Deciphering the Mechanism Behind the Fe/I2 Catalyzed Ortoleva–King Type Reaction: A DFT Study

ABSTRACT Imidazo[1,2‐]pyridine derivatives have garnered significant attention due to their diverse pharmacological applications, driving the development of several synthetic methodologies. Among the various strategies employed, transition metal–catalyzed condensation reactions, particularly those of the Ortoleva–King type, have emerged as a prominent approach for the synthesis of imidazo[1,2‐]pyridines. Despite the ongoing experimental studies, a detailed molecular mechanistic investigation of these transformations remain insufficiently elucidated. In this study, we present a comprehensive computational investigation of an Fe/I assisted Ortoleva–King type reaction, employing aminopyridine and acetophenone as substrates. Using density functional theory (DFT) calculations at the unrestricted M06‐L/def2‐SVP level of theory, we delineate a five‐step mechanistic pathway: activation of the methyl group of acetophenone by aminopyridine in the presence of molecular iodine, nucleophilic addition of 2‐aminopyridine, redox reaction, water‐mediated cyclization to construct the imidazo core, and final dehydration to furnish the imidazo[1,2‐]pyridine scaffold. Particular emphasis is placed on elucidating the role of the iron cocatalyst, the surprising participation of water in promoting cyclization in a slightly polar medium such as chlorobenzene. We find that the presence of electron‐withdrawing groups on substrates has a substantial role in increasing the plausibility of the reaction.