偶联反应小结

偶联反应Cross-CouplingReaction经典反应式R'-X+R-MX'CatalystR--R'+MXX'SubstrateCouplingPartnerCouplingProductMetalHalideR=Alkyl,aryl,vinyl,allyl,alkynyl,benzylR'=Alkyl,aryl,vinyl,allyl,alkynyl,benzyl,acylX=I,Br,Cl,OTf,OTsM=Mg,Zn,Cu,Sn,Si,B,......(OrganometallicNucleophile)(OrganicElectrophile)(NiorPd......?)Cat.=Pd,Ni,othersCuFe......R'-X+CatalystR-R'+R-MX'MXX'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,OTs1.Kumada,Suzuki,Stille,Negishi,Hiyamacoupling(C-CFormation：C-X+C-M)2.Buchwald-Hartwigcoupling(C-N,C-O,C-SFormation:C-X+Nu(N,O,S)-H)3.a-ArylationofKetone(C-CFormation:C-X+C-H)4.Heck,Sonogashiracoupling(AlkeneandalkyneFormation:C-X+C-H)GeneralMechanismKumada,Kumada-CorriuCoupling1960年Chatt和Shaw:L2NiRX+R'MgXL2NiRR'+12L2NiXXMgX2(bipy)Ni++34RRR'-X(bipy)NiR'XR-R1970年Uchino等:RMgXR'X'NiX2L2R-R'+MgXX'+催化剂:NiX2L2(L2=双膦)溶剂:Et2OorTHF反应条件:0oC~R.T.,reflux,1~20h,[Ni]/R’X’=10-2~10-R’X’:sp2碳的卤化物Sp3C-Xsubstrate?R'X'R-R'MgXX'RMgXL2NiX22RMgX2MgX2L2NiR2R-RRL2NiR'X'L2NiR'RL2NiR'R'X'R'X'56723NiCl2L2(1%)Et2O,reflux20h+PhClBuMgBrPhBudpppdmpfdppedmpedppccis-dpenPh2P(CH2)nPPh2Me2P(CH2)2PMe2cis-Ph2PCH=CHPPh2n=2dppedmpecis-dpenn=3dpppn=4dppb配体的影响FePR2PR2R=MedmpfR=PhdppfH10B10PhPhPhPhdppcMgClH3CCH3L2NiClPh+NiCH3H3CL2PhCH2=CHCH3H-Ni-PhL2CH2CH2CH3Ni-PhL2PhH3CCH3CH2=CHCH3+PhHPhCH2CH2CH3格氏试剂上烷基部分的异构化PhMgBr+[Ni-P*]H2CCHCH2CH2BrH2CHCCMePhH*(3)反应中涉及的双键的立体化学MeMgBr+NiCl2L2MeMgBr+NiCl2L2PhBrPhCH3PhBrPhCH3++NiCl2(dmpe)PhMgBrPhArPhArArX(4)碳－碳键的不对称形成(Asymmetricformationofcarbon-carbonsinglebonds)PhMeCHMgCl+Br[Ni*]PhMeCHCH=CH2*PPFAY:83~99%ee:52~63%(R)-(S)-PPFA63%ee(S)(S)-(R)-PPFA59%ee(R)(S)-(R)-PPFANMe2HMePPh2PPh2Me2NHRR3R2R1R3R2R1R4X'[ML*]R3R2R1(S)-Valphos(R=i-Pr)81%ee(S)(R)-t-Leuphos(R=t-Bu)94%ee(R)R4X'[ML*]R3R2R1R4CCH2CMgXCXMgCR4CDynamickineticResolutionFe-catalystLowinitialtemperature(-20°C)isbeneficialMolander,G.A.et.al.TetrahedronLett.1983,24,5449.HBrHPh+PhMgXReactioncondition:Fe(dbm)3cat.,1-2hDME,-20oCtortHPhHPh(1equiv)(1equiv)HBrHPh+PhMgXHPhHPh(1equiv)(3equiv)THF,25oC(32%)(90%)NewdevelopmentofthecatalystPhOO-PhdbmArylchlorides,triflatesandtosylatesarebettersubstratesthanarylbromidesandiodidesEntryXYield(GC,%)ab1I27462Br38503Cl95-4OTf95-5OTs95-Fürstner,A.et.al.Angew.Chem.Int.Ed.Engl.2002,41,609.XOMeOn-HexMgBrFe(acac)3(5mol%)THF-NMP0oCtort,5minHexOMeOOMeO+a,couplingproductb,reductionproductβ-Hydrideeliminationandhomocouplingarethemajorsetbackwiththecross-couplingof1oand2oalkylsubstrateswitharylGrignardreagentsEntrySolventProductYield(%)CDEF*1THF/NMP252524262THF272720253Et2O601912124Et2O(reflux)691899Hayashi,T.et.al.Org.Lett.2004,6,1297.*Amountafter0.05mmol(equivalenttocatalyst)subtracted.MgBr+BrFe(acac)3(5mol%)Solvent,20oC,30min(CH2)5PhC+++EFDBA(Desiredproduct)AlkylDerivativesasSubstrateAlkylDerivativesasSubstrateTMEDAplaysacrucialroletoreduceβ-hydrideeliminationEntryaAdditiveProductYield(GC,%)CDEAF1None5790462Et3N37801153N-Methylmorpholine8720454DABCO20207535NMP153Trace7946TMEDA71193Trace10Nakamura,E.et.al.J.Am.Chem.Soc.2004,126,3686.aPhMgBr(1.2equiv),additive(1.2equiv),30min.Br+PhMgBrFeCl3Cat.THF,AdditivePhPh-Ph+++ABCDEFMe2NNMe2TMEDA(Desiredproduct)-78oCto0oC30minFürstner,A.et.al.Angew.Chem.Int.Ed.2003,42,308.Fürstner,A.et.al.J.Org.Chem.2004,69,3950.SynthesisofR-(+)-MuscopyridineandimmunosuppressiveagentFTY720NFe-catalyzedcross-coupling(R)-(+)-MuscopyridineNNClOTfMgBrMgBr1.Fe(salen)Cl1(5mol%)THF-NMP0oC2.(60%)Fe(salen)Cl1NFeNOOHHClH2NOHOHImmunosuppressiveagentFTY720OOFe(acac)3cat.OOTfOTHF-NMP,rt,2h(84%)Fe-catalyzedcross-couplingOctMgBr1.RCM2.H2/cat.Fürstner,A.et.al.Angew.Chem.Int.Ed.2003,42,5358.SynthesisofLatrunculinBOOOHNSOOHFe-catalyzedcross-couplingFe-catalyzedcross-couplingLatrunculinBOORTfOOORMgBrFe(acac)3(10mol%)THF,-30oCRNSOORNSOClOFe(acac)3(1.5mol%)(97%)(85%)THF,-78oCto0oCMeMgBrIndustrialexamplesHokkoChemicalIndustry,JapanScale:20t/ySolvent:FromEthertoTHF,withTolueneasco-solvent.SuzukiCouplingR-X[Pd]R-R'+R'-B(1)催化量的钯(2)反应是区域及立体专一性的(Regio-andStereo-specific)(3)碱的存在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+X2=(Sia)2OOHRHBX2RHHBX2RPhB(Sia)2+Pd(0)Base87~42%RB(Sia)2+Pd(0)BaseBrRPhCH2BrR9-BBNPdCl2(dppf)222324OOBrOOBrBOONaOHPh+K3PO4-3H2Otoluene,100oCPhB(OH)2RBrR83-98%Pd(PPh3)4Ph+RBrHCOORK3PO4-3H2Otoluene,100oCRHCOORPhB(OH)2Pd(PPh3)4BuC4H9+Ph86%X2=(Sia)21%PdCl2/2%PPh3NaOEt-EtOHBenzene+88%(purity:98%)+BrPhn-BuBX2OOn-C4H9OBOC4H9C6H13Brn-C6H13n-C4H9BX2BrC6H13-n49%(purity:98%)C6H13-nHexBX2HexCl1210+Y=OAc,OMeClClClYes11ClClClPdY(PPh3)2NoLosartan,Merck(1994),抗高血压药物JOC,1994,59,6391PharmaciaCo.andDow抗真菌剂fungizideBoscalid,BASF,1000t/yCancercellgrowthinhibitor,NovartisTreatmentforHIVSti