Phosphine-Catalyzed Dehydrative Annulation of 2-Picolylamines with Carboxylic Acids to Access Imidazo[1,5- a ]pyridines by Sequential C–N Bond Formation

Abstract

Imidazo[1,5-a]pyridines constitute a privileged class of N-fused heterocycles widely found in bioactive molecules and functional materials, yet their synthesis often relies on harsh, stoichiometric activating reagents. Herein, we report a phosphine-catalyzed condensation-annulation strategy for the synthesis of imidazo[1,5-a]pyridines from readily available 2-picolylamines and carboxylic acids under mild and neutral conditions. The method exhibits broad functional group tolerance and achieves chemoselective dehydrative coupling, proceeding efficiently in the presence of sensitive functionalities such as esters, ketones, and tertiary amides. Notably, this protocol is amenable to the late-stage functionalization of pharmaceutically relevant molecules. Mechanistic studies support a cascade PIII/PV═O catalytic manifold enabling amide formation and intramolecular cyclization. Preliminary cytotoxicity assays were also conducted to provide an initial assessment of the synthesized scaffolds under the tested conditions.