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第二章烃化反应有机物分子中氢原子(包括-OH、-NH2、-SH、-C上的氢原子)被烃基取代的反应第一节氧原子上的烃化反应一醇的O—烃化1卤代烃为烃化剂ROH+B+HBR'X+R'OR+(Williamson1850)ROORX(1)伯卤代烷按SN2历程，叔卤代烷按SN1历程，得烯烃。仲卤代烷按SN1和SN2历程；RIRBrRCl(活性)(2)采用RO-、OH-试剂。溶剂：ROH、DMSO、DMF、HMPT等；MeONa+MeOH/Ph=8~964~660C,3hMeOCH2COOMe+(88.4%)ClCH2COOMeNaClPh吸电子作用，使O更稳定△NaOH/XYLCH2CH2NMe2PhPh+PhPhCHOHCHOClCH2CH2NMe2.HCl(3)用ROTl作试剂(改进的williamson合成法)COOEtR'I/CH3CNR'OOR'600C,20hCOOEtCOOEtCOOEtCOOEtCOOEt(79%)COHHOTlHOTlOCHCHCHCHCHEtOTlR'=Me-,n-C6H13-ROR'R'XROHEtOTC6H6ROTCH3CN(4)用NaH作试剂,可得立体专一性的甲醚CH3I/NaH/THF500C,1h(100%)OHCH3CH3OCH3CH3OHOCH3CH3(5)卤代醇在碱性条件下,环化为分子内Williamson反应OO碱+HOXXX(6)叔卤代烃在特殊条件下，也可制得叔醚t—BuClSbF5/SO2ClF-700C[t—Bu]t—BuOH/i—Pr2NEt-80~00Ct—BuOBu—t(100%)(7)当有强吸电子基存在于芳环上时,X可被亲核取代。芳环上的亲核取代(周效磺胺)EtOH/NaOHOEtClNO2NO2OMeOMeOMeH2NNSO2MeONaMeOHNaNNH2NNSO2NaNNClOMeOMeHOAcNHH2NSO2NN碱催化机理:OR'R'OHR'OδδOR'OR'+CHCH2ROOHOCHCH2RCHCH2R2环氧乙烷为烃化剂酸催化机理:NuNu+OHCHHHRCOCHHHRCCHHHRCHOHNuNuaOHCH2RCHNubNuCHHHRCHOOHCH2RCHPh△.6h△.5h+PhOMePhOMePhOMePhOMe++90%10%25%75%CHCH2OH2SO4CH3ONaMeOHOHCH2CHOHCH2CHOHCH2CHOHCH2CH二酚的O-烃化R'ORR'+++OHRXOHXH2O碱:NaOH、Na2CO3溶剂：水、醇、丙酮、DMF、DMSO、苯、二甲苯试剂：R-X、Me2SO4、CH2N2Me2SO4/NaOHCH3OHOCH3OCH3OCHOCHO镇痛药降压药甲基多巴中间体OEtEtBr/NaOH80-1000C(75%)CONH2OHCONH2CH2N2(过量)2molCOOMeOMeOMeOMeCOOMeCOOHOHOHOHCH2N2活性：-COOH-OH+δN2(R=Ar,R'C)δCH2NHORCH3ORCH3ORNNNNNCH3RCOOO三醇、酚羟基的保护1甲醚保护基适合于保护酚羟基，不适合于保护醇羟基MeOHBr/HOAcMe700C,2hOMeOMeMe+OHNNBrBrBrNNBrNNBrOOHHH(90%)NNBrHHOOOMeMeOPy/HCl1800C,2hOHOHHOOOOHHOOOHO缺点：温度高时结构发生改变MeOOMeOMeCOOMeMeOOMeCOOMeMeOCBCl3ClBCl2OOMeOOMeCOOMeCOOMeCOOMeMeO(87%)BCl2OOOH缺点：只脱COOMe邻位-OMe2叔丁醚保护基POCl3/PCl5t—BuOH/NaHt—BuO83%OBu—tNOHHOBrNNBrNClClNBrNn—BuLiOBu—tt—BuOLiNNOBu—tt—BuO+PhPhOBu—tt—BuOPhPhOBu—tt—BuO+PhPhLiNNOOOOCHONNOOOOOHHONNOOOOHCl/MeOH40sec△HCl/MeOH40sec△+(A)40%(B)27%(A)+(B)12%76%OHOHOOHOHNNOHHOOOHOHOHNNOH3苄基醚保护基抗肿瘤药阿糖胞苷ROROROOMeOMe+r.t.3dayRORORONH3/MeOH1000C,68%OMe(1)OClNNCH2Cl2NNOOROROROH2/PdCl280%(2)NNOONH2NNOONH2OHHOHO4四氢吡喃醚保护基(相当于对双键加成)对碱、格氏试剂、烷基锂、氢化铝锂、烃化、酰化稳定；用酸处理，可脱除。δδOR++ROHOHOcat:Y%BF3Et2O67TsOH71PyHOTs100+OOHOHOOO第二节氮原子上的烃化反应一氨及脂肪胺的N-烃化1伯胺(RCH2NH2)的制备(1)NH3大过量(70当量)(70%)CH3CHBrCOOHNH3NH2CH3CHCOOH(2)Gabriel合成法OOKOH/EtOHRX/DMFOOOONHNKNRHCl/H2OOO++NH2NHCOOHNHCOOHNH2RNH2RNH2(多采用肼解)(条件苛刻)145-1500C,2h,(75%)+NHOOBrBr(CH2)3CHCH3Na2CO3CH3CH(CH2)3BrNOOMeO140-1500C,8h,93%+MeONH2NHCH3CH(CH2)3NNNOONa2CO3NH2NH2H2O(80%)△,6hNaOH,(30%)TOLMeONHCH3CH(CH2)3NH2N(3)环六亚甲基四胺(NH3+HCHO)法乌洛托品(4)C数5的醛与NH3与在Raney镍存在下还原烃化法HCl/EtOHNNNNRXRXRNH2NNNNRaneyNi++(90%)(7%)PhCHONH3PhCH2NH2(PhCH2)2NH2仲胺的制备(1)由仲卤代烃制备1100C,18h+2(78%)CH3CHBrCH3NH2NHNCH3CH3CHCH3CH3CH3CHCH3CH3(2)Hinsberg反应(3)还原烃化法ArSO2Cl/NaOHRNHSO2ArR'XR'酸or碱R'RNH2NaOHRNSO2ArH2ONHR2PhCHOH2/RaneyNi++81%12%NH3(PhCH2)2NHPhCH2NH23叔胺的制备(1)仲胺与卤代烃作用(降压药伏降中间体)(81%)CH2NHCH3HCCCH2ClCH2NCH2CCH3CH(2)还原烃化法+++H2/PtCHNCH0.02%21%73%H2/PtH2/PtCH3NHCHCH3C2H5OCCHNHCHCH3CH3C2H5C2H5CH3NHCHC2H5CH3C2H5OCC2H5C2H5C2H5C2H5HCHOCH3C2H5C2H5C2H5HCHO/MeOH/H2/Nir.t.4h(88%)NNHCOH2NCH3COH2N二芳香胺及杂环胺的N-烃化1N-烷基及N，N-双烷基芳香胺的制备(1)苯胺与卤代烃反应(2)芳胺与脂肪伯醇反应(3)酰胺法(4)伯胺与羰基化合物反应(1)苯胺与卤代烃反应NHMeNMe2+NH2MeIMeICH(OEt)3/H2SO4EtNHEt1200C,80~86%65~79%ClNCHONH2ClCl(2)芳胺与脂肪伯醇反应MeOH/H2/SiO2—Al2O31800C,压力,3hNMe2(98%)NH2△.16hROH/RaneyNiNHR(82%)R=Et,Pr,BrNH2(3)酰胺法MeI/TOLArNMeCOCH3ArNHCOCH3NaOHArNCOCH3ArNHMe(90%)KOH(4)伯胺与羰基化合物反应CHMeH2/RaneyNiNHCH2Me(88%)NH2MeCHON2芳胺的N-芳烃化U11mann反应CuSO4/NaOH,PH=5-6△+(56%)NH2ClCOOHClClNHCOOH氯灭酸3杂环胺N-烃化123456789Me2SO4/NaOH,PH=9-10Me2SO4/NaOH,PH=4-8MeMeMeMeMe(90%)(68%)ONHNHONNH350CONHONNONONNNN(A)(B)(C)A物:1位酸性较强，应在碱性介质下反应才能甲基化；3位和7位酸性较弱，碱性较强，在近中性条件下可被甲基化。选择不同条件，可得不同产物。第三节碳原子上的烃化反应一芳烃的烃化(1)反应速度:叔碳仲碳伯碳RFRClRBrRI，也可用ROH、烯等作烃化剂++RXAlCl3HXR++++RHRAlCl3XAlCl3XHRAlCl3HX(2)供电子基(芳环上)有利于反应，吸电子基不利于反应O、P产物如：(3)AlCl3、BF3等Lewis酸，也可用质子酸i—PrOH/HFNO2OMei—PrOH/HFOMeCH(CH3)2NO2NO284%(不反应)(4)有异构化产物+CH3CH2CH2BrCH3CHCH3BrAlCl3CH(CH3)2+CH3CH2CH2BrAlCl3CH3CH2CH2AlCl3BrAlCl3BrCHCH3CH3(稳定)++++AlCl3BrCHCH3CH3HCHCH3CH3AlCl3BrHCH(CH3)2AlCl3HBr二炔烃的烃化R'XR'RCCHNaNaNH2RCCRCC1RIRBrRClRF中等分子量的卤化物好,仲、叔及位有侧链时易消除(强碱作用下)。X不易反应β2需要无水操作，否则生成醇及醚等.例如：Liq,NH3(84%)Br(CH2)5BrHCCNaC(CH2)5CCHHC三羰基化合物位C-烃化1活性亚甲基化合物的C-烃化CH2COOEt+n—Bu—BrBu—n(69-72%)CH3CCHCOOEtEtONaOCH3COCH(OOEt)2+(61%)CH2(COOEt)2ClEtONaαOEtCOOEt+OEt+EtOHCOCHCH2OCCH3COCH3Bu—nCOOEtn—Bu—BrδδCOOEt+BrCCH3CHOCHCH3CO(1)可用来合成酮和羧酸Bu—nCOOEtH2O/OHBu—n△Bu—n(52-61%)C7H15Br/BuONa(1)H2O/OH(2)H△(66-75%)++CHCH3COCHCH3COCOOHCH3COCH2CH2(COOEt)2C7H15(COOH)2C8H17COOH(COOEt)2CHC7H15CH(2)双烃化反应NaOEt/EtOHCOOEtCOOEt(55%)CH2(COOEt)2BrCH2CH2CH2Cl(3)可引入两个烃基Me2CHCH2CH2Br/EtONa/EtOH75-780C,6hMe2CHCH2CH2EtBr/EtONaEtOH,350C,10h65-700C,1hEtMe2CHCH2CH2CH2(COOEt)2HC(COOEt)2C(COOEt)2先引入大基团,后引入小基团(4)副反应仲、叔卤代烃进行烃化反应时，易脱卤化氢++(COOEt)2HCBrHC(COOEt)22酮的位C-烃化αR2CHCH2R'R2CCHR'CH2R'kakbR2CHCOBCOCOKB=[A][B]K动力学控制：非质子溶剂，酮不过量热力学控制：质子溶剂，酮过量均采用Ph3CLi强碱Ph3CLi/MeOCH2CH2OMer.t.0.5hor1h+CH3OCH3OCH3O动力学控制28%72%热力学控制(酮过量)94%6%3烯胺C-烃化++NHOCH3NCH3NCH3相排斥90%10%ABA:稳定，B不稳定。要求N和共平面，故A稳定。CC66%ONHNCHCH2BrCH2H2ONCHCH2CH2OCH2CH2CH四相转移烃化反应有机相水相有机相水相C8H17Cl+R4NCNC8H17CN+R4NClNaCl+R4NCNNaCN+R4NCl有机相水相若不加R4NCl，反应几天也得不到壬腈，加入少量R4NCl后，2h即定量得到壬腈。RCl+NaCNRCN+NaCl加冠醚，也可达到此目的OOOOOOKCN18-冠-6冠醚与络合，使转移至有机相中，加速反应进行。KCN1O-烃化PhCH2Cl/5