Formation of β-Aminoalkyl Carbonyl Compounds: The Mannich Reaction

A three-component condensation reaction involving an enolizable carbonyl compound, a non-enolizable aldehyde, and a primary or secondary amine is known as the Mannich reaction. The reaction occurs under mildly acidic conditions, producing a β-amino carbonyl compound called a Mannich base.

The reaction begins when the acid catalyst protonates the non-enolizable aldehyde, which reacts with the amine to generate a hemiaminal. The subsequent loss of water produces an electrophilic iminium cation. The acid also protonates the oxygen of the enolizable carbonyl compound, which loses the acidic α hydrogen and transforms into its nucleophilic enol form. The iminium cation and the enol react in an aldol-type reaction to give the Mannich base.

Mannich bases are effective synthetic intermediates in the generation of α,β-unsaturated carbonyl compounds via β-elimination. The reaction of Mannich bases with organolithium or Grignard reagents is also used to synthesize β-amino alcohols.