1C. The Synthetic & MechanisticOrganic Chemistry of Palladium- Heck Reactions- Stille, Suzuki, Negishi, Sonogashira etc Cross Couplings- π-Allyl Palladium Chemistry- Heteroatom Couplings- Applications in Natural Product SynthesisDr. P. Wipf14/11/20062The Heck ReactionHerbert C. Brown Award for Creative Research in SyntheticMethods(sponsored in part by Sigma-Aldrich since 1998).Richard F. Heck (retired) – University of Delaware (USA)Professor Heck, of “Heck Reaction/Coupling” fame, has had along and distinguished career in chemistry. Beginning with Co-mediated hydroformylation, Heck was one of the first to applytransition metal catalysis to C-C bond formation. His studiesof the mechanisms of transition metal catalyzed reactions ledto Pd-mediated couplings that have had a profound impact inmany areas of chemistry and materials science.Reviews: Shibasaki, M.; Vogl, E. M.; Ohshima, T. "Asymmetric Heckreaction." Advanced Synthesis & Catalysis 2004, 346, 1533-1552.Dounay, A. B.; Overman, L. E. "The asymmetric intramolecular Heck reactionin natural product total synthesis." Chem. Rev. 2003, 103, 2945-2963.Beletskaya, I. P.; Cheprakov, A. V. "The Heck reaction as a sharpening stoneof palladium catalysis." Chem. Rev. 2000, 100, 3009-3066.Dr. P. Wipf24/11/20063The Complex. Among Pd(0) and Pd(II) complexes commonly used arePd(PPh3)4, Pd2(dba)2, and Pd2(dba)2CHCl3. Pd(PPh3)4 should be stored cold andunder inert gas; the dibenzylideneacetone complexes are more stable catalystprecursors. Both phosphine structure and phosphine/Pd ratio effect catalyststructure and reactivity (the lower the phosphine/Pd ratio, the more reactive thecatalyst). A general ratio for high activity system is 2:1.Pd(II) precatalysts include Pd(OAc)2, PdCl2(CH3CN), Pd(PPh3)2Cl2, andPd[(allyl)Cl]2. These complexes are air stable and reduced by phosphines, water,and amines.In most cases, 5-20 mol% catalyst is used, even though more stablecatalysts such as the Herrmann-Beller palladacycle can be used at much lowerloadings.Palladacycles have emerged as promising catalysts for Heck and Suzuki cross-couplings since they exhibit higher air and thermal stability than palladium(0)complexes and can operate through a Pd(II)-Pd(IV) cycle instead of the traditionalPd(0)-Pd(II) mechanism.The Ligand. Among the phosphines used for the Heck reaction are PPh3, P(o-tol)3,P(furyl)3, PCy3, 2-(di-t-butylphosphanyl)-biphenyl, dppe, dppp, dppb, and dppf aswell as AsPh3. PCy3 has been found effective for aromatic chlorides. Bidentatephosphines are used when monodentate ligands are ineffective or to influencestereoselectivity in combination with triflates (cationic pathway).Similarly, N-heterocyclic carbene ligands (for example with N,N'-bis(2,4,6-trimethylphenyl)imidazolium chloride (IMES•HCl)) provide useful, highly reactivecatalytic systems.Dr. P. Wipf34/11/20064The Base. A stoichiometric amount of base is needed, and NaOAc, NaHCO3,Li2CO3, K2CO3, CaCO3, Cs2CO3 and K3PO4 as well as TEA, Hünig’s base, protonsponge, TMEDA, DBU have been used. Silver and thallium salts shift the pathwayto the cationic manifold; they often increase the rate of the reaction, lowerreaction temperatures, minimize alkene isomerization, modify regioselectivity, andalter enantioselectivity. Halide salts (NaX, KX, LiX, TBAX, etc) can divertreactions of triflate precursors from the cationic to the neutral pathway (or,possibly, the anionic pathway).The Salts. The heterogeneous conditions reported by Jeffery are routinelyemployed. TBACl or TBABr are added in stoichiometric amounts and canincreases reaction rates and decrease temperatures. It has been proposed thatthe ammonium halides stabilize the catalytic species by halide coordination, shiftthe equilibrium from the hydridopalladium species to the catalytically active Pd(0),and promote the anionic pathway.The Solvent. Common solvents for the Heck reaction are THF, DMF, NMP,DMAC, and MeCN. Toluene, benzene, EtOH, and water are also used, as arefluorous reaction conditions. Reaction temperatures vary between roomtemperature and reflux.Useful user guidelines: Chapters 3 & 6 by de Meijere and Overman, respectively,in “Metal-catalyzed cross-coupling reactions”, (Diederich & Stang, Eds.), VCH1997.Dr. P. Wipf44/11/20065Mechanism(s)Two mechanistic variants, the “neutral” and the “cationic” pathway havebeen described. In the neutral pathway, the active catalyst is acoordinatively unsaturated 14-electron palladium complex 3. From thehydridopalladium complex 8, a stoichiometric amount of baseregenerates the active catalyst 3.When the substrate is a triflate, or the reaction of halide substrates iscarried out in the presence of halide scavengers, a cationic variant isfollowed. The Pd(II)-intermediate 9 looses a labile X group to give thecationic 10. Coordination of an alkene delivers 11 which, after migratoryinsertion and recoordination of a ligandyields the cationic complex 12. β-Hydrideelimination provides the Heck product 7.Dr. P. Wipf54/11/20066A third mechanism was postulated by Amatore and Jutand, "AnionicPd(0) and Pd(II) intermediates in palladium-catalyzed Heck and cross-coupling reactions." Acc. Chem. Res. 2000, 33, 314-321).Dr. P. Wipf64/11/20067Chen, C.; Liebermann, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P.J. J. Org. Chem. 1997, 62, 2676. A bicyclic amine is necessary to resistoxidation to the imine.Dr. P. Wipf74/11/20068Collini, M. D.; Ellingboe, J. W., "The solid phase synthesis of tri-substituted indoles." Tetrahedron Lett. 1997, 38, 7963. This is a variantof the synthesis of indoles reported by Arcadi and Cacchi.Huang, Q.; Larock, R. C., "Synthesis of isoquinolines by palladium-catalyzedcyclization, followed by a Heck reaction." Tetrahedron Lett. 2002, 43, 3557-3560.Dr. P. Wipf84/11/20069Yang, D.; Ye, X.-Y.; Xu, M., "Enantioselectivetotal synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptquinonide." J. Org.Chem. 2000, 65, 2208-2217. An application ofCrisp’s method for the synthesis of γ-lactonesfrom β-keto esters.Overman, L. E.; Paone, D. V.; Stearns, B. A., "Direct stereo- andenantiocontrolled synthesis of vicinal stereogenic quaternary carboncenters. Total synthesis of meso- and (-)-chimoanthine and (+)-calycanthine." J. Am. Chem. Soc. 1999, 121, 7702-7703.Dr. P. Wipf94/11/200610Scopadulcic Acid
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