The Aza‐Cope/Mannich Reaction

Abstract

Because of their ability to rapidly build molecular complexity, reactions that construct several carbon-carbon bonds are of special value in organic synthesis. Among these transformations, cascade reactions form several bonds by an orchestrated sequence in which the first bond-forming step reveals functionality that allows subsequent bond forming transformations. In 1979 such a sequence for the synthesis of 3-acylpyrrolidines and azacyclic structures that contain this unit was reported. This reaction is now commonly called the aza-Cope/Mannich reaction, a [3,3]-sigmatropic rearrangement of an unsaturated iminium cation generates the iminium ion and enol that are participants in a subsequent intramolecular Mannich reaction. The aza-Cope/Mannich reaction has not been the subject of comprehensive review. This chapter covers the common version of the transformation discussed above along with the formation of 3-acylpyrrolidines by a related base-promoted cascade sequence. Keywords: Aza-Cope/Mannich reactions; 1- Aminobut-3-en-2-ols; Amine alkylation; Iminium ion; Vinyl substituents; Stereochemistry; Mechanisms; Condensation; Solvent; Acid; Ring enlarging; Rearrangements; Base-promoted reactions; Experimental procedures