有机合成Class_No_4

第四章Heck反应HRX++Base[Pd]R+Base-HXRPdXRXPd(0)RBaseRHPdXHHPdX+Base-HXR-Helimination12§4.1分子间Heck反应1.插入反应的区域选择性HCO2CH3HH3CH2CCH3PhPhHHH3CPhHH3CHHHNOCH2=CHCO2CH3CH2=CHCNCH2=CHPhCH2=CHCH(OCH3)2CH2=CH-CH-CH31001001009611001009377921802010090104060OH2.立体选择性MePhPhPhMePhBrEt3NPd(OAc)2PPh3E-isomerE-isomer70%++MePhPhPhMePhBrEt3NPd(OAc)2PPh3Z-isomerZ-isomer79%++HMeHPhPd+PhMeHPhHPd+HPhMePhHMePhHPhPd+-PhEisomerSyn-additionrotationelimination3MeHHPhPd+PhHMePhHPd+HMePhPhHPhMeHPhPd+-PhZisomerSyn-additionrotationelimination43.卤代物的活泼性零价钯对卤代物的氧化加成的难易程度，取决于碳－卤键的强弱。一般说来，碘化物比溴化物活泼，而氯化物则在一般情况下不反应。对于芳基卤化物，芳环若带有吸电子基团，有利于氧化加成。4.反应类型(1)简单烯烃的反应HRX+cat.PdbaseRR=1-alkenyl,allylic,benzyl,1-alkynyl,arylX=OTf,Br,I,I+Ph,SO2Cl,COCl,etc.PhI+COOMecat.Pd(OAc)2,NaHCO3n-Bu4NCl,30oC,1dCOOMePhPhI+COMecat.Pd(OAc)2,NaHCO3n-Bu4NCl,25oC,2dCOMePh94%98%IC4H9+COOMecat.Pd(OAc)2,NaHCO3n-Bu4NCl,27oC,4hCOOMe96%C4H9(2)共轭双键+RXPdBase-HeliminationNu-Nu+Nu6785RPdLnHHRHRR(3)烯丙醇IC6H13+OHC6H13OHC6H13CHOC6H13HaPdOHHbpathaPd(OAc)2,Ag2CO3Bu4NHSO4,CH3CN54%pathbPd(OAc)2,PPh3AgOAcDMF,61%91011(4)卤代烷与末端炔的偶联反应HCCRR'CCR+R'XBasecat.PdCl2(PPh3)2cat.CuI(3)(Ph3P)2PdCl2[Et2NH2]ClRCuI,Et2NH(Ph3P)2Pd(C=CR)2RR(Ph3P)2Pd(0)R'X(Ph3P)2PdR'XRCuI,Et2NH[Et2NH2]X(Ph3P)2PdR'RRR'121314ClR2HR1+R3PdCl2L2,CuINHR2HR1R3upto97%(4)+RPdCl2(PPh3)2IHOCuIRHOR=aryl,CH2OH,alkyl(5)OTfOTf+R1L2PdCl2CuI,i-Pr2NHOTfR1R2R1R2151617(6)R1ClNR2+R3L2PdCl2Et3N,CuIR1NR2R351-79%1819(7)BrR1R2R3+R5R42.5mol%Pd(OAc)210mol%PPh3Cs2CO3,DMF,130oCR1R2R3HR5R4Chem.Lett.1997,823.(5)联烯+RXPdPdLnNu-20CH2R'RR'-Helimination21RR'NuRR'22§4.2分子内Heck反应(1)碳－碳双键(包括共轭双烯)的分子内Heck反应XRnPd((0)PdXRnPdXnR232425(8)(2)联烯的分子内Heck反应XnPd((0)RPdXnRnRPdX262728(9)(3)碳－碳叁键的分子内Heck反应XRnPd((0)PdXRnPdXnR293031(10)4.2.1以－H消除终止的分子内Heck反应一、芳基、烯基卤代物的分子内Heck反应1、成环大小的一般规律和影响因素NOPhINOPhPdINOPhPdILnHNOPhNOPh(CH2)nNOPh(CH2)n(CH2)n(CH2)nban-Bu4NClPd(OAc)2Ph3PK2CO3CH3CN(CH2)n(CH2)n-Helimination-Heliminationab323537333436LnIPdNIOPd(OAc)2n-Bu4NClPh3PK2CO3CH3CNNO3839(11)BrEEPd(OAc)2Ph3P,K2CO3CH3CN,67%EE+EE404142E=COOEt5:4EEPdBrLnEEPdBrLnPdBrLnEE434445ZBrZZ=CH47aZ=N47b(12)Z=CH46aZ=N46b[Pd]70-90%OHHBrOHHOHH+4849502:1(13)5%Pd(OAc)210%PPh380℃,23h,67%BrHNPdBrLnPdBrLnPdBrLnNPdBrLnNPdBrLnPd+HPdLnXHPdLnXNH5157(4%)525354555658596061(8%)Pd(OAc)2,P(OEt)3CH3CN,125℃,12hPdIIPd(OAc)2PPh3CH3CNababexoexo62636465(1)立体位阻对成环的影响PdIIPdIPdIHHPdILnPd(OAc)2PPh3CH3CNababK2CO3-Helimination-Heliminationno-H666768697068:70=1:1.5(2)电子效应对成环的影响HOHIOCat.Pd(OAc)2K2CO3,n-Bu4NClDMF53%H717273(14)IEEEEEEEE()12120oC,12h2166%[Pd](15)7475(3)－H对成环的影响BrRNOPdBrLnRNORNLnBrPdORNOPdBrLnRNORNOPd(OAc)2100oCEt2O767778798081R=H;52%;85:88=9:1R=Me;50%(88)NIORRRRNLnIPdORRRRNORRRRLnIPdNOORRRRNPdILnORRRRNORRRRNNORRRRPdILnNORRRRPd(0)abab-HeliminationR=H828384858687888990(4)卤素原子对成环大小选择性的控制BrEEPd(OAc)2Ph3P,K2CO3CH3CN,67%EEEE919495E=COOEtEEPdBrLnEE9392BrBrBrBrPdBrLn2影响环化产率的因素(1)碳－碳双键取代基对分子内Heck反应的影响BrHNRPhOHNPhROPd(OAc)2,P(o-tol)3100oC,Et3NR=H58%R=CH321%9697(16)NMeOBrONMeONMe+Pd(OAc)2Et3NPPh358%Ag2CO39899100(17)(2)电子效应的影响BrOHNHOHOHOHNHOONHBrOAcNAcOAcOAcOAcNAcOAcOAcNAcAc2O(63%)6%Pd(0)1.HPdX2.[O]89%36%1011021031041051062x2.5%Pd(0)NR2OR3R1R1R2INR2OR3R1R1R2Pd(OAc)2,PPh3n-Bu4NCl,K2CO3107108a:R1=R2=R3=Hb:R1=OMe,R2=R3=Hc:R1=R2=OMe,R3=Hd:R1,R1=OCH2OR2=OMe,R3=Hyield(%)575138233、分子内Heck反应中新生成双键的位置（1）－H消除的方向I5%Pd(PPh3)4,NEt3CH3CN-THF,reflux6h109110ICOOMeCOOMePdILnHHCOOMeH5%Pd(PPh3)4NEt3,1.5equivMeOH,THFreflux,20hCO2EtICO2EtHPdILnH3.0%Pd(OAc)29.0%PPh3CH3CN,Ag2CO380oCCO2EtH42%111112113114115116(2)新生成双键的异构化IHNHNPdILnHNHNHNPdILnHHN2%Pd(OAc)2NEt3,2.5equiv.Et3N,Bu4NCl,DMFHPdXLn73%117118119120121122ICO2EtCO2EtCO2EtCO2EtCO2EtCO2EtPd(PPh3)4NEt3,MeCN,THFreflux82%126127(19)Br5%Pd(PPh3)4,NEt3CH3CN,reflux+68%17%1231241251h0.5h82%1%NCOOCH3IN-COOCH3N-COOCH3Pd(OAc)2PPh3,Et3Na:X=Ib:X=BrYield:82%52%1/1.68/1+128129130(20)NCH3IONCH3O+doublebondregioisomera:1%Pd(OAc)2,3%PPh32equiv,Et3N,CH3CN,3hb:1%Pd(OAc)2,3%PPh32equiv,Et3N,3h1equiv.AgNO31:126:1Yield:70%131132(21)2.烯丙基卤化物及醋酸酯和苄基类卤化物的分子内Heck反应ClEClEEEPd(PPh3)4NEt3(72%)(64%)5%Pd(PPh3)4NEt3(1.5equiv)CH3CN,reflux,6h133134135136EEAcOEEAcOEEHE=COOEtPd(PPh3)4HOAc1h,84%Pd(PPh3)4HOAc4h,55%137139138NCOCF3AcONCOCF3NCOCF3Pd(PPh3)4HOAc59-76%+90:10140141142(22)3.联烯的分子内碳－钯化反应Br.I69%Br.I66%.IEE.EEI58%.IEE.EEI56%8.BrEEEEII62%()39Br.II48%()610E/Z=73:27I.II57%()711I:5%PdCl2(PPh3)2,K2CO3(5equiv),EtOH(10equiv),DMF.II:5%PdCl2(PPh3)2,K2CO3(5equiv),n-Bu4NCl(1equiv),DMF.E=COOEtOOII100oC,2h52%,74%byNMROOII100oC,21h5%byNMRBrII120oC,12h55%()29()5BrII120oC,12h2%()29()5()5+++dimer,trimer,etc102%IEEEEEEEEII80oC,29h()41250%IEEEEEEEEHEEEEII80oC,35h()418%()4+37%13IEEEEEEEEII120oC,5h()122086%IEEEEEEEEEEEE()12II120oC,12h205%21+66%I=5%Cl2Pd(PPh3)2,K2CO3(5equiv)andEtOH(10equiv),DMFII=5%Cl2Pd(PPh3)2,K2CO3(5equiv)andn-Bu4NCl(1equiv),DMFE=COOEtBrEEEEII120oC,23hEEEEBrEEEEII120oC,18hEEEE66%69%143144145146.n-Prn-PrEEPdLnX.n-Prn-PrEENn-Prn-PrEEPhn-Prn-PrEEEEn-Prn-PrEEOPhn-Prn-PrIEE56%64%51%54%iiiiiiivE=COOEti:I,CH2E2(3equiv),0.05M,120oC,23hii:II,PhSn(n-Bu)3(2.2equiv),0.014M,120oC,11hiii:II,PhOH(5equiv),0.013M,80oC,24h,120oC,7hiv:II,piperidin