定义Definition
曼尼希反应是含 α-活泼氢的羰基化合物、甲醛（或其他醛）与伯胺或仲胺三组分缩合，生成 β-氨基羰基化合物（曼尼希碱）的反应。
The Mannich reaction is a three-component condensation of an enolisable carbonyl compound, formaldehyde (or another aldehyde) and a primary or secondary amine, giving a β-amino carbonyl compound (a Mannich base).
机理Mechanism
胺与甲醛缩合脱水生成亚胺正离子（埃申莫瑟盐 CH₂=NMe₂⁺ 即其稳定形式）；羰基化合物的烯醇形式进攻亚胺正离子碳，形成新的 C–C 键，得 β-氨基酮。
The amine and formaldehyde condense to an iminium ion (Eschenmoser’s salt, CH₂=NMe₂⁺, is a stable version); the enol of the carbonyl compound attacks the iminium carbon, forming the C–C bond and the β-amino ketone.
由来与生物合成Origin and biosynthesis
德国化学家卡尔·曼尼希于 1912 年报道。1917 年罗宾逊用丁二醛、甲胺和丙酮二羧酸一锅“仿生”合成托品酮，被视为全合成史上的里程碑，模拟了生物碱的生物合成。
Reported by Carl Mannich in 1912. In 1917 Robinson’s one-pot ‘biomimetic’ synthesis of tropinone from succinaldehyde, methylamine and acetonedicarboxylic acid — a Mannich cascade — became a landmark mimicking alkaloid biosynthesis.
应用Applications
曼尼希碱可消除胺得到 α-亚甲基酮（迈克尔受体）。用于药物（如曲马多、氟西汀相关中间体）和生物碱合成；脯氨酸催化的不对称曼尼希反应是有机催化的代表反应之一。
Mannich bases eliminate the amine to α-methylene ketones (Michael acceptors). Used in drug and alkaloid synthesis; proline-catalysed asymmetric Mannich reactions are flagship organocatalytic transformations.
反应Reactions
胺盐酸盐、多聚甲醛，乙醇中回流；或预制的埃申莫瑟盐
Amine hydrochloride and paraformaldehyde in refluxing ethanol, or preformed Eschenmoser’s salt
胺与甲醛生成亚胺正离子。
Amine and formaldehyde form an iminium ion.
酮烯醇化。
The ketone enolises.
烯醇进攻亚胺正离子生成 β-氨基酮。
The enol attacks the iminium ion to give the β-amino ketone.
典型曼尼希碱。
A typical Mannich base.
反应机理图Mechanism
红色弯箭头表示一对电子的移动方向：从电子来源（孤对电子或化学键）指向电子去向。Red curly arrows show where an electron pair moves: from its source (lone pair or bond) to its destination.
甲醛与二甲胺先生成亚胺正离子；酮的烯醇式进攻它
Formaldehyde and dimethylamine first form an iminium ion; the ketone’s enol attacks it
质子化的产物
Protonated adduct
曼尼希碱（β-氨基酮）
Mannich base (β-amino ketone)
年表Timeline
- 1912
曼尼希报道该反应
Mannich reports the reaction
- 1917
罗宾逊仿生合成托品酮
Robinson’s biomimetic tropinone synthesis
- 2000
李斯特报道脯氨酸催化不对称曼尼希反应
List reports proline-catalysed asymmetric Mannich reactions