DFT perspective toward [3 + 2] annulation reaction of enals with α-ketoamides through NHC and Brønsted acid cooperative catalysis: mechanism, stereoselectivity, and role of NHC

A systematic theoretical study has been carried out to understand the possible mechanisms and stereoselectivity of the N-heterocyclic carbene (NHC)-catalyzed [3 + 2] annulation reaction of enals with α-ketoamides using density functional theory (DFT) calculations. The calculated results reveal that the favorable pathway comprises of seven steps, i.e., addition of the catalyst, formation of the Breslow intermediate, formation of the enolate intermediate, the C–C bond formation step, the proton transfer process, the ring-closure process and the regeneration of the catalyst. For the proton transfer process, apart from the direct proton transfer mechanism, the base TMEDA and the in situ generated Brønsted acid TMEDA·H+ mediated proton transfer mechanisms are also investigated; the free energy for the crucial proton transfer steps is found to be significantly lowered by explicit inclusion of the Brønsted acid TMEDA·H+. The computational results show that the C–C bond formation step is the stereoselectivity-determining step, in which two chirality centers assigned to the coupling carbon atoms are formed, and the RR-configured diastereomer is the predominant product, which is in good agreement with the experimental observations. Global reaction index (GRI) analysis has been performed to confirm that NHC mainly plays a role of a Lewis base catalyst. In addition, the distortion/interaction, NCI, and NBO analyses show that the strong interaction and electron delocalization of the reaction active site determine the stereoselectivity, with the RR-configured product being generated preferentially. The mechanistic insights obtained in the present study should be valuable for the rational design of an effective organocatalyst for this kind of reaction with high stereoselectivity.