Theoretical Study on Ir-Catalyzed α-Amidation of 2-Acylimidazoles: Mechanism and Insertion Selectivity

The mechanism and reactivity of Ir-catalyzed α-amidation of 2-acylimidazoles have been investigated at the B3LYP-D3 level, with the emphasis on nitrene insertion selectivity. The calculation results show that the catalytic mechanism consists of iridacycle formation, CO2 release, nitrene insertion, and amido protonation processes. Thereinto, nitrene insertion is both rate- and selectivity-determining steps. The origin of the nitrene group favorably inserting into an Ir–Cα over Cγ–H bond was further unraveled. In addition, this work also explored the α-amidation reactivity difference between α-mono- and α,α-di-substituted 2-acylimidazoles and the source of this difference was identified. These meaningful insights may serve as the basis for the further design and development of transition-metal-catalyzed α-amidation systems featuring high reactivity and selectivity.