A DFT study on NHC‐catalyzed [4 + 2] annulation of 2H‐azirines with ketones: Mechanism and selectivity

Abstract

AbstractTo examine the mechanisms and stereoselectivities in the [4 + 2] annulation between an 2H‐Azirine and a ketone catalyzed by a N‐heterocyclic carbine (NHC), M06‐2X density functional theory (DFT) calculations were performed. The reaction was found to proceed via five steps: (Step 1) the NHC adds nucleophilically to the 2H‐azirine; (Step 2) 1,2‐proton transfer affording the Breslow intermediate; (Step 3) three‐membered ring opening accompanied by another proton transfer; (Step 4) addition to the ketone and (Step 5) regeneration of the active catalyst to give the [4 + 2] cycloadduct. For Step 2, we investigated both direct and mediators (H2O and HCO3−) assisted proton transfer, and we found that the HCO3− assisted mechanism is preferred. In addition, we found that Step 3 (ring opening) determines the regioselectivity of this reaction and favors the cleavage of the CN bond. Step 4, that is, the CN bond formation step is found to be responsible for the stereoselectivity of the reaction, and the R‐ and S‐configurational products should compete with each other. DFT results agree well with the experimental findings. Moreover, we performed GRI, and NBO analyses to investigate the role the NHC. The mechanistic insights gained herein should be useful for rational designing new NHC‐catalyzed ring opening reactions in the future.