A computational study on NHC-Catalyzed [3+4] annulation between isatin-derived enal and aurone-derived azadiene: Insights into mechanism and stereoselectivity

Abstract

Using density functional theory (DFT), a systematic computation has been conducted on the reaction between an enal and an azadiene in the presence of N-heterocyclic carbene (NHC) to explore the catalytic mechanisms and origins of stereoselectivity. Several possible pathways leading to benzofuroazepinone have been investigated. We found that the preferred pathway proceeds via six steps, i.e. (1) the nucleohilic addition wherein the NHC adds to the enal, (2) 1,2- proton transfer allows to form the Breslow intermediate, (3) the carbon−carbon bond formation, (4) 1,3- proton transfer, (5) intramolecular cyclization and (6) catalyst regeneration that eventually leads to the RR-configurational cycloadduct benzofuroazepinone. The DFT results agree well with the experimentally observed stereoselectivity. We also found that HOAc plays a vital role as proton shuttle in proton transfer steps. The 1,3-proton transfer was the stereoselectivity-determining step. Furthermore, we conducted global reactivity index (GRI), distortion/interaction and noncovalent interaction (NCI) analyses to identify the role of the NHC in the reaction as well as the origin of the experimentally observed stereochemistry.