Mechanistic studies on the N-heterocyclic carbene-catalyzed reaction of isatin-derived enals with hydrazones

The possible reaction mechanism and origin of stereoselectivity of the NHC-catalyzed annulation reaction between isatin-derived enals and hydrazones were theoretically studied by using density functional theory (DFT). According to the computational results, the Michael addition process was identified to be the stereoselectivity determining step and led to the experimentally observed S-configured product predominantly. The distortion-interaction analysis showed that the electrostatic interaction between two interactive fragments controls the stereoselectivity. Moreover, the types of interactions were further verified by non-covalent interaction analysis, in which the pi MIDLINE HORIZONTAL ELLIPSIS pi, C-HMIDLINE HORIZONTAL ELLIPSISF and LPMIDLINE HORIZONTAL ELLIPSIS pi interactions involved in the favorable transition state are the key for determining the stereoselectivity.