12 the suzuki reaction

Myers Chem 115 The Suzuki Reaction Reviews: Analysis of Elementary Steps in the Reaction Mechanism Suzuki, A J Organometallic Chem 1999, 576, 147–168 Oxidative Addition Br Suzuki, A In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Stang, P J., Eds.; WileyVCH: New York, 1998, pp 49-97 Br Pd0Ln L isomerization Pd L PdII Br L Miyaura, N.; Suzuki, A Chem Rev 1995, 95, 2457-2483 L trans cis B-Alkyl Suzuki reaction: Chemler, S R.; Trauner, D.; Danishefsky, S J Angew Chem., Int Ed Engl 2001, 40, 4544–4568 Solid phase: Franzén, R Can J Chem 2000, 78, 957–962 • Relative reactivity of leaving groups: I – > OTf – > Br – >> Cl – • Oxidative addition is known to proceed with retention of stereochemistry with vinyl halides and with inversion with allylic or benzylic halides 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 or triflate using a palladium catalyst It is a powerful cross-coupling method that allows for the synthesis of conjugated olefins, styrenes, and biphenyls: • Oxidative addition intially gives a cis complex that rapidly isomerizes to its trans isomer Casado, A L.; Espinet, P Organometallics 1998, 17, 954–959 Transmetallation n-Bu B O O + n-Bu benzene/NaOEt Br 80 ˚C, h B(OR)2 98% n-Bu Miyaura, N.; Suzuki, A J Chem Soc., Chem Commun 1979, 866–867 L2Pd Mechanism: X Ph Path B n-Bu X Ar L2Pd H n-Bu B H OR Ph PhL2Pd B(OR)2 + n-Bu O OR OR R Ph Br Pd0L Oxidative Addition n Reductive Elimination Ph n-Bu EtO L2Pd n-Bu RO– + B(OR)3– + Path A B O n-Bu PdIILn Ph PdIILn Br NaOEt Ph PdIILn EtO B O O NaBr Transmetallation O + L O n-Bu L PdII EtO B O • Organoboron compounds are highly covalent in character, and not undergo transmetallation readily in the absence of base • The base is postulated to serve one of two possible roles: reaction with the organoboron reagent to form a trialkoxyboronate which then attacks the palladium halide complex (Path A), or by conversion of the palladium halide to a palladium oxo complex that reacts with the neutral organoboron reagent (Path B) 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 Reductive Elimination L • The conditions shown on the left are the original conditions developed for the cross-coupling by Suzuki and Miyaura n-Bu L PdII L • The reaction is stereo- and regiospecific, providing a convenient method for the synthesis of conjugated alkadienes, arylated alkenes, and biaryls n-Bu n-Bu PdII + Pd0Ln L cis trans • 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 • Isomerization to the cis complex is required before reductive elimination can occur • Relative rates of reductive elimination from palladium(II) complexes: aryl–aryl > alkyl–aryl > n-propyl–n-propyl > ethyl–ethyl > methyl–methyl Miyaura, N.; Suzuki, A Chem Rev 1995, 95, 2457-2483 Catalyst and ligands Conditions R BY2 n-Bu P(PPh3)4 X R' + R R' benzene, 80 ºC Ph Br B O O base time (h) yield (%) NaOEt 80a NaOEt 80a NaOEt 81a NaOEt 100b Ph Br CH3 Br CH3 I Ph Br Ph Cl Ph Miyaura, N.; Yamada, K.; Suzuki, A Tetrahedron Lett 1979, 20, 3437–3440 Miyaura, N.; Suzuki, A J Chem Soc., Chem Commun 1979, 866–867 c Miyaura, N.; Yanagi, T.; Suzuki, A Synth Commun 1981, 11, 513–519 d Miyaura, N.; Yano, T.; Suzuki, A Tetrahedron Lett 1980, 21, 2865–2868 b • 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) • "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, 61–68 N 63b 98b NaOEt NaOEt NaOEt 3b NaOEt 93b H3C CH3 H3C N CH3 H3C H3C CH3 N CH3 + N Cl– CH3 H3C H3C CH3 H3CO Br (HO)2B + I Ph 2M NaOH 62c Br Ph 2M Na2CO3 88c Cl Ph NaOEt 0c 2M NaOH 87d 2M NaOH 99d B(OH)2 n-Bu H3C Br Cl Pd2(dba)3 (1.5 mol%), (3 mol%), Cs2CO3 H3C dioxane, 80 ºC, 1.5 h 96% • The nucleophilic N-heterocyclic carbene is the active ligand, and is formed in situ from • The use of ligand 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) B Br Zhang, C.; Huang, J.; Trudell, M L.; Nolan, S P J Org Chem 1999, 64, 3804-3805 Andrew Haidle, Chris Coletta, Fan Liu 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 compatibility with the coupling partners and availability (see section on synthesis of organoboranes) N-methyliminodiacetic acid (MIDA) Boronates • This trivalent boron protecting group attenuates transmetallation, and is unreactive under anhydrous coupling conditions (see example below) • Some of the more common organoboranes used in the Suzuki reaction are shown below: R B(OH)2 H3C N O R B(OiPr)2 B O O R B O R B R B O O O O CH3 CH3 EtO B B O O K3PO4, THF, 65 oC PCy2 Br CH3 CH3 H3C N p-Tol-B(OH)2 Pd(OAc)2 O O H3C • 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 BF3K Br OCH3 Pd(OAc)2, K2CO3 OCH3 R 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 B O O O O 1M NaOH, THF 10 OH B OH R aq NaHCO3 MeOH, 3.5 h Gillis, E P.; Burke, M D J Am Chem Soc 2007, 129, 6716-6717 Gillis, E P.; Burke, M D J Am Chem Soc 2008, 130, 14084-14085 • Many unstable boronic acids, such as 2-heteroaryl, vinyl and cyclopropyl, form bench-stable MIDA complexes • "Slow release" of boronic acid allows effective coupling of these substrates Molander, G A.; Biolatto, B J Org Chem 2003, 68, 4302–4314 OtBu 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, 4324–4330 H3C N S B O O O O Ot-Bu Cl Pd(OAc)2, SPhos K3PO4, dioxane, water 60 oC, h S 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 Bulky, Electron-Rich Phosphines as Ligands for the Suzuki Reaction TlOH and TlOEt as Rate-Enhancing Additives for the Suzuki Reaction TBSO OTBS OTBS TBSO I OTBS OTBS OTBS + TBSO O (HO)2B OTBS OTBS R (H3C)2N P(t-Bu)3 R = PCy2 (1) R = P(t-Bu)2 (2) OTBS OTBS OTBS OCH3 O Cy2P R R' TBSO OTBS R P(Cy)3 R = PCy2 (3) R = P(t-Bu)2 (4) R R = OCH3, R' = H "SPhos" R = Oi-Pr, R' = H "RuPhos" R = R' = i-Pr "XPhos" OTBS R OCH3 Cl + (HO)2B base temp (°C) time yield relative rate KOH 23 2h 86 R ligand Pd source base solvent temp (°C) time (h) yield (%) TlOH 23