Science of Synthesis

Bernardi, L.; Ricci, A., Science of Synthesis: Multicomponent Reactions, (2014) 1, 125.

When performing a Mannich reaction in its initial three-component design, selectivity is sometimes difficult to obtain due to competition with side processes, primarily the auto-aldol condensation. A common solution to this problem is to preform the enolates followed by the sequential indirect performance of the reaction. Activation of the in situ generated imine component by a Lewis or Brønsted acid catalyst is often mandatory for promoting the attack of the nucleophilic enolate species (mostly silyl enolates). The same acidic catalyst can also assist imine formation, and its employment in chiral enantiopure form gives an entry to catalytic asymmetric versions of the indirect Mannich reaction. As these catalysts are tolerant to the water generated during imine formation, some of these reactions can even be performed in water, especially when Brønsted acid catalysts are used. The employment of silyl dienolates instead of enolates shifts the nucleophilic reactivity of the carbonyl compounds from the usual α- to the γ-position, giving the vinylogous version of the Mannich reaction furnishing δ-amino α,β-unsaturated carbonyl compounds.