Buchler Glossary

Enantioselective Mannich Reaction

In general the Mannich reaction is an aminoalkylation reaction, involving the condensation of an enolizable carbonyl compound (α-CH acidic compound) with a nonenolizable aldehyde (like formaldehyde) and ammonia; or a primary or a secondary amine to furnish a β-aminocarbonyl compound, also known as Mannich base. The Mannich reaction starts with the nucleophilic addition of an amine to a carbonyl group. This is followed by dehydration to the Schiff base. In a second step the electrophilic Schiff base reactis with α-CH-acidic compound. In the field of synthetic organic chemistry, especially enantioselective Mannich reaction has wide applications in the construction of C-C bonds.

Enantioselective Mannich Reaction

The asymmetric Mannich reaction ranks among the most potent enantioselective and diastereoselective C–C-bond forming reactions and is one of the most useful reactions for the synthesis of chiral molecules containing nitrogen. The resulting β-amino carbonyl compounds are valuable synthons in the preparation of many chiral intermediates for the medicinal and agrochemical industry. Among catalytic asymmetric C-C bond forming reactions, like for instance Michael addition, the Mannich reaction has received the most attention in the past. Cinchona alkaloid catalysts are the preferred chiral catalytic systems used for carrying out asymmetric Mannich-type reaction.

These Cinchona alkaloids have been successfully applied as catalysts in direct Mannich reactions. In many cases remarkable high diastereoselectivities and/or enantioselectivities have been achieved. Especially thiourea based Cinchona alkaloids have been successfully screened operating as the best stereocontrolling module in terms of product yield and stereoselectivity.

The enantioselective Mannich reaction has been explored to many systems. Among them the nitro-Mannich also called aza-Henry are most important in the synthesis of active ingredients in the pharmaceutical and agriculture industry.

For further information please take a look into our free of charge Chiral Catalyst Data Base. Several examples for asymmetric Mannich reactions are summerized here.

Example from literature

The Mannich Reaction of Malonates with Simple Imines Catalyzed by Bifunctional Cinchona Alkaloids: Enantioselective Synthesis of β-Amino Acids. (Song et al.; J. Am. Chem. Soc. 2006, 128, 18, 6048–6049.)

Mannich reaction

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