Mechanistic studies on stereoselective domino [4 + 2]/retro[3 + 2]/[3 + 2] cycloaddition reactions of oxadiazoles with strained and unstrained cycloalkenes

This work reports a systematic mechanistic study on the domino cycloaddition reaction of symmetric and asymmetric 1,3,4 oxadiazoles OD and substituted variants with strained and unstrained cycloalkenes. The investigations were carried out using hybrid density functionals M06-2X, B3LYP and MPWB1K in conjunction with split valence triple zeta basis set 6-311++G(d,p). The domino cycloaddition reaction stereoselectively leads to the formation of either the cis or trans polycyclic domino adduct with fascinating synthetic features owing to the ubiquity of these structures in a broad range of natural products and pharmaceuticals. The cycloaddition reactions proceed through a rate-determining [4 + 2] cycloaddition between the OD and cycloalkene to form an isolable adduct (although not necessary to isolate the intermediates in domino cycloadditions). The Diels–Alder adduct easily undergo extrusion of nitrogen gas, N2 (retro [3 + 2]) to form a highly unstable carbonyl ylide. The pseudodiradical TAC (carbonyl ylide) undergoes a rapid [3 + 2] cycloaddition reaction with a cycloalkene to furnish the domino polycyclic adduct. The results reported herein are in excellent agreement with previous experimental works and provide further insights for future experiments. The domino cycloaddition reaction is stereoselective toward the cis isomer when highly strained unsaturated bicyclic alkene (norbornene) reacts with the asymmetric OD and stereoselective toward trans-isomer when unstrained cycloalkenes with less (angle) strain react with the asymmetric OD. Cyclooctene is found to participate in the domino process with its cis conformer which was hitherto unknown. Global electron density transfer (GEDT) analysis reveals the polar nature of the domino scheme of reactions. Overall, the feasibility of these domino cycloaddition reactions depends on the polar nature of the first [4 + 2] cycloaddition reactions, which depends on the electrophilic and nucleophilic character of the participating reagents.