Acetic Acid-Catalyzed Regioselective C(sp2)–H Bond Functionalization of Indolizines: Concomitant Involvement of Synthetic and Theoretical Studies

An atom economical and environmentally benign protocol has been developed for the regioselective C­(sp2)–H bond functionalization of indolizines. The acetic acid-catalyzed cross-coupling reaction proceeds under metal-free conditions, producing a wide range of synthetically useful indolizine derivatives. The present protocol showed good functional group tolerance and broad substrate scope in good to excellent yields. Quantum mechanical investigation using density functional theory (DFT) has played a crucial role in understanding that acetic acid is the key player in determining the actual pathway as the catalyst and its ultrafast nature. Different pathways involving inter- and intramolecular proton transfer, with or without acetic acid, were investigated. Calculated results revealed that a proton shuttle mechanism is involved for the least energetic, most favorable acetic acid-catalyzed pathway. Furthermore, regioselectivity has also been explained theoretically.