DFT studies on the diastereoselectivity and regioselectivity of multicomponent domino Knoevenagel/Diels–Alder reaction

In this study, mechanism and stereochemistry of multicomponent domino Knoevenagel/Diels–Alder reaction were investigated theoretically. Structures of reagents, transition states, intermediates, and products were optimized at M062X/6-31[Formula: see text]G(d,p) level of theory. Although the mechanism of this reaction involved several processes, including bond rotation, isomerization, asymmetric cycloaddition, acid-base, and nucleophile–electrophile competitions, critical processes were studied to provide a clearer picture of the mechanism of this valuable reaction in terms of stereochemistry considerations. According to the results, the ring closure step of reaction performed via a polar Dield-Alder mechanism, having enthalpy at approximately 40[Formula: see text]kcal/mol. The diastereoselectivity of the reaction was controlled by the interaction of dienophile with the less hindered face of diene through a more stable endo transition state ([Formula: see text] and 27.31 in methanol and gas phase, respectively). HSAB criteria could explain the regioselectivity of this reaction by considering the least softness difference ([Formula: see text]) for interacting C-atoms based on Hirshfeld populations. The result was the creation of cis-spiro cyclohexanone under kinetic and thermodynamic controls as a predominant diastereoselective and regioselective product.