Tandem [4+1+1] Annulation Approach to 4-Acyl-3,4-dihydropyrrolo[1,2- a]pyrazines: Diastereoselective Construction of Dihydropyrazine Units from Pyrroles

Efficient construction of new chemical space by way of strategic use of tandem reactions is highly important in drug discovery. Described herein is an atom-economical [4+1+1] annulation approach to 3-(hetero)aryl-4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazines, a new chemical space, via a one-pot three-component reaction under mild reaction conditions. Formation of multiple bonds (one C-C and two C-N) was achieved by a cascade reaction sequence consisting of generation of a Schiff base, a diastereoselective Mannich reaction, and intramolecular imine formation. This modular and environment-friendly process allowed rapid access to a wide range of 4-acylated 3,4-dihydropyrrolo[1,2-a]pyrazines and their analogues, opening opportunity to explore biological activity associated with this scaffold.