A quantum mechanical study of the mechanism and stereoselectivity of the N-heterocyclic carbene catalyzed [4 + 2] annulation reaction of enals with azodicarboxylates

A systematic theoretical study has been carried out to understand the mechanism and stereoselectivity of [4 + 2] annulation reaction between γ-oxidized enals and azodicarboxylates catalyzed by the N-heterocyclic carbene (NHC). The calculated results reveal that the catalytic cycle can be characterized by three stages (Stages 1, 2, and 3). Stage 1 is the nucleophilic addition of the NHC catalyst to enals upon the intramolecular proton transfer to generate the Breslow intermediate. In this stage, apart from the direct proton transfer mechanism, the H2O (H2O and 2H2O cluster) and bicarbonate anion (HCO3−) mediated proton transfer mechanisms are also investigated; the free energy barrier for the crucial proton transfer steps in Stage 1 is found to be significantly lower by explicit inclusion of the bicarbonate anion (HCO3−). For Stage 2, the removal of the leaving group occurs, followed by C–C bond rotation for the formation of cis-dienolate. Stage 3 is the endo/exo [4 + 2] cycloaddition and dissociation of the catalyst from the final products. The formal [4 + 2] cycloaddition step is calculated to be the enantioselectivity determining step, and the R-configured PR is the predominant product according to the computations, which is in good agreement with the experimental observations. Moreover, the stereoselectivity associated with the chiral carbon center is attributed to the CH–π interaction between Cα−H and the mesityl group of NHC and the variation in the distortion of the dienolate. The mechanistic insights obtained in the present study should be valuable for the other NHC-catalyzed reactions.