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.