藥物合成反應(yīng)(第三版-聞韌)第五章--重排反應(yīng)PPT

1、Organic Reactions for Drug Synthesis第五章第五章 重排反應(yīng)重排反應(yīng) Rearrangement ReactionOrganic Reactions for Drug Synthesis定義：定義：受試劑或介質(zhì)的影響，受試劑或介質(zhì)的影響，同一有機(jī)分子內(nèi)的一個(gè)基團(tuán)或原同一有機(jī)分子內(nèi)的一個(gè)基團(tuán)或原子從一個(gè)原子遷移到另一個(gè)原子上子從一個(gè)原子遷移到另一個(gè)原子上,使分子構(gòu)架發(fā)生使分子構(gòu)架發(fā)生改變而形成一個(gè)新的分子的反應(yīng)稱為重排反應(yīng)。改變而形成一個(gè)新的分子的反應(yīng)稱為重排反應(yīng)。AWBABWA:重排起點(diǎn)原子重排起點(diǎn)原子,B:重排終點(diǎn)原子重排終點(diǎn)原子,W:重排基團(tuán)重排基團(tuán)分類分

2、類: 離子型機(jī)理（親核重排離子型機(jī)理（親核重排,親電重排）親電重排） 自由基重排自由基重排 周環(huán)機(jī)理重排（周環(huán)機(jī)理重排（-鍵遷移重排）鍵遷移重排）Organic Reactions for Drug Synthesis從碳原子到碳原子的重排從碳原子到雜原子的重排從雜原子到碳原子的重排-鍵遷移重排Organic Reactions for Drug Synthesis重排反應(yīng)的應(yīng)用形成C-C、C-N、C-O鍵定向引入官能團(tuán)形成環(huán)狀化合物Organic Reactions for Drug Synthesis第一節(jié) 從碳原子到碳原子的重排Wagner-Meerwein重排Pinacol重排二苯基乙

3、二酮-二苯基乙醇酸型重排Favorski重排Wolff重排Organic Reactions for Drug Synthesis一、Wagner-Meerwein重排 終點(diǎn)碳原子上羥基、鹵原子或重氮基等，在質(zhì)子酸或Lewis酸催化下離去形成碳正離子，其鄰近的基團(tuán)作1,2-遷移至該碳原子，同時(shí)形成更穩(wěn)定的起點(diǎn)碳正離子，后經(jīng)親核取代或質(zhì)子消除而生成新化合物的反應(yīng)稱為Wagner-Meerwein重排。Organic Reactions for Drug SynthesisR2CR3R1COHR4R5R2CR3R1CR4R5R1CR2CR3R4R5R1CR2CR3R4R5OHH+(-H2O)重 排

4、H2O(-H+)Organic Reactions for Drug Synthesis1 1 形成形成C C+ + 形式形式 (CH3)3C-CH2Cl(CH3)3C-CH2+AgClAg (AgNO3)(CH3)3C-CH2N2Cl-N2(CH3)3C-CH2(CH3)3C-CH3NH2NaNO2HCl(CH3)3C-CH2OH(CH3)3C-CH=CH2(CH3)3C-CH2(CH3)3C-CH-CH3H+-H2OH+(a)鹵代烴鹵代烴 Ag+ AlCl3 (b)含含-NH2,重氮化放氮重氮化放氮 (c)-OH, 加加 H+ (-H2O)Organic Reactions for Dru

5、g Synthesis苯的遷移速度為甲基的苯的遷移速度為甲基的30003000倍倍CCH3CH2ClH3CH3CCCH2CH3H3CCCH2CH3Ag+H3CCCH3CH2ClCH3H3C CCH3CH2CH3H3CCCH3CHCH3Ag+PhCCH3CH3HCCH3OTsH3CCCH3HCCH3PhOrganic Reactions for Drug Synthesis 遷移基團(tuán)遷移順序 ClR3C-R2CH-RCH3-CH3-H-OCH3Organic Reactions for Drug SynthesisOHHCH2CH2-H莰烯莰烯異冰片異冰片Organic Reactions fo

6、r Drug SynthesisCPhCHCH3CH3CH3OTsPhHCH3CCPhCH3CH3*CPhCHCH2CH3CH3*HCPhCCH3CH3CH3*CH3CCPhCH3CH3*+Organic Reactions for Drug Synthesis反應(yīng)機(jī)理？反應(yīng)機(jī)理？CH2CH3CH3CH3H3CCH3CH3CH3TsOHC6H6Organic Reactions for Drug SynthesisOrganic Reactions for Drug SynthesisH3COHHH3COHNaNO2/HOAcH3CONH2Organic Reactions for Drug

7、Synthesis二、Pinacol重排 鄰二醇類化合物鄰二醇類化合物在酸催化下，失去一分子在酸催化下，失去一分子水重排生成醛或酮的反應(yīng)，稱為水重排生成醛或酮的反應(yīng)，稱為Pinacol重排重排反應(yīng)。反應(yīng)。CCR4R2R1OHR3OHHCCR4R2R1R3OOrganic Reactions for Drug Synthesis(一)機(jī)理HCCRRROHROHCCRORRRHCCROHRRRHCCRORRROrganic Reactions for Drug Synthesis(二) 基團(tuán)的遷移能力1.對(duì)稱的鄰二醇芳基烴基供電子取代芳基吸電子取代芳基CCR1R1R2OHR2OHOrganic R

8、eactions for Drug Synthesis主產(chǎn)物主產(chǎn)物次產(chǎn)物次產(chǎn)物+PhCCCH3CH3OPhH3C CCPhCH3OPhHPhCCPhCH3CH3OHOHOrganic Reactions for Drug Synthesis94%6%+pCH3OC6H4C CC6H4OCH3PhOPhpC6H4OCH3pC6H4OCH3pCCPhO PhHpCH3OC6H4C C C6H4OCH3pPh PhOHOHOrganic Reactions for Drug Synthesis2.不對(duì)稱的鄰二醇羥基離去后碳正離子的穩(wěn)定性：羥基離去后碳正離子的穩(wěn)定性：叔碳叔碳仲碳仲碳伯碳伯碳CCR2R

9、1R1OHR2OH重排的方向決定于羥基失去的難易Organic Reactions for Drug Synthesis72%28%+pCH3OC6H4CCOHp CH3OC6H4PhOHPhH2SO4pCH3OC6H4CCPhpCH3OC6H4OPhpCH3OC6H4CCOC6H4OCH3PhpPhOrganic Reactions for Drug SynthesisPhCCCH3PhCH3OHPhCCCH3PhCH3OPhCCCH3PhCH3OHPhCCCH3PhCH3OHOHH2SO4Organic Reactions for Drug SynthesisPhCCCH3PhOH OHC

10、H3PhCCCH3OPhCH3Ac2O/ZnCl2或醋酸+微量硫酸為什么？分析反應(yīng)機(jī)理有何不同。為什么？分析反應(yīng)機(jī)理有何不同。PhCCCH3PhOH OHCH3PhCCCH3PhOH OAcPhCCCH3OPhCH3CH3Ac2O/ZnCl2Organic Reactions for Drug Synthesis3.3.三取代的鄰二醇三取代的鄰二醇對(duì)于三取代的鄰二醇，其中的叔碳上形成對(duì)于三取代的鄰二醇，其中的叔碳上形成的碳正離子較穩(wěn)定，所以一般是仲碳上的的碳正離子較穩(wěn)定，所以一般是仲碳上的基團(tuán)基團(tuán)( (或氫原子或氫原子) )遷移。遷移。 Organic Reactions for Drug S

11、ynthesis如果需要叔碳上的基團(tuán)遷移，如果需要叔碳上的基團(tuán)遷移，可采用衍生物法在堿性條件下重排?？刹捎醚苌锓ㄔ趬A性條件下重排。Organic Reactions for Drug Synthesis4.羥基位于脂環(huán)環(huán)擴(kuò)大或縮小OHCOHPhPhH2SO4/Et2Or.t.2hOPhPh99%Organic Reactions for Drug Synthesis螺環(huán)的形成：螺環(huán)的形成：Organic Reactions for Drug Synthesis對(duì)于羥基共環(huán)的情形，總是處在離去的羥基反式對(duì)于羥基共環(huán)的情形，總是處在離去的羥基反式的基團(tuán)遷移，這在一定程度上說(shuō)明的基團(tuán)遷移，這在一定

12、程度上說(shuō)明PinacolPinacol重排可重排可按分子內(nèi)按分子內(nèi)SN2SN2機(jī)理進(jìn)行。機(jī)理進(jìn)行。 Organic Reactions for Drug SynthesisOHOHH+HOHOHOOOrganic Reactions for Drug Synthesis(三) Semipinacol重排R C CRRO RR C CRR ROHYR C CRR ROHYNH2XOSO2RY為 Organic Reactions for Drug SynthesisCHCPhOHPh NH2ClCHCPhOHPhClCHCPhOPhClHNO2Organic Reactions for Drug

13、 SynthesisOSO2ArCH3HOHCH3H3CtBuOKHOHCH3H3CCH3Organic Reactions for Drug SynthesisTiffeneau環(huán)擴(kuò)大反應(yīng) 1-氨基甲基環(huán)烷醇用亞硝酸處理，經(jīng)重排形成多一個(gè)碳的環(huán)烷酮的反應(yīng)，稱為Tiffeneau環(huán)擴(kuò)大反應(yīng)。(CH2)nCOHCH2NH2HNO2(CH2)nCH2COOrganic Reactions for Drug Synthesis環(huán)庚酮環(huán)庚酮NaNO2/HOAcH2/NiCH3NO2/OH2.1.OOHCH2NH2O環(huán)己酮環(huán)己酮Organic Reactions for Drug Synthesis三、

14、二苯基乙二酮 二苯基乙醇酸重排 二苯基乙二酮(苯偶酰)類化合物用堿處理，生成二苯基-羥基酸(二苯乙醇酸)的反應(yīng)稱為苯偶酰-二苯乙醇酸重排反應(yīng)。CC6H5C6H5COOOHKOH/C2H5OHC6H5C C C6H5O OOrganic Reactions for Drug SynthesisC6H5C C C6H5O OC6H5C C OHO C6H5O+OHC6H5C C OHOOC6H5C6H5C C OOOHC6H5Organic Reactions for Drug Synthesis遷移能力：吸電子基取代的芳環(huán) 供電子基取代的芳環(huán)ArC CArO OArCC OHOHOAr+HO C

15、 CArO OHArOrganic Reactions for Drug SynthesisOOOHref.COOHOHOrganic Reactions for Drug SynthesisOOKOHHOOOHOOOOOHOHOOHOH+Organic Reactions for Drug SynthesisHNHNOOOHCOOHH2OCH3O /CH3OH2)1)HNHNOOOOHOHOOCC8H17KOH/C3H7OH.H2OOOC8H17甾體縮環(huán)甾體縮環(huán)92100%97%Organic Reactions for Drug Synthesis四、Favorski鹵代酮重排 -鹵代酮在

16、親核堿(NaOH,RONa等)存在的條件下，發(fā)生重排得到羧酸鹽、酯或酰胺的反應(yīng)稱為Favorski鹵代酮重排反應(yīng)。PhCH2C CH2ClONaOHPhCH2CH2COOOrganic Reactions for Drug SynthesisRHCHCRCOOEtRH2CHCRCOOEta)HRHCHCREtOOCRHCH2CRCOOEtb)HRH2C CHC RXOEtONaRHC CHC RXO-XRHCHCRCOEtONaRHCHCRCOOEtabOrganic Reactions for Drug SynthesisClO*O*OEtOCOEtOEtONa-ClEtONaOClCOEt

17、O+*50%50%*-H+Organic Reactions for Drug SynthesisCHXCCH3OEtONa/EtOHNaOHNaNH2H2CCCH2OXCH2CH2COHOCH2CH2COROCH2CH2CNH2OOrganic Reactions for Drug SynthesisClCCH3OOOCOOEtCH2CH2COOEtEtONaEtONaEtOC 所連接的取代基越少越穩(wěn)定主Organic Reactions for Drug SynthesisFavorski鹵化酮重排應(yīng)用制備碳上多烴基取代羧酸衍生物合成有張力的脂環(huán)烴羧酸衍生物大環(huán)類化合物的縮環(huán)Organic

18、 Reactions for Drug Synthesis91%64%ClOKOH/C2H5OHCOOHOrganic Reactions for Drug Synthesis有雜原子參與的有雜原子參與的FavorskyFavorsky重排：重排： 酰胺氮原子上的氫具酸性，同樣可以酰胺氮原子上的氫具酸性，同樣可以在堿性條件下去質(zhì)子。在堿性條件下去質(zhì)子。Organic Reactions for Drug Synthesis五、Wolff重排 重氮酮重氮酮在銀、銀鹽或銅存在條件下，在銀、銀鹽或銅存在條件下，或用光照射或熱分解都消除氮分子而重排或用光照射或熱分解都消除氮分子而重排為烯酮，生成的烯酮

19、進(jìn)一步與羥基或胺類為烯酮，生成的烯酮進(jìn)一步與羥基或胺類化合物作用得到酯類、酰胺或羧酸的反應(yīng)化合物作用得到酯類、酰胺或羧酸的反應(yīng)稱為稱為WolffWolff重排反應(yīng)。重排反應(yīng)。Organic Reactions for Drug SynthesisRCCRNNOOCCRR光 或 熱Ag +或 Cu2+RCCRO+N2OCCHRH2OROHNH3RNH2RCH2COOHRCH2COORRCH2CONH2RCH2CONHROrganic Reactions for Drug SynthesisBr(CH2)9C CHN2ONH3.H2O/AgNO3Br(CH2)9CH2CONH2N2OCH3OHHH

20、3COOCh75%49%Organic Reactions for Drug SynthesisArndt-Eistert(阿恩特-艾斯特爾)同系列羧酸的合成反應(yīng) 由于由于重氮酮不易制備，使該重排反應(yīng)受到重氮酮不易制備，使該重排反應(yīng)受到一定限制，一定限制，Arndt-Eistert等用酰氯與重氮甲等用酰氯與重氮甲烷反應(yīng)得到烷反應(yīng)得到重氮酮，再經(jīng)過(guò)重氮酮，再經(jīng)過(guò)Wolff重排，生成重排，生成比原來(lái)酰氯多一個(gè)碳原子的羧酸，該反應(yīng)稱為比原來(lái)酰氯多一個(gè)碳原子的羧酸，該反應(yīng)稱為Arndt-Eistert合成。合成。Organic Reactions for Drug Synthesis反應(yīng)包括下列三個(gè)步

21、驟：1.酰氯的形成；2.酰氯和重氮甲烷作用生成重氮酮；3.重氮酮經(jīng)Wolff重排變?yōu)橄┩?，再轉(zhuǎn)變?yōu)轸人峄蜓苌?。Organic Reactions for Drug SynthesisRCOOHRCOClCH2N2RCOCHN2RCH C OH2ORCH2COOHCOClCH2COOC2H5CH2N2PhCOOAg/EtOH/TEA1.2.8492%Organic Reactions for Drug SynthesisSOCl2H3COCOOCH3H(CH2)2COOCH32.1.CH2N2H3COCOOCH3HCH2COOH84%Organic Reactions for Drug Syn

22、thesis第二節(jié) 從碳原子到雜原子的重排Beckmann重排Hofmann酰胺重排為胺類Curtius重排Schmidt羰基化合物的降解反應(yīng)Baeyer-Villiger氧化重排Organic Reactions for Drug Synthesis一、Beckmann重排醛肟或酮肟類化合物在酸性催化劑的作用下，重排成取代酰胺的反應(yīng)稱為Beckmann重排。CNOHRRCRONHRHOrganic Reactions for Drug SynthesisBeckmann重排的應(yīng)用將酮轉(zhuǎn)變?yōu)轷０反_定酮的結(jié)構(gòu)擴(kuò)環(huán)成內(nèi)酰胺化合物制備仲胺Organic Reactions for Drug Synt

23、hesis機(jī)理反式遷移RCRNOHHRCRNOH2RCNRRCNRRCNHRH2OO-HRCNROH2RCNROHOrganic Reactions for Drug Synthesis(1)催化劑催化劑:質(zhì)子酸質(zhì)子酸 H+ ,H2SO4 , HCl, H3PO4 非質(zhì)子酸非質(zhì)子酸PCl5, SOCl2, TsCl, AlCl3 RCRNOHRCRNOHH用質(zhì)子酸用質(zhì)子酸( (極性溶劑中）催化時(shí)存在異構(gòu)化問(wèn)題極性溶劑中）催化時(shí)存在異構(gòu)化問(wèn)題Organic Reactions for Drug Synthesis 質(zhì)子酸催化時(shí)，極性溶劑的存在使基團(tuán)遷移質(zhì)子酸催化時(shí)，極性溶劑的存在使基團(tuán)遷移的選擇

24、性降低，所以溶劑以非極性為主?；鶊F(tuán)遷的選擇性降低，所以溶劑以非極性為主?；鶊F(tuán)遷移后，形成一個(gè)碳正離子，所以使用親核性溶劑移后，形成一個(gè)碳正離子，所以使用親核性溶劑時(shí)，往往得不到期望的酰胺，而是生成該溶劑的時(shí)，往往得不到期望的酰胺，而是生成該溶劑的相應(yīng)反應(yīng)產(chǎn)物，如醇中的相應(yīng)反應(yīng)產(chǎn)物，如醇中的BeckmannBeckmann重排。重排。Organic Reactions for Drug Synthesis(2)肟的結(jié)構(gòu)肟的結(jié)構(gòu) OCH3NCH3HOH2NOHHNHOCH3脂環(huán)酮肟發(fā)生擴(kuò)環(huán)反應(yīng)生成內(nèi)酰胺脂環(huán)酮肟發(fā)生擴(kuò)環(huán)反應(yīng)生成內(nèi)酰胺Ph CHCH3CCH3NOHCH3CONHCHPhCH3*H構(gòu)型

25、保持率99.6%遷移基團(tuán)在遷移過(guò)程中構(gòu)型保留遷移基團(tuán)在遷移過(guò)程中構(gòu)型保留 Organic Reactions for Drug Synthesis140H2SO4NOH+RNH2RCOOOHHCRONHRCNOHRRNHO95%Organic Reactions for Drug SynthesisH3CC NOHLiAlH4AlCl3THFEt2ONHCH2CH3C NOHPhPhLiAlH4AlCl3PhCH2NHPh酰胺還原成仲胺酰胺還原成仲胺Organic Reactions for Drug SynthesisCNPhOHH3CPhCH3SOCl2C6H6CNPhOH3CPhCH3S

26、OClPhCNCCH3PhCH3-HCCH2PhCH3在重排條件下，酮肟也可發(fā)生裂解在重排條件下，酮肟也可發(fā)生裂解( (消除消除) )的副反應(yīng)的副反應(yīng)( (異常異常BeckmannBeckmann重排重排) )，得到腈。，得到腈。 Organic Reactions for Drug Synthesis醛肟和醛肟和LewisLewis酸反應(yīng)易發(fā)生消除反應(yīng)，得到腈。酸反應(yīng)易發(fā)生消除反應(yīng)，得到腈。 Organic Reactions for Drug Synthesis二、Hofmann酰胺重排為胺類 酰胺用溴(或氯)和堿處理轉(zhuǎn)變?yōu)樯僖粋€(gè)碳原子的伯胺的反應(yīng)稱為Hofmann酰胺重排為胺類反應(yīng)或稱為

27、Hofmann降解反應(yīng)。R C NH2ORNH2NaOXor X2/NaOHOrganic Reactions for Drug Synthesis機(jī)理重排后R保留原來(lái)手性2CO3+RNH2H2O/OHR N C OR CNOBrR CNHBrOR CNH2OBr2OHOrganic Reactions for Drug SynthesisR CHNOBrR C NH2OBr2-HBrR C NOBrOHR CNO-BrOC N RHO CN ROCH3H3CO C NHROH3CO C OHOHOCH3NH2R+Organic Reactions for Drug SynthesisHofm

28、ann降解反應(yīng)適用范圍 本重排的酰胺包括脂肪、脂環(huán)、芳脂、芳香及或雜環(huán)等的單酰胺，用以制備各類伯胺。Organic Reactions for Drug Synthesis(C2H5)2NCH2CH2CONH2NaOCl/H2O(C2H5)2NCH2CH2NH2NaOBr/H2ONCONH2NNH26571%Organic Reactions for Drug Synthesis RHCXCONH2RHCXNH2R COHH2OX=鹵素, -OH, -NH2C2H5CC2H5BrCONH2C2H5CC2H5ONaOBrH2OPhHCHCCONH2PhHCCHNH2PhH2CCHNHPhH2CC

29、HONaOBrH2OH2OOrganic Reactions for Drug Synthesis芳環(huán)鄰位有-NH2,-OH等時(shí)，可成新環(huán)NNF3CNH2CONH2Br2/KOH05, 105minNNF3CNH2N C ONNF3CNNHOH72%Organic Reactions for Drug Synthesis HofmannHofmann重排的應(yīng)用：環(huán)丙胺重排的應(yīng)用：環(huán)丙胺( (環(huán)丙沙星中間體環(huán)丙沙星中間體) )的合成。的合成。 Organic Reactions for Drug Synthesis類似地，用堿處理異羥肟酸及其衍生物也類似地，用堿處理異羥肟酸及其衍生物也可經(jīng)由異氰

30、酸酯中間體得到少一個(gè)碳的胺，可經(jīng)由異氰酸酯中間體得到少一個(gè)碳的胺，稱為稱為L(zhǎng)ossen(Lossen(洛森洛森) )重排。重排。 Organic Reactions for Drug Synthesis三、Curtius（庫(kù)爾提斯）重排 ?；B氮化合物在惰性溶液中加熱分解為異氰酸酯的反應(yīng)稱為Curtius重排反應(yīng)。R CN3OR N C ON2Organic Reactions for Drug Synthesis機(jī)理烴 基遷移與脫氮同時(shí)發(fā)生重排不影響遷移基的光學(xué)活性R CNON NO CN N NRO CN RN2Organic Reactions for Drug Synthesis1 1

31、 酰氯與疊氮化鈉的反應(yīng)酰氯與疊氮化鈉的反應(yīng)+ROCClNaN3ROCN32 2 羧酸與氯甲酸酯反應(yīng)得混合酸酐，再與羧酸與氯甲酸酯反應(yīng)得混合酸酐，再與疊氮化鈉反應(yīng)疊氮化鈉反應(yīng)+ROCOHClCOOC2H5Et3NOC2H5NaN3ROCOOCROCN3?；B氮化合物的生成?；B氮化合物的生成Organic Reactions for Drug Synthesis 3 3 酰肼與亞硝酸的反應(yīng)酰肼與亞硝酸的反應(yīng)RCONHNH2HONORCONHNHNORCONHNNOHH2ORCON3Organic Reactions for Drug SynthesisCurtius重排的應(yīng)用 引入氨基 -COO

32、H-NH2PhCOOH1.2.ClCOOC2H5NaN3PhCON3PhNH2.HClH2O/H1.2.7681%Organic Reactions for Drug Synthesis四、Schmidt（希米特）重排羰基化合物的降解反應(yīng)包括三類反應(yīng)：包括三類反應(yīng)：(一一)羧酸和疊氮酸在硫酸或羧酸和疊氮酸在硫酸或Lewis酸的催化下，酸的催化下，得到比原來(lái)羧酸少一個(gè)碳原子伯胺。得到比原來(lái)羧酸少一個(gè)碳原子伯胺。RCOOHHN3H2SO4RNH2CO2N2+機(jī)理與機(jī)理與Curtuis重排類似重排類似Organic Reactions for Drug Synthesis(二)醛類和疊氮酸在硫酸的催

33、化作用下生成腈類和胺類的甲酰基衍生物。RCHOHN3H2SO4+RCNRNHCHOH2O和N2+RCORRCONHR+ HN3H2SO4+N2(三三)酮類和疊氮酸在硫酸的催化作用下酮類和疊氮酸在硫酸的催化作用下生成酰胺。生成酰胺。Organic Reactions for Drug SynthesisCOOHNH2NaN3/H2SO4OH1.2.6080%HOOCCOOHCH3CH3NaN3/H2SO4/CHCl3HOOCNH2CH3CH325,2.5h(位阻大者易反應(yīng))87%Organic Reactions for Drug Synthesis 當(dāng)當(dāng)R為手性碳原子時(shí)，重排后手性碳為手性碳原

34、子時(shí)，重排后手性碳原子的構(gòu)型不變?cè)拥臉?gòu)型不變： Organic Reactions for Drug SynthesisOCOOHH2SO4HN3NHOCOOHH2O+HOOC(CH2)4CHCOONH3H2SO4HN3H3N(CH2)4CHCOONH374%賴氨酸的制備Organic Reactions for Drug SynthesisHofmann降解RCONH2Br2OHRNH2+4RCON3R N C OHRNH2N2H+RNH2HN3RCOOH操作簡(jiǎn)便操作簡(jiǎn)便收率較高收率較高Schimidt重排重排Curtius重排Organic Reactions for Drug Synt

35、hesis五、Baeyer-Villiger氧化重排 酮類用過(guò)氧酸(如過(guò)氧乙酸、過(guò)氧三氟醋酸等)氧化，在烴基與羰基之間插入氧原子而成酯的反應(yīng)稱為Baeyer-Villiger反應(yīng)。R CROC6H5COOOHR C OROOrganic Reactions for Drug SynthesisR CROR C ORO+ C6H5CO3HHCRRO HO OCC6H5OHCRROHO OCC6H5HOR COHORH機(jī)理Organic Reactions for Drug Synthesis常用的過(guò)氧酸有：CF3CO3H, ClCO3HCO3HCH3CO3H等后發(fā)現(xiàn)廉價(jià)、方便的H2O2/HOAc

36、Organic Reactions for Drug Synthesis遷移基團(tuán)的構(gòu)型保持不變遷移基的遷移能力： 叔烷基環(huán)己基、仲烷基、芐基、苯基伯烷基甲基有給電子取代基的芳基有吸電子取代基的芳基Organic Reactions for Drug SynthesisHCOCH3C6H5CO3H/CHCl3HOCOCH381%COPhCF3CO3H / CH2Cl2COPh90%250CH2OOOHOrganic Reactions for Drug SynthesisCH3CO3HCONO2HAcO CONO2供電子環(huán)有利95%OOCF3CO3H/CHCl3O近雙鍵有利56%Organic

37、Reactions for Drug Synthesis氫的遷移能力大于烷基，所以醛與過(guò)氧乙氫的遷移能力大于烷基，所以醛與過(guò)氧乙酸反應(yīng)生成酸。但間氯過(guò)氧化苯甲酸在室酸反應(yīng)生成酸。但間氯過(guò)氧化苯甲酸在室溫下可將某些醛氧化為甲酸酯。溫下可將某些醛氧化為甲酸酯。 Organic Reactions for Drug Synthesis第三節(jié) 從雜原子到碳原子的重排Stevens(史蒂文斯)重排Sommelet-Hauser（沙米爾脫）重排Wittig（維提希）重排Organic Reactions for Drug Synthesis機(jī)理Y CHR堿BBHYCRYCROrganic Reaction

38、s for Drug Synthesis一、Stevens重排 季銨鹽分子中連于氮原子的碳原子上具有吸電子的基團(tuán)取代時(shí)，在強(qiáng)堿性條件下，可重排生成叔胺的反應(yīng)稱為Stevens重排反應(yīng)。A CHNR3R2R1NaNH2A CH2N R2R2R1Organic Reactions for Drug SynthesisA為：常用的堿為NaOH,RONa,NaNH2等R COR O COCH2CHAr及等,Organic Reactions for Drug Synthesis機(jī)理R2N CH2AR1R3:BR2NCH AR1R3NCH AR1R2R3為分子內(nèi)重排遷移基構(gòu)型保持Organic Reac

39、tions for Drug SynthesisStevens重排的應(yīng)用由季銨鹽制得烴基叔胺制備芳烴制備縮環(huán)或螺環(huán)化合物Organic Reactions for Drug SynthesisN(CH3)2CH2PhCH3ONaCH3OH(CH3)2NCH2PhNCCH2PhCCH2CH CH2.BrKOHCH3OHPhC CCHCH2CH CH2N(100%)Organic Reactions for Drug SynthesisH3COH3COCH2NCH3CH3RCOCH2Br+H3COH3COCH2N CH2CORCH3CH3.BrNa2CO3液CH3IKOH,H2O1.2.H3COH

40、3COCH CHCOR H H3COH3COCH2CH2CH2RH3COH3COCH2CHCORN(CH3)285%Organic Reactions for Drug SynthesisNOCH3OCH3H3COH3COCH3CH3SOCH2NaDMSONH3COH3COCH3H3COOCH380%Organic Reactions for Drug Synthesis二.Sommelet-Hauser苯甲基季銨鹽重排 苯甲基季銨鹽經(jīng)氨基鈉或鉀處理后，重排生成鄰位烴基取代苯甲基叔胺的反應(yīng)稱為Sommelet-Hauser苯甲基季銨鹽重排反應(yīng)。CH2N(CH3)3.XNaNH2CH2N(CH3

41、)2CH3Organic Reactions for Drug SynthesisCH2N(CH3)3.INaNH2CH2N(CH3)2CH3NH3CH N CH3CH3CH3CH2N CH3CH3CH2CH2CH2NCH3CH3H機(jī)理9095%Organic Reactions for Drug SynthesisSommelet-Hauser與Stevens重排共同點(diǎn)： 季銨鹽負(fù)碳季銨內(nèi)翁鹽重排:B低溫Sommelet Hauser重排Stevens重排Organic Reactions for Drug Synthesis.BrNCH3CH2PhPhLi/Bu2O120NaNH2/NH3

42、-33N CH3CH2PhN CH3CH3Organic Reactions for Drug SynthesisSommelet-Hauser重排的用途制備鄰甲芳基化合物NaNH2 NH3CH3CH2N(CH3)3.XCH3CH3CH2N(CH3)2CH3CH3CH3CH3CH3COOHCH3CH3CH3(CH3)2NCH2Organic Reactions for Drug SynthesisNCH2N(CH3)2CH3CH3NaNH2 NH3.XNCH2N(CH3)3CH3OCH3CH2N(CH3)2.XOCH2N(CH3)3NaNH2 NH379%76%Organic Reaction

43、s for Drug Synthesis三、Wittig醚重排 醚類化合物和烷基鋰或氨基鈉作用重排生成醇的反應(yīng)，稱為Wittig醚重排反應(yīng)。R1CH2OR2R3LiCH OHR1R2Organic Reactions for Drug Synthesis機(jī)理烴基構(gòu)型可發(fā)生改變烴基構(gòu)型可發(fā)生改變R1CH2OR2R3LiR1CHO R2LiCH OLiR1R2CH OHR1R2Organic Reactions for Drug Synthesis基團(tuán)的遷移能力： CH2=CH-CH2,C6H5CH2- CH3-,CH3CH2-,p-NO2C6H5Ph-Organic Reactions for

44、Drug SynthesisHOCH2CH CHCH3OCH2CH CHCH3KOHOrganic Reactions for Drug Synthesis2,3-Wittig2,3-Wittig重排是烯丙醚的重排，重排是烯丙醚的重排，反應(yīng)機(jī)理為：反應(yīng)機(jī)理為： Organic Reactions for Drug Synthesis第四節(jié) -鍵遷移重排Organic Reactions for Drug Synthesis定義： 協(xié)同反應(yīng)中，一個(gè)原子或基團(tuán)從起點(diǎn)原子上的-鍵越過(guò)共軛的電子系統(tǒng)，遷移到分子內(nèi)的一個(gè)新位置上，形成新的 鍵稱為-遷移重排。C1MC CmC CCMm2m+1Organi

45、c Reactions for Drug Synthesis 遷移重排的命名 遷移重排可用數(shù)字遷移重排可用數(shù)字i,j予以分予以分類，將類，將 鍵兩端用鍵兩端用1，1依次編號(hào)依次編號(hào)， i,j分別代表終點(diǎn)分別代表終點(diǎn) 鍵所連原子的編鍵所連原子的編號(hào)，稱作號(hào)，稱作i,j 鍵遷移重排。鍵遷移重排。Organic Reactions for Drug Synthesis54321CH3H3CH3CCH31,5遷移CHH2CCH2H321CHH2CCH2H1,3遷移Organic Reactions for Drug SynthesisCCCCCCCCCC1 2 3 4 51 2 3 4 5CCCCCC

46、CCCC1 2 3 4 51 2 3 4 5CCCCCCCCCC1 2 3 4 51 2 3 4 5CCCCCCCCCC1 2 3 4 51 2 3 4 53,3遷移3,5遷移Organic Reactions for Drug Synthesis3,3遷移重排Claisen重排Cope重排Fischer吲哚合成Organic Reactions for Drug Synthesis內(nèi)消旋內(nèi)消旋3,4-二甲基二甲基-1,5-己二烯己二烯 Z,E-2,6-辛二烯辛二烯EZCH3HCH3RSHCH3CH3H3,3 3,3 鍵遷移重排特點(diǎn)：鍵遷移重排特點(diǎn)：類椅式過(guò)渡態(tài)類椅式過(guò)渡態(tài)Organic Reactions for Drug Synthesis一、Claisen重排 烯醇或酚的烯丙基醚當(dāng)加熱到足夠高的溫度時(shí)發(fā)生重排而形成C-烯丙基衍生物的反應(yīng)稱Claisen重排。O231231O3,3遷移Organic