

Transmetallation n-Bu benzene/NaOEt n-Bu O B + Br – O 80 ˚C, 4 h Path A B(OR)3 X B(OR)2 + L2Pd Ar H OR 98% n-Bu n-Bu B OR n-Bu RO– H + Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866–867. X B(OR) PhL2Pd O L Pd OR 2 R 2 + Mechanism: Ph L2Pd Path B Ph n-Bu n-Bu Ph Br 0 Pd Ln Oxidative Addition L n-Bu O Reductive Elimination II Pd + EtO B L O Ph PdIIL Ph n-Bu n PdIIL Br n • Organoboron compounds are highly covalent in character, and do not undergo transmetallation EtO O B NaOEt readily in the absence of base. O Ph PdIIL • The base is postulated to serve one of two possible roles: reaction with the organoboron reagent to EtO n NaBr form a trialkoxyboronate which then attacks the palladium halide complex (Path A), or by n-Bu conversion of the palladium halide to a palladium oxo complex that reacts with the neutral B O Transmetallation organoboron reagent (Path B). O

Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–470. Carrow, B.P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116–2119. Suzuki, A. Pure & Appl. Chem. 1985, 57, 1749–1758. Andrew Haidle, Chris Coletta, Eric Hansen

1 Reductive Elimination • The conditions shown on the left are the original conditions developed for the cross-coupling by Suzuki and Miyaura. L • The reaction is stereo- and regiospeciﬁc, providing a convenient method for the synthesis of n-Bu n-Bu II n-Bu conjugated alkadienes, arylated alkenes, and biaryls. Pd II L Pd + Pd0L L n • Note that under the conditions shown above, aryl chlorides are not acceptable substrates for the L reaction, likely due to their reluctance to participate in oxidative addition. trans cis a Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437–3440. • Isomerization to the cis complex is required before reductive elimination can occur. b Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866–867. • Relative rates of reductive elimination from palladium(II) complexes: c Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513–519. aryl–aryl > alkyl–aryl > n-propyl–n-propyl > ethyl–ethyl > methyl–methyl d Miyaura, N.; Yano, T.; Suzuki, A. Tetrahedron Lett. 1980, 21, 2865–2868. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. Catalyst and ligands Conditions • The most commonly used system is Pd(PPh ) , but other palladium sources have been used P(PPh ) 3 4 3 4 including PdII pre-catalysts that are reduced to the active Pd0 in situ: R BY2 + X R' R R' benzene, 80 ºC • Pd2(dba)3 + PPh3 base time (h) yield (%) • Pd(OAc)2 + PPh3 • PdCl2(dppf) (for sp3-sp2 couplings-see section on B-alkyl Suzuki reaction) Ph a Br NaOEt 2 80 n-Bu O B • "Ligand-free" conditions, using Pd(OAc)2, have also been developed. Side reactions often Ph O associated with the use of phosphine ligands (phosphonium salt formation and aryl-aryl exchange NaOEt 2 80a Br between substrate and phosphine) are thus avoided.

CH Br 3 Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1997, 75, 61–68. NaOEt 2 81a CH3

I Ph NaOEt 2 100b CH3 H3C CH3 H3C + NaOEt 2 63b N N N N Br Ph b Cl– NaOEt 4 98 H3C CH3 H3C CH3 CH3 H3C CH3 H3C Cl Ph NaOEt 2 3b 1 2

H3CO NaOEt 4 93b Pd2(dba)3 (1.5 mol%), Br H3C (HO)2B 2 (3 mol%), Cs2CO3 + H3C Cl dioxane, 80 ºC, 1.5 h I Ph 2M NaOH 6 62c B(OH)2 96%

c Br Ph 2M Na2CO3 6 88 • The nucleophilic N-heterocyclic carbene 1 is the active ligand, and is formed in situ from 2. Cl Ph NaOEt 6 0c • The use of ligand 1 allows for utilization of aryl chlorides in the Suzuki reaction (see the section on d Br 2M NaOH 2 87 bulky, electron-rich phosphines as ligands for use of aryl chlorides as coupling partners as well). n-Bu B Br Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804-3805. 2M NaOH 2 99d Andrew Haidle, Chris Coletta, Fan Liu

2 Organoboranes: A variety of organoboranes may be used to effect the transfer of the organic coupling N-methyliminodiacetic acid (MIDA) Boronates partner to the reactive palladium center via transmetallation. Choice of the appropriate organoborane • This trivalent boron protecting group attenuates transmetallation, and is unreactive under will depend upon the compatibility with the coupling partners and availability (see section on synthesis anhydrous coupling conditions (see example below). of organoboranes).

H3C N • Some of the more common organoboranes used in the Suzuki reaction are shown below: p-Tol-B(OH)2 H C O 3 N Pd(OAc)2 B O O O O O o B O K3PO4, THF, 65 C R B(OH)2 R B(OiPr)2 R B O O O PCy2 Br H3C R CH3 O CH3 R B B EtO B O CH3 CH 3 • MIDA boronates are stable to chromatography but are readily cleaved under basic aqueous conditions: • Use of Aryltrifluoroborates as Organoboranes for the Suzuki Reaction

H3C N 1M NaOH, THF OH O 10 min Pd(OAc)2, K2CO3 B O B O OH BF3K Br OCH3 OCH3 R O R aq. NaHCO CH3OH, reﬂux 3 2h, 95% MeOH, 3.5 h

Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716-6717. • The aryltrifluoroborates are prepared by treatment of the corresponding arylboronic acid with Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084-14085. excess KHF2. • Many unstable boronic acids, such as 2-heteroaryl, vinyl and cyclopropyl, form bench-stable MIDA complexes. • According to the authors, aryltrifluoroborates are more robust, more easily purified, and less prone to protodeboronation compared to aryl boronic acids. • "Slow release" of boronic acid allows effective coupling of these substrates.

Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–4314.

OtBu H C Solvent: The Suzuki reaction is unique among metal-catalyzed cross-coupling reactions in that it can 3 N Ot-Bu be run in biphasic (organic/aqueous) or aqueous environments in addition to organic solvents. Cl O S B O S O O Pd(OAc)2, SPhos Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112, 4324–4330. K3PO4, dioxane, water 60 oC, 6 h 94%

(Yield from the corresponding boronic acid: 37%)

Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961-6963.

Andrew Haidle, Chris Coletta, Eric Hansen

3 TlOH and TlOEt as Rate-Enhancing Additives for the Suzuki Reaction Bulky, Electron-Rich Phosphines as Ligands for the Suzuki Reaction

TBSO OTBS R I R Cy2P R TBSO OTBS OTBS P(Cy)3 OTBS OTBS R' OTBS TBSO + (H C) N TBSO OTBS 3 2 P(t-Bu)3 R R = PCy (1) R = PCy (3) O 2 2 R = OCH3, R' = H "SPhos" (HO)2B OTBS R = P(t-Bu) (2) R = P(t-Bu) (4) OTBS 2 2 R = Oi-Pr, R' = H "RuPhos" OTBS OCH3 OTBS R = R' = i-Pr "XPhos"

O OTBS R Cl + (HO)2B OCH3

base temp (°C) time yield relative rate

KOH 23 2 h 86 1 R ligand Pd source base solvent temp (°C) time (h) yield (%)

TlOH a 23 <<30 s 92 1000 CH3 PPh3 Pd2(dba)3 Cs2CO3 dioxane 80 5 0

Pt-Bu Pd (dba) Cs CO dioxane 80 5 86a CH 3 2 3 2 3 • TlOH greatly accelerates the rate of coupling, which the authors attribute to acceleration of the 3 b 4 Pd(OAc)2 KF THF 23 6 95 hydroxyl–halogen exchange at palladium. a Pt-Bu3 Pd2(dba)3 Cs2CO3 dioxane 80 5 89 CH3O 4 Pd(OAc) KF THF 45 6 93b Uenishi, J.; Beau, J.; Armstrong, R. W.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756–4658. 2 a NH2 Pt-Bu3 Pd2(dba)3 Cs2CO3 dioxane 80 5 92 O • TlOH vs. TlOEt a Pt-Bu3 Pd2(dba)3 Cs2CO3 dioxane 80 5 91 H3C

t-BuO2C CO2t-Bu (HO)2B OH t-BuO2C CO2t-Bu (5 equiv) a Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020–4028. b Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550–9561. Pd(PPh3)4 (10 mol %) I TlOEt (1.8 equiv) • Bulky phosphine ligands lead to a monoligated palladium species which is highly reactive to

CO2Me 3:1 THF:H2O 97% CO2Me oxidative addition. THF (anhydrous) 93% HO • These ligands are commercially available. • 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 • The increased activity of the ligands shown above allows unactivated aryl chlorides and bromides to aqueous solutions are both air and light sensitive. be employed in Suzuki couplings under mild conditions. • The largest problem with using TlOEt is that some boronic acid–TlOEt adducts are not very soluble. Using water as a cosolvent helps to alleviate this problem in many cases. Christmann, U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44, 366–374. Fu, G. Acc. Chem. Res. 2008, 41, 1555–1564. Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 2691–2694.

Chris Coletta, Eric Hansen, Fan Liu

4 Selected Applications in Industry Alkyl Di-tert-butylphosphane-Ligated Palladium(I) Dimers as Catalysts for the Suzuki Reaction • The Suzuki reaction is routinely used in the fine chemical, agrochemical and pharmaceutical Br industries. I I [t-Bu2(1-Ad)P]Pd Pd [P(1-Ad)t-Bu2] Br Br + (HO)2B SO2Me KOH, THF, 15 min, RT SO2Me 1. Pd(PPh3)4 (4 mol%) 95% Et2B aq. NaOH + •HCl N n-Bu4NBr, THF • As a solid, the catalytic complex is stable indefinitely in the air. It is believed that the catalyst Br 66 oC, 89.6% N fragments to form the monomeric subunits under the reaction conditions. (14.5 kg) (9.13 kg) (11.44 kg) 2. HCl; ﬁltration

• Reactions of phenylboronic acids with (deactivated) aryl chlorides occurred rapidly at room temperature, but conversion did not exceed 70%. Lipton, M. F.; Mauragis, M. A.; Maloney, M. T.; Veley, M. F.; VanderBor, D. W.; Newby, J. J.; Appell, R. B.; Daugs, E. D. Org. Proc. Res. Dev. 2003, 7, 385–392.

Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem. Int. Ed. 2002, 41, 4746-4748. • Application to the synthesis of a tyrosine kinase inhibitor:

• Ligand 5, accessible in kilogram quantities and stable indefinitely in the air, was found to be highly F F effective for Suzuki coupling of sterically congested substrates. O O O Cl HN N CH3 HN N CH3 H2N H H P Ph Pd(OAc) (2 mol%) t-Bu N + 2 N dppf (2 mol%) H CO OCH H N Br 3 3 H 2 Pd (dba) (1 mol%) Ph i-Pr B 2 3 O O K3PO4, EtOH, H2O (21.6 kg) (50.0 kg) N (40.9 kg) 5 (2 mol%) 5 55 oC, 84% + i-Pr H C CH N 3 3 H K3PO4, toluene H3C CH3 Linifanib (ABT-869) i-Pr 100 ºC, 96% i-Pr

(HO) B i-Pr 2 Kruger, A. W.; Rozema, M. J.; Chu-Kung, A.; Gandarilla, J.; Haight, A. R.; Kotecki, B. J.; Richter, S. i-Pr M.; Schwartz, A. M.; Wang, Z. Org. Proc. Res. Dev. 2009, 13, 1419–1425.

• Application to the synthesis of Xalkori!, an anti-cancer drug for treatment of non-small cell lung carcinoma: • Other ligands such as SPhos, RuPhos, XPhos, PPh3, PCy3, and Pt-Bu3 generally proceeded with <20% conversion. NH Boc N Br N N 1. Pd(dppf)Cl2-CH2Cl2 Cl CH 3 N N (0.9 mol%) CH3 H3CO Pd (dba) (1 mol%) H3C H CO 2 3 3 N + TBAB, Cs CO 5 (2 mol%) O 2 3 Cl CH Br + (HO)2B OCH3 3 OCH3 NH2 B Toluene, H2O N K3PO4, toluene Cl O O 70 oC, 76% O CH H3CO F 3 100 ºC, 96% H3C H3CO NH2 (49.6 kg) H3C CH3 2. HCl, EtOH, 80% Cl H C CH3 3 F (20.7 kg) (59.1 kg) Crizotinib (Xalkori!) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. Angew. Chem. Int. Ed. 2010, 49, 5879–5883. de Koning, P. D. et. al. Org. Proc. Res. Dev. 2011, 15, 1018–1026. Chris Coletta, Eric Hansen, Fan Liu

5 B-Alkyl Suzuki Reaction sp3-sp3 Suzuki Coupling

PdCl2(dppf) (3 mol%) R' Br + B R R' R • By employing a bulky, electron-rich ligand (similar to the ligands used in aryl chloride Suzuki THF, NaOH, reﬂux couplings) Fu and coworkers are able to effect the Suzuki coupling of primary alkyl bromides or chlorides and 9-alkyl-9BBN: vinyl bromide 9-alkyl-9-BBN product yield (%)

4% Pd(OAc)2 9-BBN CH3 CH3 8% PCy Br Ph 85 3 Ph 7 6 + Br CH3 CH3 B 9 K2PO4•H2O 9 CH3 9-BBN OCH3 CH3 85% THPO Br 2 THPO OCH3 OCH3 80 OCH3 Netherton, M. R.; Dai, C.; Klaus, N.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099–10100. CH3 CH3 9-BBN CH Br 3 CH3 7 98 6 5% Pd2(dba)3 CH CH 3 3 20% PCy3 + Cl OTBS 4 OTBS O O B CsOH•H2O dioxane, 90 ºC 4 9-BBN CN 81 72% 8 H3C H3C Br (CH2)8CN H3C H3C 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. Suzuki Cross-Coupling of Unactivated Secondary Alkyl Halides

• Other suitable coupling partners include aryl or vinyl triﬂates and aryl iodides. • Fu and coworkers have developed a Ni0-catalyzed Suzuki coupling of unactivated secondary • Secondary alkyl boron compounds are not suitable coupling partners for this reaction. alkyl bromides and iodides: Ph Ph • 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. N N Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314–321. 1 4% Ni(cod)2 Sato, M.; Miyaura, Suzuki, A. Chem. Lett. 1989, 1405–1408. 8% 1 Br + (HO)2B • The large bite angle of the dppf ligand has been noted and is believed to provide a catalyst with a KOt-Bu, s-butanol more favorable ratio of rate constants for reductive elimination versus !-hydride elimination. 60 ºC, 5h 91% Cl 88° Cl PPh2 4% Ni(cod)2 8% 1 Pd + dppf = Fe I (HO)2B O KOt-Bu, s-butanol PPh2 99° Ph2P PPh2 O 60 ºC, 5h 62% Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158–163. Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340–1341. Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta. 1994, 220, 249–259. Chris Coletta

6 sp3-sp3 Suzuki Cross-Coupling of Unactivated Secondary Alkyl Halides • Nickel catalysts have been effective with electrophiles that are inert to palladium catalysts, including • Diamine 2 was found to be an effective ligand for metal-catalyzed cross-coupling of unactivated alkyl carbonates, carbamates, sulfamates, esters, phosphate esters and ethers. electrophiles. Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270–5298.

H3C NH HN CH3 2

R R NiCl2(PCy3)2 NiCl2-glyme (6 mol%) (HO) B 2 K PO 2 (8 mol%) Ph + 3 4 Br + 9-BBN Ph X OMe KOtBu, i-BuOH Toluene, 110 oC OMe dioxane, 23 ºC 75% X = OC(O)NEt2 R = H 52%

X = OSO2NMe2 R = H 83% X = OPiv R = Me 79% NiCl2-glyme (6 mol%) 2 (8 mol%) + 9-BBN Ph KOtBu, i-BuOH Ph Br dioxane, 23 ºC 65%

• "endo-2-bromonorbornane is converted into the exo product, most likely due to a radical pathway for oxidative addition." –– Gonzalez-Bobes, F.; Fu, G. J. Am. Chem. Soc. 2006, 128, 5360–5361. Quasdorf, K. W.; Reiner, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748– 17749. Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602–9603. Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008, 130, 14422–14423.

Nickel Catalyzed Suzuki Couplings

NiCl2(PPh3)2 K PO (HO) B 3 4 Cl + 2 N N N N MeO MeO 2-Me-THF 100 oC, 91%

Ramgren, S.D.; Hien, L.; Ye, Y.; Garg, N. K. Org. Lett. 2013, 15, 3950–3953

Eric Hansen

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

I t–BuO O CH3 CH3 Ph3P CH3 1. TlOH (2.6 equiv) CH3 (2 equiv) CH3 O O TBSO MOMO 2. B (0.36 equiv) CHO CH OTBS CH3 –78 °C ! 23 °C, 3 O 3. Pd(PPh3)4 (20 mol %) CH3 PMP OMOM OTES THF, 2.5 h OTBS O O THF, 23 °C, 45 min CH3 CH3 B = H OTBS 40 % 77% CH3 CH3 CH3 O CH3 CH3 CH3 I TBSO E:Z 15:85 CH3 O O TBSO MOMO CH B(OH) CH 3 2 I 3 CH PMP OMOM 3 A

1. t–BuLi (2 eq) t–BuO O

CH3 CH3 CH3 Et2O, –78 ˚C CH3O CH CH CH I 3 3 3 B Li 2. CH3 OTBS PMBO OTES CH BOCH3 3 PMBO OTES CH3 O OTES O CH3 OTBS O THF OTBS CH3 CH H 3 1. K3PO4 (2.3 equiv), 23 °C O CH3 2. A, DMF CH3 TBSO CH3 3. PdCl2(dppf) (10 mol %), 16 h

74% CH3

CH3 CH CH3 CH3 CH3 3

CH3 O O TBSO MOMO OPMBOTES CH3 CH3 PMP OMOM CH3 CH3 O OH

CH3 O O O CH3 OH O CH3 CH3 CH3 CH3 OH CH3 CH HO H 3 CH3 O O OH OH O O CH3 CH3 CH3 CH3 CH3 HO CH O OH NH2 3

Rutamycin B CH3 (+)-Discodermolide

Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115, 11446–11459. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885–7892. Andrew Haidle

8 Palytoxin Amide: O O OTBS CH3 TBSO OTBS 1. (COCl) , DMSO, Et N, –78 ! 0 °C O O 2 3 OTBS TBSO OTBS O CH3 TEOCN OTBS O O TBSO H O TBSO TMEDA, THF, 0 °C; OTBS 2. B B H O O OH (HO)2B TBSO CH3 Li OTBS EtOAc; NaCl, HCl OTBS 3. TlOH (10% aq); B, Pd(PPh ) , 23 °C A 3 4 4. LiCH2P(O)(OCH3)2 (30 eq.)/THF, –78 °C I 75–80% OAc OTBS OTBS O O CH TBSO OTBS O O 3 OTBS CH TBSO OTBS O 3 OTBS TEOCN OTBS H O TBSO OTBS TBSO H CH3 OTBS TBSO OTBS O OTBS OAc TBSO OTBS OTBS H OTBS CH O 3 OTBS O O OTBS OH HO OH O O OTBS B HO OH OH H2N OH TBSO O HO OH OTBS H O CH3 HO OH TBSO OTBS OH OH H OH (CH O) 3 2 P OTBS OH OH O O HO OH OH O CH3 OH CH3 OH OH OH H N O 2 H OH OH OH HO CH3 HO OH OH O CH 3 O HO O CH3 OH CH OH OH 3 H O OH HO OH OH HO OH OH

Kishi, Y., et al. J. Am. Chem. Soc. 1989, 111, 7525–7530. Palytoxin amide

Kishi, Y., et al. J. Am. Chem. Soc. 1989, 111, 7530–7533. Andrew Haidle

9 Epothilone A: Synthesis of organoboron compounds:

S CH3 N BX2 H R OMOM CH3

(CH3)3Si 1. B(Oi-Pr)3 (1 equiv) OCH3 CH3 Et2O, –78 °C ! 23 °C, 4 h Li B(Oi-Pr) CH OCH 2 3 3 2. HCl/Et2O, 0 °C, 30 min 1. N-iodosuccinimide 2. (c-Hex)2BH CH3 OTIPS AgNO3, acetone Et2O, AcOH, 23 °C 84% 0 ! 23 °C, 1.5 h OTBS

CH3 Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316–1319. 3. PhSH, BF3•OEt2 4. Ac2O, Py, 4-DMAP CH2Cl2, 23 °C CH2Cl2, 23 °C 9-BBN THF, 23 °C CH3 CH 35% 3 CH3 O O CH B B 3 CH CH3 3 O O OCH3 CH3 CH3 CH3 CH3 B CH3 OCH3 O S PdCl2(dppf) (3 mol %) CH3 O N OTf O2N B CH3 CH3 2 CH3 OTIPS KOAc, DMSO, 80 ˚C O N PdCl2(dppf)2 (10 mol %) CH H 3 OAc Ph3As (10 mol %) OTBS 86% CH3 CsCO3, H2O, DMF CH3

4 h, 23 °C; 2 h, 23 °C, 75% • Aryl bromides and chlorides can also be used. I Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447–3450.

Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510. S S CH3 CH3 N N H H O O OAc BX CH CH OCH3 2 3 OH 3 CH3 R O CH OCH CH3 3 3 CH3 CH CH3 3 OTIPS O Br B(Oi-Pr)2 OTBS 1. HBBr2•S(CH3)2 KHB(Oi-Pr) Epothilone A OH n-Bu Br n-Bu 3 n-Bu CH3 CH3 B(Oi-Pr)2 2. i-PrOH Et2O 87% 89%

Meng, D.; Bertinato, P.; Balog, A.; Su, D.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S., J. J. Am. Chem. Soc. 1997, 119, 10073–10092. Brown, H. C.; Imai, T. Organometallics 1984, 3, 1392–1395. Andrew Haidle

10 1. n-BuLi, R' B(Oi-Pr) Et O, –78 °C H2 2 R 2 n-Hex BX n-Hex H n-Hex B(Oi-Pr)2 2 2. B(Oi-Pr)3 Lindlar cat. 3. HCl/Et O 2 82% 95:5 E:Z 95% I I 1. (Ipc) BH pinacol 2 n-Bu n-Bu O Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631–2634. n-Bu I B(OEt) B CH3 2. CH CHO 2 3 O CH Srebnik, M.; Bhat, N. G.; Brown, H. C. Tetrahedron Lett. 1988, 29, 2635–2638. 3 CH H3C 3

[Rh(cod)Cl]2 (1.5 mol %) CH3 P(i-Pr)3 (6 mol %) EtZnI HO OH PdCl (dppf) (1 mol%) O n-Bu O 2 TBSO = pinacol B CH3 TBSO HB (1.0 equiv) CH3 CH3 Et2O, 25 °C, 2 h CH CH O CH3 O B 3 3 CH (1.2 equiv) O O H3C 3 67% Et3N (1.0 equiv) cyclohexane, 20 °C, 2 h Moriya, T.; Miyaura, N.; Suzuki, A. Chem. Lett. 1993, 1429–1432. 72 %, 98 % Z

Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122, 4990–4991. BX2 R R'

R BX2 O O Br B n-BuLi n-Hex O n-Hex CH B 3 O Et O, –78 °C O 2 HB O 83% n-Pr n-Pr H B O THF, 70 °C O • Grignard reagents can also be used. 80% Brown, H. C.; Imai, T.; Bhat, N. G. J. Org. Chem. 1986, 51, 5277–5282.

Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370–4371. Br B(OCH3)2 n-HexBHBr•S(CH3)2 NaOCH3 n-Bu n-Hex n-Bu n-Bu Br B n-Hex Et2O, 0 °C CH3OH 1. Et3SiH, –78 °C HO OH n-Bu H n-Bu n-Bu O Br > 75% BCl2 B 2. BCl3 83% O • Exact yield not speciﬁed because the vinyl borane shown was oxidized to a ketone.

Brown, H. C.; Basavaiah, D.; Kulkarni, S. U. J. Org. Chem. 1982, 47, 3808–3810. Soundararajan, R.; Matteson, D. S. J. Org. Chem. 1990, 55, 2274–2275. Andrew Haidle

11 Comparison of the Stille and Suzuki cross-coupling methods:

B(OH)2 Sn(CH3)3 • The yields are often comparable: OCH3 OCH3

OCH3 O CH3 NO2 Pd(PPh3)4 (10 mol %) Pd2dba3 (5 mol %) NO2 MenO O CH 3 K PO P(o-tol) (40 mol %) 3 4 NO2 3 TfO OCH MenO DME, 85 °C 3 Pd(PPh3)4 (5 mol %) OTf LiCl, dioxane, 85 °C CH O CuI (4 mol %) 3 OCH3 82% 80% LiCl (4.4 equiv) NH (CH ) Sn BHT (1.8 mol %) 3 3 H Holzapfel, C. W.; Dwyer, C. Heterocycles 1998, 48, 1513–1518. N Ot–Bu p–dioxane, reflux, 1 h O Ot–Bu

O CH O 81% 3 • 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, 1–652.

O CH3 • When alkylboron and alkylstannane groups are present in the same molecule, the organoboron groups react preferentially under basic conditions. MenO O CH3

TfO OCH MenO 3 Pd(PPh3)4 (4 mol %) O CH3O CH O Na2CO3 OCH3 3 CH3 p–dioxane, reflux, 45 min PdCl2(dppf) (3 mo l%) NH Br (HO)2B K PO , DMF Sn(CH3)3 H 90% 3 4 N Ot–Bu O Ot–Bu 50–60 ˚C, 88% B Sn(CH3)3 O CH O 3 Ishiyama, T.; Miyaura, N.; Suzuki, A. Synlett 1991, 687–688.

• The cross-coupling reaction of primary organoboranes is possible, while primary organo– CH H 3 stannanes are not typically used. COOH OH O HN CH3O2C CH3 CH3 CH3 O OCH CH3 = Men 3 S H H 1. 9-BBN, THF, 0 °C CH3 CH S S 3 OH O HO 2. CH3 H Br CO CH S (+)-Dynemicin A 2 3 OAc CH3 PdCl2(dppf) (15 mol %) OAc CH3 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, Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, Y. J. Am. Chem. Soc. 1991, 113, 5402–5410. 6072–6094. Andrew Haidle

12 • Stille couplings with primary organostannanes typically involve special structural features, such as • In the following examples, the Suzuki coupling was successful but the corresponding Stille reaction an !-heteroatom, and typically cannot undergo "-hydride elimination. failed. This was attributed to a proposed slower rate of transmetalltion in the Stille reaction.

CH O O CH O O 3 H3C CH 3 3 I O CH3 B CH Bu3Sn OCH3 (1.3 equiv) O 3 CH3O O CH3O O Br PdCl (PPh ) (1 mol %) 2 3 2 OCH3 OCH3 OCH3 HMPA, 80 °C, 20 h 73% PdCl2(dppf) (3 mol %)

K3PO4, DMF, 50–60 ˚C

88% Kosugi, M.; Sumiya, T.; Ogata, T.; Sano, H.; Migita, T. Chemistry Lett. 1984, 1225–1226.

OCH3

• The Stille coupling has been used for the introduction of glycosylmethyl groups. O CH3O O CH3O O

CH3O O H3C OCH3 OCH3 O CH3 O O CH OTBS CH3 OTBS 3 OAc H versus H CH3 Bu3Sn O (7.6 equiv) CH3 O O CH3O O CH3O O OCH H OCH3 Pd(PPh3)4 (20 mol %) H 3 OTf LiCl (40 equiv) CH CH O CH3 CH3 3 3 O Sn(CH3)3 Sn(CH3)3 THF, 130 °C CH3O O CH3O O AcO O OCH OCH 52% 3 3 O CH3 CH 3 various conditions

CH3O O CH3O O Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J. I H J. Am. Chem. Soc. 1999, 121, 6563–6579.

CH3O O CH3O O

OCH3 OCH3

Zembower, D.E.; Zhang, H. J. Org. Chem. 1998, 9300–9305. Andrew Haidle