Mannich Reaction

In 1903, German chemist Bernhard Tollens observed that the reaction between acetophenone and formaldehyde in the presence of ammonium chloride led to the formation of a tertiary amine. In 1917, German chemist Carl Mannich also prepared a tertiary amine from antipyrine using the same conditions, and recognized that this reaction was general. Since then, the condensation of a CH-activated compound such as an aldehyde or ketone with a primary or secondary amine or ammonia and a non-enolizable aldehyde or ketone to prepare aminoalkylated derivatives has come to be known as the Mannich reaction.

The product of this reaction is a substituted beta-amino carbonyl compound which is often known as a Mannich base. Mannich bases are useful intermediates for synthesis since they can undergo a variety of transformations. These can include beta-elimination to afford alpha- or beta-unsaturated carbonyl compounds (Michael acceptors), reaction with organolithium or Grignard reagents to produce beta-amino alcohols, or even substitution of the dialkylamino group with nucleophiles to create functionalized carbonyl compounds. One of the best-known applications of the Mannich reaction is its use in conjunction with an aza-Cope rearrangement to generate heterocycles.