Regio- and Stereoselective Synthesis of Anticancer Imidazo[1,2-a]pyridine-chromones Assisted by Hydrogen Bonding.

Abstract

Numerous 1,2- or 1,4-addition reactions of imidazo[1,2-a]pyridines across unsaturated C═N or C═C bonds have been extensively studied. Regioselective 1,4-conjugate addition with the aid of hydrogen bonding remains unexplored. Herein, a regioselective and stereoselective approach for the synthesis of imidazo[1,2-a]pyridine-chromones has been achieved for the first time. Control experiments reveal that intramolecular hydrogen bonding plays an important role in achieving high selectivity. This protocol features operational simplicity, readily available feedstocks, and excellent regioselectivities and stereoselectivities. Significantly, evaluation of the newly synthesized compounds identified 4ag and 4ah as promising anticancer agents, exhibiting potent activity against A549 (IC50 = 1.95 and 3.10 μM, respectively) and HCT116 (IC50 = 4.11 and 3.32 μM, respectively) cell lines. This work not only provides a novel perspective on hydrogen-bonding-controlled chemical transformations but also offers an efficient, sustainable synthetic strategy for accessing new imidazo[1,2-a]pyridine-based candidates for biological evaluation.