偶联反应偶联反应Cross-Coupling Reaction2021/7/11 经典反应式经典反应式2021/7/12 Cross-Coupling ReactionsCatalystMRR'XKumada-Corriu (1972)Ni or PdMgAryl, alkyl, vinylAryl, alkyl, vinylCl, Br, I, OTsSonogashira (1975)Pd/CuICuAryl, alkylAryl, alkyl, vinylBr, INegishi (1977)Ni or PdZnAryl, allyl, benzyl, propargylAryl, alkyl, vinyl, alkynyl, benzyl, allylCl, Br, I, OTsStille (1978)PdSnAryl, vinyl,benzyl, alkynylAryl, alkyl, vinyl, benzyl, allyl, acylCl, Br, I, OTsSuzuki (1979)PdBAryl, alkylAryl, alkyl, alkynylCl, Br, I, OTsHiyama (1988)Ni or PdSiArylAryl, alkyl, vinylBr, I, OTs2021/7/13 1. Kumada, Suzuki, Stille, Negishi, Hiyama coupling (C-C Formation：C-X + C-M)2. Buchwald-Hartwig coupling (C-N, C-O, C-S Formation: C-X + Nu (N, O, S)-H)3.a-Arylation of Ketone (C-C Formation: C-X + C-H)4. Heck, Sonogashira coupling (Alkene and alkyne Formation: C-X + C-H)2021/7/14 General Mechanism2021/7/15 Kumada, Kumada-Corriu Coupling1960年年Chatt和和Shaw: 1970年年Uchino等等: 2021/7/16 Sp3 C-X substrate?2021/7/17 2021/7/18 配体的影响配体的影响 2021/7/19 2021/7/110 格氏试剂上烷基部分的异构化格氏试剂上烷基部分的异构化 2021/7/111 2021/7/112 2021/7/113 2021/7/114 2021/7/115 Fe-catalystLow initial temperature (-20 °C) is beneficialMolander, G. A. et. al. Tetrahedron Lett. 1983, 24, 5449. New development of the catalyst2021/7/116 ØAryl chlorides, triflates and tosylates are better substrates than aryl bromides and iodidesEntryXYield (GC, %)ab1I27462Br38503Cl>95-4OTf>95-5OTs>95-Fürstner, A. et. al. Angew. Chem. Int. Ed. Engl. 2002, 41, 609.2021/7/117 β-Hydride elimination and homocoupling are the major setback with the cross-coupling of 1o and 2o alkyl substrates with aryl Grignard reagentsEntrySolventProduct Yield (%)CDEF*1THF/NMP252524262THF272720253Et2O601912124Et2O (reflux)691899Hayashi, T. et. al. Org. Lett. 2004, 6, 1297. *Amount after 0.05 mmol (equivalent to catalyst) subtracted. Alkyl Derivatives as Substrate2021/7/118 Alkyl Derivatives as SubstrateTMEDA plays a crucial role to reduce β-hydride eliminationEntryaAdditiveProduct Yield (GC, %)CDEAF1None5790462Et3N37801153N-Methyl morpholine8720454DABCO20207535NMP153Trace7946TMEDA71193Trace10Nakamura, E. et. al. J. Am. Chem. Soc. 2004, 126, 3686. aPhMgBr (1.2 equiv), additive (1.2 equiv), 30 min. 2021/7/119 Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 308.Fürstner, A. et. al. J. Org.Chem. 2004, 69, 3950.Synthesis of R-(+)-Muscopyridine and immuno suppressive agent FTY7202021/7/120 Fürstner, A. et. al. Angew. Chem. Int. Ed. 2003, 42, 5358.Synthesis of Latrunculin B2021/7/121 Industrial examplesHokko Chemical Industry, JapanScale: 20t/ySolvent: From Ether to THF, with Toluene as co-solvent.2021/7/122 2021/7/123 2021/7/124 Pd(PPh3)4TON 74,000 910,000环钯催化剂PtBu328,000,000ArCl substrateWater soluble2021/7/125 反应底物反应底物•有机硼酸（酯）有机硼酸（酯）•ArBr 经格氏反应，或者经格氏反应，或者nBuLi，与，与B(OR)3反应得到反应得到•硼氢化反应硼氢化反应2021/7/126 2021/7/127 2021/7/128 2021/7/129 2021/7/130 2021/7/131 2021/7/132 2021/7/133 2021/7/134 2021/7/135 2021/7/136 Losartan, Merck (1994), 抗高血压药物JOC, 1994, 59, 63912021/7/137 Pharmacia Co. and Dow2021/7/138 2021/7/139 抗真菌剂fungizide Boscalid, BASF, 1000t/y2021/7/140 Cancer cell growth inhibitor, Novartis2021/7/141 Treatment for HIV2021/7/142 Stille偶偶联联, Stille Coupling2021/7/143 SubstratesStille偶联反应中两组份的组合偶联反应中两组份的组合 2021/7/144 2021/7/145 锡试剂的制备锡试剂的制备 2021/7/146 2021/7/147 2021/7/148 2021/7/149 2021/7/150 2021/7/151 2021/7/152 2021/7/153 2021/7/154 2021/7/155 2021/7/156 2021/7/157 2021/7/158 2021/7/159 2021/7/160 2021/7/161 2021/7/162 2021/7/163 2021/7/164 Hiyama偶联反应偶联反应 2021/7/165 F- (TBAF) activator needed2021/7/166 2021/7/167 2021/7/168 2021/7/169 2021/7/170 Hiyama-Denmark coupling2021/7/171 2021/7/172 2021/7/173 Kosugi, 19832021/7/174 2021/7/175 2021/7/176 2021/7/177 2021/7/178 2021/7/179 2021/7/180 2021/7/181 2021/7/182 2021/7/183 2021/7/184 2021/7/185 2021/7/186 2021/7/187 2021/7/188 Pfizer, CETP inhibitor CP529,4112021/7/189 2021/7/190 2021/7/191 酮的酮的a-a-芳基化反应芳基化反应 2021/7/192 2021/7/193 2021/7/194 2021/7/195 2021/7/196 2021/7/197 2021/7/198 结束语结束语若有不当之处，请指正，谢谢！若有不当之处，请指正，谢谢！ 。