A Novel Method for the Synthesis of Imidazo[1,2‐a]Pyridine Derivatives Fused With γ‐Lactone

The imidazopyridine scaffold is a privileged structure in medicinal chemistry, exhibiting diverse biological activities and serving as a key motif in numerous therapeutics. In this study, we developed a novel and efficient synthetic strategy for constructing imidazo[1,2‐a]pyridine derivatives fused with a benzene and γ‐lactone ring via a 5+1 cyclization reaction, employing DMF‐DMA as a one‐carbon synthon. The required precursors were obtained through aldol‐crotonic condensation followed by cyclization with o‐phenylenediamine derivatives. The optimized conditions afforded regioisomeric products, whose structures were confirmed by NMR spectroscopy and single‐crystal X‐ray diffraction. Computational studies revealed the presence of intramolecular hydrogen bonding that stabilizes the observed conformations. Attempts to extend this methodology to an indole‐based system were unsuccessful, likely due to competing intramolecular interactions. The proposed mechanism involves nucleophilic addition and dimethylamine elimination, leading to cyclization. This work introduces a practical and versatile route to access fused imidazopyridine–γ‐lactone systems with potential pharmaceutical relevance.