上海有机所有机合成讲义[上]许杏祥

1---()()1.(1)E+(A)---BF4RR;R-O+OR-OTs;R-OMs;XNu-RNuRX+(B)-RCXONu-RCXO-NuRCXN+R2Nu-RCXNR2Nu2(C)CCCO-NuCCCONu-(2)Nu-(A)(B)CHBC+H-B--(C)H2OCCOECCN+R2EE+CCNR2..+..ER2N+-HEHR2NE+R2N2.(1)(A)R-CH2-CO-R'base(slow)R-CH-CO-R'-CHCO-R'R3Approximateaciditiesofactivemethylenecompoundsandothercommonreagents*CompoundpkacompoundpkaCH3CO2HCH2(CN)CO2C2H5CH2(COCH3)2C6H5OHCH3NO2CH2(CN)2CH3COCH2CO2C2H5CH2(CO2C2H5)2CH3OHC2H5OH(CH3)3COH5991010111113161819C6H5COCH3CH3COCH3CH3SO2CH3CH3CO2C2H5CH3CO2-HC≡CHCH3CNC6H5NH2CH3CH=CH2(C6H5)3CHCH3SOCH31920~23~24~24~25~25~30~35~40~40*Acidichydrogenatomsareunderlined(B)-++Ph3P=CHCH3][Ph3P-CHCH3BuLiPh3P-CH2CH3SSRRBuLi-SS(C)+CCRCCHR-NH2NH3-(D)-HB-HH:(2)4+B-+BH+SolH+Sol-B-+SolHBH+Sol--CHXYCH2XY-CHXYCH2XY()1.1,3-(1)a-1t-BuOKBuLiCNCOOBuR1R2R3HtCCCCNOMsR1R2R3HCOOButCCHCCNCOOBuOXR1R2R3HtBF3.Et2OOR1R2HR3-BuOOCCHtNCBuOOCCH2NCt25NOLiOOButR1R2OR3LLDAtoluene,1.R4X/HMPA2.H3O+1.R4X/THF2.H3O+54-90%70-99%ee20-83%44-92%eeR1OR3OOR2NH2BuOOt+R1OR3OOR2R4R1OR3OOR2R4(2)g-Alkylationofa1,3-diketoneoraβ-keto-esterata'flanking'methylormethylenegroupinsteadofatthedoublyactivatedmethyleneormethinedoesnotusuallytakeplacetoanysignificantextentunder'ordinary'conditions.Itcanbeaccomplishedselectivelyandingoodyield,however,bywayofthecorrespondingdianion,itselfpreparedfromthediketoneandtwoequivalentsofasuitablestrongbasesuchassodamideorlithiumdiisopropylamide,byreactionwithoneequivalentofalkylatingagent.1(1)1eq.NaH,THFHMPA(2)1eq.BuLiBrOTHPseveralsteps(1)2eqLDA(2)C6H5SeBr(1)H2O2,CH2Cl2,0oC(2)25oCOEtOOOEtO-O-OEtOOOTHPOOOOOOSePhOOO2Syntheticallyusefulresultshavebeenobtainedwithdianionsderivedfromnitroalkanes.CH2C6H5C2H5CHNO2(1)C6H5CH2Br(2)H3O++--C2H5CNO22Li2eq.BuLiC2H5CH2NO26HNO22-2Li+(1)C6H5CH2Br-78oC-30oC(2)H3O+2eq.BuLiTHF,-80oCNO2PhNO2HMPAsameconditions2Li+(1)CH3I(2)LDA(3)C6H5CH2Br(78%)EtONO2OEtONO2-O-EtO2CNO2MePhCHOTiCl3,H3O+CH3I2Li+NO22BuLiTHF,-80oCHMPANO2NO22.Alkylationofmonofunctionalcarbonylcompounds,aldehydes,ketonesandesters,ismoredifficultthanthatofthe1,3-dicarbonylcompoundsdiscussedabove.AscanbeseenfromTable1.1,amethylormethylenegroupwhichisactivatedbyonlyonecarbonyl,esterorcyanogrouprequiresastrongerbasethansodiumethoxideormethoxidetoconverteitintotheenolateanioninhighenoughconcentrationtobeusefulforsubsequentalkylation.2.117THF,78oC(90%)CO2CH3C2H5BrrepeatusingCO2CH3Br-CO2CH3LDACO2CH32Inunsymmetricallysubstitutedketone,bothneighbouringC-Hbondsarereactiveandtheproblemofregioselectiveenolateformationarises.Thistableshowsthecompositionofmixturesofenolateanionsgeneratedfromtheketoneandatriphenylmethylmetalderivativeindimethoxyethane.Ketone,cationandreactionconditionsEnolateanioncomposition%OCH3CH3O-CH3O-K+(kineticcontrol)5545K+(equil.control)7822Li+(kineticcontrol)2872Li+(equil.control)946HOHHO-HHO-HLi+(kineticcontrol)1387Li+(equil.control)5347O-CCH2C4H9CH2C4H9CHCCH3O-C4H9CH2COCH3K+(kineticcontrol)4654K+(equil.control)5842Li+(kineticcontrol)3070Li+(equil.control)87133Acommonsidereactioninthedirectalkylationofketonesistheformationofthedi-andpoly-alkylationproductthroughinteractionoftheoriginalenolatewiththemonoalkylatedcompound.81%99%3%97%16%84%O+di-and/ortri-methylcyclopentanonesOLi5eq.MeI5eq.MeI3eq.HMPATHF,-78oC,10h97%5eq.MeI0.2eq.Me2Zn3eq.HMPATHF,-78oC,10h99%THF,0oC,3h94%(1)(A)Oneprocedureistointroducetemporarilyanactivatinggroupatoneoftheα-positiontostabilisethecorrespondingenolateanion.Anothertechniqueistoblockoneoftheα-positionbyintroductionofaremovablesubstituentwhichpreventsformationofthecorrespondingenolate.(B)()-OH3C+OHH3COHH3CH3CHO-Theketoneisaddedtoastrongbaseatlowtemperature,usuallyLDAinTHFat-78°C,themoreacidicandlessstericallyhinderedprotonisremovedinakineticallycontrolledreaction.THF,-78oCLDAOHH3CH3CHO-9Specificenolateanionsmaybeobtainedfromunsymmetricalketonebywayofthestructurallyspecificenolacetatesor,better,thetrimethylsilylenolethers.OSi(CH3)3H3COSi(CH3)3H3COSi(CH3)3H3COH3C(1)LDATHF,-78oC(97%,afterdistillation)(CH3)3SiCl,Et3N(2)(CH3)3SiClDMF,130oC8812+(84%)(7%)C6H5+OOC6H5C6H5CH2BrC6H5CH2N(CH3)3FC2H5I+(CH3)4SiDME,25oC1eq.CH3LiOSi(CH33)3OLiOC6H5Specificenolateionsofunsymmetricalketonescanalsobeobtainedbyreductionoftheα,β-unsaturatedketoneswithlithiuminliquidammonia.OO-Li+2eq.,LiNH3,(C2H5)2OexcessCH3IO(60%)10OHHHHO-t-C4H9OKt-C4H9OHC4H9IOHHC4H9OHHO-2eq.Li1eqt-C4H9OHNH3OHHC4H9C4H9I(2)R2R3Me3SiOR1RX,TiCl4CH2Cl2R2R3OR1Me3SiRX-+R2R3OR1R1BrOTiCl4+OSi(CH3)3BrCl2o(80%)OZnBr2,CH2Cl2Cl(2)(CH3)3SiCl(1)LDATHF,-78C(CH3)3SiOO311OOHH(1)LDATHF,-78oC(2)(CH3)3SiClHHOSi(CH3)3OC6H5SCH2ClZnBr2,CH2Cl2HHOOSC6H5(1)NaIO4,0oC(2)CCl4,80oCHHOO(3)()(4)Thestereochemistryoftheproductobtainedinthealkylationofcyclicketoneisimportantinthesynthesisbutisnotalwayseasytopredict.1HCH3OBrCH3HO-benzenerefluxNat-amylateCH3OBr2(1)NaNH2,THFCH3IetherNaC(C6H5)3OO-OCH3HOCH3Cl(2)312EtO2CBuHCH3BuHCH3O-OTsEtOOTsCOOEtCH3BuHLDATHF,-78oCCOOEtH2.2ab-()(1)a-(A)Oaaß'LDATHF,-78oCO-Li+H2OH2SO4OOHOBrOH3CO(1)LDA,THF-10oC(2)10eq.CH3I(1)1.2eq.LDA,THF(2)BrBr(B)13R2R2RCH2COCH=CHCH2R1base(slow)RCH2C=CH-CH=CHRO-RCH2COCHCH=CHRR2base(fast)RCH2C=CCH=CHR1--O-RR2XRCH2COCCH=CHR1-