第五章重排反应.

1、Organic Reactions for Drug Synthesis 第五章 重排反应 Rearrangement ReactionRearrangement ReactionOrganic Reactions for Drug SynthesisAWBABWA:重排起点原子重排起点原子,B:重排终点原子重排终点原子,W:重排基团重排基团分类分类: 离子型机理（亲核重排离子型机理（亲核重排,亲电重排）亲电重排） 自由基重排自由基重排 周环机理重排（周环机理重排（-键迁移重排）键迁移重排）定义：定义：受试剂或介质的影响，受试剂或介质的影响，同一有机分子内的一个基团或原子从一个同一有机分子内的

2、一个基团或原子从一个原子迁移到另一个原子上原子迁移到另一个原子上,使分子构架发生改变而形成一个新的分子使分子构架发生改变而形成一个新的分子的反应称为重排反应。的反应称为重排反应。Organic Reactions for Drug Synthesis从碳原子到碳原子的重排从碳原子到杂原子的重排从杂原子到碳原子的重排-键迁移重排Organic Reactions for Drug Synthesis第一节 从碳原子到碳原子的重排Wagner-Meerwein重排Pinacol重排苯偶酰-二苯乙醇酸型重排Favorski重排Wolff重排Organic Reactions for Drug Syn

3、thesis一、Wagner-Meerwein重排 终点碳原子上羟基、卤原子或重氮基等，在质子酸或Lewis酸催化下离去形成碳正离子，其邻近的基团作1,2-迁移至该碳原子，同时形成更稳定的起点碳正离子，后经亲核取代或质子消除而生成新化合物的反应称为Wagner-Meerwein重排。Organic Reactions for Drug SynthesisR2CR3R1COHR4R5R2CR3R1CR4R5R1CR2CR3R4R5R1CR2CR3R4R5OHH+(-H2O)重 排H2O(-H+)Organic Reactions for Drug SynthesisOHHCH2CH2-H莰烯莰烯

4、异冰片异冰片Organic Reactions for Drug SynthesisCCR4R2R1OHR3OHHCCR4R2R1R3O二、Pinacol重排 连二醇类化合物在酸催化下，失去一分子水重排生成醛或酮的反应，称为Pinacol重排反应。Organic Reactions for Drug Synthesis(一) 机理HCCRRROHROHCCRORRRHCCROHRRRHCCRORRROrganic Reactions for Drug SynthesisCCR1R1R2OHR2OH(二) 基团的迁移能力1.对称的连二乙醇芳基烃基供电子取代芳基吸电子取代芳基Organic Rea

5、ctions for Drug Synthesis主产物主产物次产物次产物+PhCCCH3CH3OPhH3C CCPhCH3OPhHPhCCPhCH3CH3OHOHOrganic Reactions for Drug Synthesis+P CH3OC6H5C CC6H5OCH3PhOPhpC6H5OCH3PC6H5OCH3PCCPhO PhHP CH3OC6H5C C C6H5OCH3PPh PhOHOH94%6%Organic Reactions for Drug Synthesis羟基离去后碳正离子的稳定性：羟基离去后碳正离子的稳定性：叔碳叔碳仲碳仲碳伯碳伯碳CCR2R1R1OHR2OH

6、2.不对称的连二乙醇重排的方向决定于羟基失去的难易Organic Reactions for Drug Synthesis+PCH3OC6H5CCOHP CH3OC6H5PhOHPhH2SO4PCH3OC6H5CCPhPCH3OC6H5OPhPCH3OC6H5CCOC6H5OCH3PhPPh72%28%Organic Reactions for Drug SynthesisPhCCCH3PhCH3OPhCCCH3PhCH3OHAc2OPhCCCH3PhCH3OHOHH2SO4PhCCCH3PhCH3OHOrganic Reactions for Drug Synthesis3.三取代的连二乙醇

7、R1CCR3R2OHHOHPhCCPhPhOH OHHPhCCPhPh OHHH+Ph CHCPhPhO(B)H在三取代邻二叔醇结构，一个是叔羟基，另一个为仲羟基例子参考p241Organic Reactions for Drug SynthesisCC6H5C6H5COOOHKOH/C2H5OHC6H5C C C6H5O O三、二苯基乙二酮 二苯乙醇酸型重排 二苯基乙二酮(苯偶酰)类化合物用碱处理，生成二苯基-羟基酸(二苯乙醇酸)的反应称为苯偶酰-二苯乙醇酸型重排反应。Organic Reactions for Drug SynthesisC6H5C C C6H5O OC6H5C C OHO

8、 C6H5O+OHC6H5C C OHOOC6H5C6H5C C OOOHC6H5Organic Reactions for Drug Synthesis迁移能力：吸电子基取代的芳环 供电子基取代的芳环ArC CArO OArCC OHOHOAr+HO C CArO OHArOrganic Reactions for Drug SynthesisOOOHref.COOHOH79%OOKOHHOHOOCOrganic Reactions for Drug SynthesisHNHNOOOHCOOHH2OCH3O /CH3OH2)1)HNHNOOOOHOHOOCC8H17KOH/C3H7OH.H2

9、OOOC8H17甾体缩环甾体缩环92100%97%Organic Reactions for Drug SynthesisPhCH2C CH2ClONaOHPhCH2CH2COO四、Favorski卤代酮重排 -卤代酮在亲核碱(NaOH,RONa等)存在的条件下，发生重排得到羧酸盐、酯或酰胺的反应称为Favorski卤代酮重排反应。Organic Reactions for Drug SynthesisRCRXCCH3ORCCH3RCOOEtRCCH3RCOOHRCCH3RCNH2OEtONa/EtOHNaOHNaNH2-卤代酮的反应基团迁移到卤素位置基团迁移到卤素位置Organic Reac

10、tions for Drug Synthesis机理机理: RH2CCHCRXOEtONa(EtO-)RHCCHCRXO-XRHCHCRCOEtONaRHCHCRCOOEtabRHCHCRCOOEtRH2CHCRCOOEta)HRHCHCREtOOCRHCH2CRCOOEtb)HOrganic Reactions for Drug SynthesisRO+ROHCOORCOOROROOClOROClOOrganic Reactions for Drug SynthesisClCCH3OOOCOOEtCH2CH2COOEtEtONaEtONaEtOC 所连接的取代基越少越稳定主Organic R

11、eactions for Drug SynthesisR C CRO N NR C CROC C ORRROHCHRRC ORO五、Wolff重排 重氮酮在银、银盐或铜存在条件下，或用光照射或热分解都消除氮分子而重排为烯酮，生成的烯酮进一步与羟基或胺类化合物作用得到酯类、酰胺或羧酸的反应称为Wolff重排反应。Organic Reactions for Drug SynthesisBr(CH2)9C CHN2ONH3.H2O/AgNO3Br(CH2)9CH2CONH2N2OCH3OHHH3COOCh75%49%Organic Reactions for Drug Synthesis第二节 从碳

12、原子到杂原子的重排Beckmann重排Hofmann酰胺重排为胺类Curtius重排Schmidt羰基化合物的降解反应Baeyer-Villiger氧化重排Organic Reactions for Drug SynthesisCNOHRRCRONHRH一、Beckmann重排醛肟或酮肟类化合物在酸性催化剂的作用下，重排成取代酰胺的反应称为Beckmann重排。Organic Reactions for Drug Synthesis机理CNOHRRCRONHRHCNRROH2CNOH2RRCRN RH2OCRN ROH反式迁移Organic Reactions for Drug Synthes

13、is(1)催化剂催化剂:质子酸质子酸 H+ ,H2SO4 , HCl, H3PO4 非质子酸非质子酸PCl5, SOCl2, TsCl, AlCl3 RCRNOHRCRNOHHR和 R相差不大时,会发生异构化但R=CH3, R=Ph不会发生异构化用质子酸用质子酸(极性溶剂中）催化时存在异构化问题极性溶剂中）催化时存在异构化问题Organic Reactions for Drug Synthesis(2)肟的结构肟的结构 OCH3NCH3HOH2NOHHNHOCH3脂环酮肟发生扩环反应生成内酰胺脂环酮肟发生扩环反应生成内酰胺PhCHCH3CCH3NOHCH3CONHCHPhCH3*H构型保持率9

14、9.6%迁移基团在迁移过程中构型保留迁移基团在迁移过程中构型保留 Organic Reactions for Drug SynthesisBeckmann重排的应用将酮转变为酰胺确定酮的结构扩环成内酰胺化合物制备仲胺Organic Reactions for Drug Synthesis140H2SO4NOH+RNH2RCOOOHHCRONHRCNOHRRNHO95%Organic Reactions for Drug SynthesisH3CC NOHLiAlH4AlCl3THFEt2ONHCH2CH3C NOHPhPhLiAlH4AlCl3PhCH2NHPhOrganic Reaction

15、s for Drug Synthesis2+2+4+2H2OBrCO3RNH2OHBr2RCONH2二、Hofmann酰胺重排为胺类 酰胺用溴(或氯)和碱处理转变为少一个碳原子的伯胺的反应称为Hofmann酰胺重排为胺类反应或称为Hofmann降解反应。Organic Reactions for Drug Synthesis机理重排后R保留原来手性2CO3+RNH2H2O/OHR N C OR CNOBrR CNHBrOR CNH2OBr2OHOrganic Reactions for Drug SynthesisHofmann降解反应适用范围 本重排的酰胺包括脂肪、脂环、芳脂、芳香及或杂环等

16、的单酰胺，用以制备各类伯胺。Organic Reactions for Drug Synthesis(C2H5)2NCH2CH2CONH2NaOCl/H2O(C2H5)2NCH2CH2NH2NaOBr/H2ONCONH2NNH26571%Organic Reactions for Drug Synthesis RHCXCONH2RHCXNH2RCOHH2OX=卤 素 , -OH, -NH2C2H5CC2H5BrCONH2C2H5CC2H5ONaOBrH2OPhHCHCCONH2PhHCCHCONH2PhH2CCHNHPhH2CCHONaOBrH2OH2OOrganic Reactions fo

17、r Drug SynthesisNNF3CNH2CONH2Br2/KOH05, 105minNNF3CNH2N C ONNF3CNNHOH72 % 芳环邻位有-NH2, -OH等亲核试剂时，可成新环Organic Reactions for Drug SynthesisCNHCOOCOOHNH2COOHCONH2NaOClRNH2生成伯胺Hoffmann重排RCOOHRCONH2 二元酸的酰亚胺：二元酸的酰亚胺：Organic Reactions for Drug SynthesisR CN3OR N C ON2三、Curtius重排 酰基叠氮化合物在惰性溶液中加热分解为异氰酸酯的反应称为Cu

18、rtius重排反应。Organic Reactions for Drug Synthesis机理烃 基迁移与脱氮同时发生重排不影响迁移基的光学活性R CNON NO CN N NRO CN RN2Organic Reactions for Drug SynthesisPhCOOH1.2.ClCOOC2H5NaN3PhCON3PhNH2.HClH2O/H1.2.7681%Curtius重排的应用 引入氨基 -COOH-NH2Organic Reactions for Drug SynthesisR C O O HH N3H2S O4R N H2C O2N2+机理与机理与Curtuis重排类似重排

19、类似四、Schmidt羰基化合物的降解反应包括三类反应：(一)羧酸和叠氮酸在硫酸或Lewis酸的催化下，得到比原来羧酸少一个碳原子伯胺。Organic Reactions for Drug SynthesisRCHOHN3H2SO4+RCNRNHCHOH2O和N2+RC ORRC ONHR+ HN3H2SO4+N2 (三三) 酮类和叠氮酸在硫酸的催化作用下生成酰胺。酮类和叠氮酸在硫酸的催化作用下生成酰胺。(二) 醛类和叠氮酸在硫酸的催化作用下生成腈类和胺类的甲酰基衍生物。Organic Reactions for Drug SynthesisCOOHNH2NaN3/H2SO4OH1.2.608

20、0%HOOCCOOHCH3CH3NaN3/H2SO4/CHCl3HOOCNH2CH3CH325,2.5h(位阻大者易反应)87%Organic Reactions for Drug Synthesis 当当R为手性碳原子时，重排后手性碳原子的构型不变为手性碳原子时，重排后手性碳原子的构型不变： Organic Reactions for Drug SynthesisOCOOHH2SO4HN3NHOCOOHH2O+HOOC(CH2)4CHCOONH3H2SO4HN3H3N(CH2)4CHCOONH374%赖氨酸的制备Organic Reactions for Drug SynthesisHofm

21、ann降解RCONH2Br2OHRNH2+4RCON3R N C OHRNH2N2H+R N H2H N3R C O O H操作简便操作简便收率较高收率较高Schimidt重排重排Curtius重排Organic Reactions for Drug SynthesisR CROC6H5COOOHR C ORO五、Baeyer-Villiger氧化重排 酮类用过氧酸(如过氧乙酸、过氧三氟醋酸等)氧化，在烃基与羰基之间插入氧原子而成酯的反应称为Baeyer-Villiger反应。Organic Reactions for Drug SynthesisR CROR C ORO+ C6H5CO3HH

22、CRRO HO OCC6H5OHCRROHO OCC6H5HOR COHORH机理Organic Reactions for Drug SynthesisCF3CO3H, ClCO3HCO3HCH3CO3H等后发现廉价、方便的H2O2/HOAc常用的过氧酸有：Organic Reactions for Drug Synthesis迁移基团的构型保持不变迁移基的迁移能力： 叔烷基环己基、仲烷基、苄基、苯基伯烷基甲基有给电子取代基的芳基有吸电子取代基的芳基Organic Reactions for Drug SynthesisHCOCH3C6H5CO3H/CHCl3HOCOCH3CH3CO3HCl

23、ClCOCH3ClClOCOCH381%80%Organic Reactions for Drug SynthesisCH3CO3HCONO2HAcO CONO2供电子环有利95%OOCF3CO3H/CHCl3O近双键有利56%Organic Reactions for Drug Synthesis第三节 从杂原子到碳原子的重排Steven重排Sommelet-Hauser重排Wittig重排Organic Reactions for Drug SynthesisACHNR3R2R1NaNH2ACH2N R2R2R1一、Stevens重排 季铵盐分子中连于氮原子的碳原子上具有吸电子的基团取代时

24、，在强碱性条件下，可重排生成叔胺的反应称为Stevens重排反应。Organic Reactions for Drug SynthesisR COR O COCH2CHAr及等,A为：常用的碱为NaOH,RONa,NaNH2等Organic Reactions for Drug Synthesis机理R2N CH2AR1R3:BR2NCH AR1R3NCH AR1R2R3为分子内重排迁移基构型保持Organic Reactions for Drug SynthesisStevens重排的应用由季铵盐制得烃基叔胺制备芳烃制备缩环或螺环化合物Organic Reactions for Drug S

25、ynthesisN(CH3)2CH2PhCH3ONaCH3OH(CH3)2NCH2PhNCCH2PhCCH2CH CH2.BrKOHCH3OHPhC CCHCH2CH CH2N(100%)Organic Reactions for Drug SynthesisH3COH3COCH2NCH3CH3RCOCH2Br+H3COH3COCH2N CH2CORCH3CH3.BrNa2CO3液CH3IKOH,H2O1.2.H3COH3COCH CHCOR H H3COH3COCH2CH2CH2RH3COH3COCH2CHCORN(CH3)285%Organic Reactions for Drug SynthesisNOCH3OCH3H3COH3COCH3CH3SOCH2NaDMSONH3COH3COCH3H3COOCH380%Organic Reactions for Drug SynthesisCH2N(CH3)3.XNaNH2CH2N(CH3)2CH3二.Sommelet-Hauser苯甲基季铵盐重排 苯甲基季铵盐经氨基钠或钾处理后，重排生成邻位烃基取代苯甲基叔胺的反应称为Sommelet-Hauser苯甲基季铵盐重排反应。Organic Reactions for Drug SynthesisCH2N(CH3)3.INaNH2CH2N(CH3)2CH3NH3CH