药物合成4缩合反应

第四章缩合反应第一节α-羟烷基、卤烷基、氨烷基化反应第二节β-羟烷基、β-羰烷基化反应第三节亚甲基化反应第四节环加成反应一）羰基a位碳原子的a-羟烷基化(Aldol缩合)羟醛缩合(Aldol缩合):碱或酸下,醛或酮a-活性氢,与另一醛或酮缩合,得b-羟基醛或酮。若继续脱水得a,b-不饱和醛或酮。1、含有a-活性氢的醛或酮的自身缩合H2OCCCOR'RR'RCH2RCH2COR'+RCHCOR'OH或HRCH2CR'CRCOR'HOHHR,R'=H,脂烃基或芳烃基第一节a-羟烷基、卤烷基、氨烷基化反应一、a-羟烷基化反应1）碱催化反应机理RCH2COR'+BRCHCOR'RCHCR'O+BHRCH2COR'+RCHCR'OCCH-COR'R'RORCH2CCH-COR'+BHR'RORCH2CCH-COR'+BR'ROHRCH2CCH-COR'+BR'ROHRCH2CCR'RCH2RCOR'+BH+OH*例2(CH3)2CHCHOKOHCH(CH3)2CHOHCCH3CH3CHO(85%)2CH3CH2CH2CHONaOH25°NaOH80°CH3CH2CH2CHCHCHOOHC2H5(75%)(65%)CH3CH2CH2CH=CCHOC2H5*例：丙酮的自身缩合用Soxhlet抽提器进行丙酮的自身缩合。COCH3CH3+H2CHCOCH3Ba(OH)2CH3COHCH3CHCHOCHOI2或H3PO4CH3CCH3CHCOCHO(71%)加热器反应物和产物催化剂2）酸(包括质子酸及Lewis酸)催化反应机理RCH2CR'+HAORCH2CR'OHRCH2CR'OH+ARCH2CR'OHR-CH=CR'+HOHRCH2CR'+OHR-CH=CR'OHRCH2CR'OHCHRCOHR'RCH2CR'OHCHRCOHR'RCH2CR'OHCHRCOR'+HRCH2CR'OHCHRCOR'+HRCH2CR'OH2CHRCOR'H2O,HCCR'RCH2RCOR'3）醛醇缩合在有机合成中的应用2CH3CHO5%NaOH15～18°H2/Ni140～150°CH3CH=CHCHOCH3CH2CH2CHO10%NaOH70～80°CH3(CH2)2CH=CCHOC2H5H2/Cu160°CHCHOC2H5CH3(CH2)3*分子内的自身缩合OHC(CH2)3CHC3H7CHOH2O115°C3H7CHO(62%)2CH3(CH2)nCOCH3OH或HC=CHCO(CH2)nCH3CH3CH3(CH2)n2CH3CH2COCH3C6H5NMgBrCH3PhH/Et2OCCH3OHCH2CH3CH3CH2COH2(50～57%)OCH2COCH3KOHO(90%)*不对称酮的自身缩合O2(t-BuO)4AlO(78%)2、甲醛与含有a-活性氢的醛、酮之间的缩合1）反应可增加一个羟甲基(Tollens缩合)或亚甲基。*Tollens缩合HCH+RCH2CHOOOHHOCH2CRCHOHH2OCH=CCHORHCHO+CH3COCH3稀NaOH40～42°HOCH2CH2COCH3COOHCOOHH2OCH2=CH-COCH3(45%)2HCHO+CH3CH2CH2CHOK2CO314～20°CCH2OHCH2OHCH3CH2CHO(90%)COCH2NHCOCH3+HCHOO2NNaHCO3/EtOH35～40°,pH7.2～7.5COCHNHCOCH3+HCHOO2NCH2OH2）羟甲基化后无a-氢的醛在强碱中能和甲醛发生Cannizzaro反应，最终产物为多羟基化合物CH3CHO3HCHO/25%Ca(OH)215～16°CCHOCH2OHCH2OHHOCH2HCHO/Ca(OH)255～60°CCH2OHCH2OHCH2OHHOCH2(55～57%)3）醛醇缩合与氢化合用可增长碳链CH3CH2CHONaOH40～42°(89%)CH3CH2CH=CCH3CHOH2/RaneyNi压力,100°(77%)CCH3CHOCH3CH2CH2HHCHO/30%NaOH85～87°(95%)CCH3CHOCH3CH2CH2CH2OH3、芳醛与含有a-活性氢的醛、酮之间的缩合1）Claisen-Schimidt反应CHO+CH3CHOK1CH3CHCH2CHOOHOHK2CHOHCHCHOHH2OCHCHCHOK2K1OCHO+CH3COCH3NaOHH2OOCCHCOCH3H(60～66%)CHO+CH3CH2COCH2CH3KOHCH=C-COCH2CH3CH3PhCHOKOHCHCCHCHHOCH3OCH3环合加成OOCH3CH32）反应产物均为反式构型CHO+CH3CONaOH/H2OEtOH,15-30°CCHCHO(85%)CHO+CH3COCH3NaOH/H2OEtOH,20-25°(90-94%)CCCHCHHHOOHHPhHHRCOOHHPhHCORHHRCOPhHCORHPhHOHOH3）一个a-活性氢的反应，产品单一CHONaOH/H2O/EtOH(94%)O2NC6H5COCH3+CH=CHCOC6H5O2N(99%)H2SO4/HOAc4）有两个a-活性氢的反应可得不同产物CHOCH3COCH2CH3+CH=CHCOCH2CH3NaOHHClCH=CCOCH3CH35）芳二醛的缩合CHOCHO+CH3CH2COCH2CH3EtONaOCH3CH3(60%)4、催化剂对反应的影响1）碱强度：强碱用于活性差、位阻大的2）碱浓度：浓度稀反应慢；浓度高副反应多3）对碱敏感的醛或易于烯醇化的二酮：用伯胺或仲胺(少量醋酸存在下)催化OBrOO+CHO(CH3)2NNH2/HOAcOBrOON(CH3)2(55%)二）有机金属化合物的a-羟烷基化1、Reformatsky反应锌存在下醛或酮与a-卤代酸酯缩合而得b-羟基酸酯或a,b-不饱和酸酯。COR1R2+XCHHCOOR1)Zn2)H2OCCR1R2OHHHCOORH2OCCHR1R2COOR2、反应机理XCRR'COOC2H5+ZnXZnCRR'COOC2H5有机锌化合物XZnCRR'COOC2H5CCRR'OC2H5OZnXIII*经I催化的反应机理COR1R2+CCR1R2OZnXRR'COOC2H5XZnCRR'COOC2H5H3OCCR1R2OHRR'COOC2H5+ZnOHXH2OR=HCCR1R2R'COOC2H5*经II催化的反应机理COC2H5BrCH2O+ZnC6H6Et2OCOC2H5CH2OZnBrC6H5CHOOCHCH2COBrZnOC2H5C6H5H3OOHCHCH2COOC2H5C6H53）影响反应的因素a.反应物的活性b.a-卤代酸酯的活性XCH2COOC2H5XCHCOOC2H5RXCCOOC2H5RR'RCORRCOOC2H5RCHOc.反应条件：*无水条件。*常用的溶剂：非质子性溶剂。BrZnCH2COOC2H5CH3COOC2H5+Zn(OH)Br4）Reformastsky反应的应用*在醛、酮的羰基上增加两个碳原子CHO+BrCHCOOC2H5RPhH/Et2OZnHCOHCHCOOC2H5RH2OCHC-COOC2H5R还原CH2CHCH2OHR氧化CH2CHCHOR*以b-紫罗兰酮经两次Reformastsky反应合成维生素A。OBrCH2COOC2H5ZnCH2COOC2H5OHH2OHCOOC2H5(80%)LiAlH4(O)CHOCH3COCH3(i-PrO)3AlO(99%)BrCH2COOC2H5ZnCOOC2H5(96%)LiAlH4CH2OH(75%)2、Grignard和Normant反应１）Grinard反应(简称格氏反应)醚中有机卤化物与金属镁制得格氏试剂，再与羰基化合物反应得相应醇类。RMgXR'-CO-R'R'CHOHCHORCH2OMgXR'CHOMgXRC-OMgXRR'R'H2OH2OH2ORCH2OH+Mg(OH)XR'CHOH+Mg(OH)XRC-OH+Mg(OH)XRR'R'2）Normant改进法乙醚中卤代烯或炔烃与镁反应一般得不到格氏试剂。THF中可制得不饱和烃基卤化镁，称为Normant试剂。X+MgTHF40-50°MgXX=Br或ClNormant反应的应用*烯烃上a-羟烷基的引入*苄氯菊酯类杀虫剂中间体的合成CH2=CHMgBr+RCOR'THFCROHR'CH2=CH(60-85%)(CH3)3C-OHBr2H2O(CH3)2CCH2BrBrKOH/CH2OHCH2OHKBr(CH3)2C=CHBrMg/THF(CH3)2C=CHMgBr1)CCl3CHO2)NH4Cl/H2OCCHCH3CH3CHCCl3OH*a-炔醇的合成CCBr+MgCH2CH2(CH3)2CHTHF/I50-80°CCMgBrCH2CH2(CH3)2CHCH3COCH3CCC(CH3)2CH2CH2(CH3)2CHOMgBrH3OCCC(CH3)2CH2CH2(CH3)2CHOH有机镁化合物(RMgX,R2Mg)和各种亲核试剂的反应基质生成物基质生成物R'X质子共给体O2X2(Br2,I2)R'CORCO2R'CONMe2R'CNR'N3CNR'R'RRR'RHROOH,ROH等RXRR'RCOHRCOOHRR'CORR'C=NH及RR'CORNHNHR'RR'RCHNHR'OR'CH(OEt)3CS2ClCOOR'R'SOORSnSO2SO2ClNR'COSRR'CHCH2OHRCH(OEt)2及RCHORSOSHRCOOR'R'SOR+ROHRSHRSOOHR2SORR'CO(H2O,ROH,RNH2等)二、a-卤烷基化反应(Blanc反应)一）Blanc氯甲基化反应芳烃在甲醛,氯化氢及无水ZnCl2或质子酸等存在下引入氯甲基二）反应机理CH2=O+HCH2=OHCH2OHAr-H+Ar-CH2OH+CH2OHHAr-CH2OH+HClAr-CH2Cl+H2O用氯甲基甲醚/氯化锌的机理CH2ClAr-H+Ar-CH2Cl+HCH3-O-CH2Cl+ZnCl2CH3OCH2ClZnCl2CH3-O-ZnCl2+CH2ClCH3-O-ZnCl2+HCH3OHZnCl2CH3OH+ZnCl2三）影响反应的因素1、芳环上的电子云密度CH3OHCHOHClCH3OCH2ClCH3OCH2ClClCH2CH3OClCH2++(60%)(7%)CH3OOOCH3+(CH2O)n+HClHOAc70°,4hCH3OOOCH3ClCH2(87%)CH3CH3HCHO/HCl/ZnCl2CH3CH3CH2Cl(69%)2、活性较小的芳烃可用氯甲基甲醚试剂CHOOHO2NClCH2OCH3/AlCl3CHOOHO2NCH2Cl(90%)3、反应条件剧烈可引入两个或多个氯甲基4、用其它醛可得相应氯甲基衍生物COCH3OHHCHO/HCl25-30°COCH3OHClCH2HCHO/HClCOCH3OHClCH2CH2ClCH3OCH3CHO/HCl/HCH3OCHClCH3(50%)四）氯甲基化反应在有机合成中的应用HCHO/HClHOAc/H3PO480°,(77%)CH2ClKCNCH2CNH2OCH2COOHAr-CH2ClCH2(COOEt)2OEtAr-CH2CH(COOEt)21)水解2),CO2Ar-CH2CH2COOH三、a-氨烷基化反应一）Mannich反应1、酸催化下，活性氢化合物与甲醛(或其它醛)、胺(氨，叔胺除外)，进行a-氨甲基化反应，亦称a-氨甲基化反应。2、Mannich碱(盐)：b-氨基酮类化合物COCH3+(CH2O)n+(CH3)2NH2ClHCl/EtOH,(68-72%)COCH2CH2N(CH3)2HClMannich碱(盐)3、反应机理酸催化机理碱催化机理（自己阅读）4、Mannich反应中的活性氢化合物1）酮类COCH3+HC