Chinese name: Mannich reaction (mbth: Mannich reaction alias: Mannich reaction application discipline: application scope of organic chemistry: reaction mechanism of chemical production: nucleophilic addition reaction of amine to carbonyl group: overview, reaction mechanism, development history, application, stereoselectivity of reaction, overview of amines in the reaction are generally secondary amines, such as piperidine and dimethylamine. If primary amine is used, the condensation product after the reaction still has hydrogen on nitrogen, so the reaction can continue. Therefore, primary amines can sometimes be used as needed, and primary amines and formaldehyde will dehydrate rapidly at room temperature to form Schiff base. If tertiary amine or aromatic amine is used, imine ions cannot be generated in the reaction and stay in the quaternary ammonium ion step. The function of amine/ammonia is to activate another reactant aldehyde. Formaldehyde is the most commonly used aldehyde, and its aqueous solution, paraformaldehyde or paraformaldehyde are generally used. Besides formaldehyde, other aldehydes can also be used outside. The reaction is usually carried out in water, acetic acid or alcohol, and a small amount of hydrochloric acid is added to ensure the acidity. The compounds containing α-hydrogen are usually carbonyl compounds (aldehydes, ketones, carboxylic acids, esters), nitriles, fatty nitro compounds, terminal alkynes, α-alkylpyridines or imines. If asymmetric ketones are used, the product is a mixture. Heterocyclic compounds such as furan, pyrrole and thiophene can also react. Mannich reaction usually needs to be carried out in proton solvent at high temperature, which takes a long time and is easy to produce by-products. Reaction mechanism The mechanism of the reaction is shown in the following figure. Imine ion intermediates can be obtained by protonation of carbonyl group, nucleophilic addition of amine to carbonyl group, deprotonation, electron transfer on nitrogen and departure of water. Taking dimethylamine as raw material, this intermediate is N, N- dimethyl-methylene ammonium chloride, which was first discovered by Kinact and others in 1970s. It has strong reactivity and can make many reactions that are difficult to carry out under normal conditions go smoothly. Reaction mechanism Imine ions, as electrophilic reagents, attack the enol structure of compounds containing active hydrogen, lose protons and get products. The product Mannig base is relatively stable. Using it as raw material, α, β-unsaturated ketone can be obtained by methylation and Hoffman elimination reaction, or by decomposition reaction under the action of alkali during distillation. The latter can react with nucleophiles, such as Michael addition, and is a very useful synthetic precursor. However, because it is generally unstable and easy to polymerize, it is usually decomposed by Mannig base to generate unsaturated ketone, which can react with other reagents in situ. Compounds with active α-H, such as aldehydes, ketones (acids, esters, nitro compounds, cyano compounds, terminal alkynes, etc. ) reflux with formaldehyde and amine (primary amine, secondary amine or ammonia) in ethanol solution, so that α-H of ketone is replaced by aminomethyl. This reaction is also called amine methylation, and the product obtained becomes Mannig base. Look at the development history. As early as 1895, Mannig base with phenol as acid component was discovered and patented. Later, Tollens, L. Henry, Duden, Franchimont and others discovered other Mannich reactions, including those with nitroalkanes and primary nitramine as acid components, but they did not realize the universal significance of these reactions. In 19 12, Karl Mannig reacts with thalidomide and urotropine to obtain water-insoluble precipitate. The structure of this product was explained within one year, which prompted him to study the reaction of this kind of compounds containing active hydrogen with formaldehyde and amine, thus laying the foundation for Mannich reaction. Many alkaloids are synthesized by Mannich reaction. The synthesis of tropinone is a classic example of Mannich reaction and is considered as one of the classic reactions in total synthesis. 190 1 year, Willst &；; AumlTter first synthesized this compound from cycloheptanone. After 14 step, the total yield was only 0.75%. In 19 17, Robert Robinson uses butyraldehyde, methylamine and 3- oxoglutaric acid as raw materials, and uses Mannich reaction under bionic conditions to obtain tropine in only one step. The initial yield of the reaction is 17%, which can be improved to 90%. Apply 1. Synthesis of nitrogen-containing heterocycles, such as tropine. 2. Introducing double bonds on the designated carbon: the generated Mannig base reacts with methyl iodide to obtain quaternary ammonium salt, and the quaternary ammonium salt is thermally eliminated to form unsaturated bonds. Stereoselective Mannich reaction will produce two prochiral carbon atoms, so the products are two enantiomers. Chiral induction can be used to make the reaction produce stereoselective products. In 2002, List et al. found that in Mannich reaction of cyclohexanone, formaldehyde and aniline with various substituents on benzene ring, the stereoselectivity of the product can reach 98% ee after adding proline as catalyst, as shown in the reaction diagram. Asymmetric Mannich reaction