定义Definition
费歇尔吲哚合成是芳基腙（由苯肼与醛或酮缩合得到）在酸催化下加热，经 [3,3]-σ 迁移重排和环化、失去氨，生成吲哚的反应。
The Fischer indole synthesis heats an arylhydrazone (from a phenylhydrazine and an aldehyde or ketone) with acid; a [3,3]-sigmatropic rearrangement, cyclisation and loss of ammonia give an indole.
机理Mechanism
苯腙互变异构为烯肼；质子化后发生 [3,3]-σ 迁移重排，断裂 N–N 键、形成 C–C 键；随后芳构化、分子内胺对亚胺加成闭合五元环，最后消除 NH₃ 得芳香吲哚。¹⁵N 标记证明失去的是靠近苯环的那个氮。
The hydrazone tautomerises to an ene-hydrazine; after protonation a [3,3]-sigmatropic shift breaks N–N and forms C–C; rearomatisation and intramolecular amine addition close the five-membered ring, and loss of NH₃ gives the indole. ¹⁵N labelling shows the nitrogen attached to the ring is retained.
由来Origin
埃米尔·费歇尔与弗里德里希·乔丹于 1883 年报道。费歇尔还因糖和嘌呤研究获 1902 年诺贝尔化学奖。
Reported by Emil Fischer and Friedrich Jourdan in 1883; Fischer won the 1902 Nobel Prize for sugar and purine chemistry.
应用Applications
是合成吲哚最常用的方法之一，用于制备色胺类、吲哚美辛、曲普坦类抗偏头痛药物等。催化剂可用 ZnCl₂、多聚磷酸、BF₃ 或质子酸；不对称酮可得两种区域异构体。
One of the most used indole syntheses, applied to tryptamines, indometacin and triptan migraine drugs. Catalysts include ZnCl₂, polyphosphoric acid, BF₃ and protic acids; unsymmetrical ketones can give two regioisomers.
反应Reactions
苯肼与羰基化合物在乙酸、多聚磷酸或 ZnCl₂ 中加热（可一锅完成成腙与环化）
Heat a phenylhydrazine and carbonyl compound in acetic acid, PPA or with ZnCl₂ (one-pot hydrazone formation and cyclisation)
苯肼与羰基缩合成腙，互变异构为烯肼。
Condensation to the hydrazone and tautomerisation to the ene-hydrazine.
[3,3]-σ 迁移重排形成新的 C–C 键。
[3,3]-Sigmatropic rearrangement forms the new C–C bond.
芳构化、环化成氨缩醛胺。
Rearomatisation and cyclisation to an aminal.
消除 NH₃ 得吲哚。
Loss of NH₃ gives the indole.
以多聚磷酸为催化剂。
Using polyphosphoric acid.
年表Timeline
- 1883
费歇尔与乔丹发现该反应
Fischer and Jourdan discover the reaction
- 1924
罗宾逊夫妇提出 [3,3] 重排机理
The Robinsons propose the [3,3] mechanism