C₃-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel–Crafts Reaction Catalyzed by Y(OTf)₃

Abstract

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Keywords

• imidazo[1,2-a]pyridines
• aza-Friedel–Crafts reaction
• Lewis acid catalyst
• alkylation
• three-component reaction