偶联反应小结

偶联反应

Cross-CouplingReaction经典反应式Cross-CouplingReactionsCatalystMRR'XKumada-Corriu(1972)NiorPdMgAryl,alkyl,vinylAryl,alkyl,vinylCl,Br,I,OTsSonogashira(1975)Pd/CuICuAryl,alkylAryl,alkyl,vinylBr,INegishi(1977)NiorPdZnAryl,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)NiorPdSiArylAryl,alkyl,vinylBr,I,OTsKumada,Suzuki,Stille,Negishi,Hiyamacoupling(C-CFormation：C-X+C-M)Buchwald-Hartwigcoupling(C-N,C-O,C-SFormation:C-X+Nu(N,O,S)-H)a-ArylationofKetone(C-CFormation:C-X+C-H)Heck,Sonogashiracoupling(AlkeneandalkyneFormation:C-X+C-H)GeneralMechanismKumada,Kumada-Corriu

Coupling1960年Chatt和Shaw:

1970年Uchino等:

Sp3C-Xsubstrate?配体旳影响

格氏试剂上烷基部分旳异构化

Fe-catalystLowinitialtemperature(-20°C)isbeneficialMolander,G.A.et.al.TetrahedronLett.

1983,24,5449.NewdevelopmentofthecatalystArylchlorides,triflatesandtosylatesarebettersubstratesthanarylbromidesandiodidesEntryXYield(GC,%)ab1I27462Br38503Cl>95-4OTf>95-5OTs>95-Fürstner,A.et.al.Angew.Chem.Int.Ed.Engl.

2023,41,609.β-Hydrideeliminationandhomocouplingarethemajorsetbackwiththecross-couplingof1oand2oalkylsubstrateswitharylGrignardreagentsEntrySolventProductYield(%)CDEF*1THF/NMP252524262THF272720253Et2O601912124Et2O(reflux)691899Hayashi,T.et.al.Org.Lett.

2023,6,1297.*Amountafter0.05mmol(equivalenttocatalyst)subtracted.

AlkylDerivativesasSubstrateAlkylDerivativesasSubstrateTMEDAplaysacrucialroletoreduceβ-hydrideeliminationEntryaAdditiveProductYield(GC,%)CDEAF1None5790462Et3N37801153N-Methylmorpholine8720454DABCO20207535NMP153Trace7946TMEDA71193Trace10Nakamura,E.et.al.J.Am.Chem.Soc.

2023,126,3686.aPhMgBr(1.2equiv),additive(1.2equiv),30min.Fürstner,A.et.al.Angew.Chem.Int.Ed.

2023,42,308.Fürstner,A.et.al.J.Org.Chem.

2023,69,3950.SynthesisofR-(+)-MuscopyridineandimmunosuppressiveagentFTY720Fürstner,A.et.al.Angew.Chem.Int.Ed.

2023,42,5358.SynthesisofLatrunculinBIndustrialexamplesHokkoChemicalIndustry,JapanScale:20t/ySolvent:FromEthertoTHF,withTolueneasco-solvent.Pd(PPh3)4TON74,000910,000环钯催化剂PtBu328,000,000ArClsubstrateWatersoluble反应底物有机硼酸（酯）ArBr经格氏反应，或者nBuLi，与B(OR)3反应得到硼氢化反应Losartan,Merck(1994),抗高血压药物JOC,1994,59,6391PharmaciaCo.andDow抗真菌剂fungizideBoscalid,BASF,1000t/yCancercellgrowthinhibitor,NovartisTreatmentforHIVStille偶联,StilleCouplingSub