Insights into the N-Heterocyclic Carbene (NHC)-Catalyzed Oxidative γ-C(sp3)-H Deprotonation of Alkylenals and Cascade [4 + 2] Cycloaddition with Alkenylisoxazoles.

The N-heterocyclic carbene (NHC)-catalyzed oxidative C-H deprotonations have attracted increasing attention; however, the general mechanism regarding this kind of oxidative organocatalysis remains unclear. In this paper, the competing mechanisms and origin of the stereoselectivity of the NHC-catalyzed oxidative γ-C(sp3)-H deprotonation of alkylenals and cascade [4 + 2] cycloaddition with alkenylisoxazoles were systematically investigated for the first time using density functional theory (DFT). The computed results indicate that the oxidation of the Breslow intermediate by 3,3',5,5'-tetra- tert-butyl diphenoquinone (DQ) via a hydride transfer to oxygen (HTO) pathway is the most favorable among the four competing pathways. In addition, the analyses demonstrate that oxidant DQ plays a double role, i.e., strengthening the acidity of the hydrogen of the γ-carbon of alkylenal and forming π···π interactions with conjugated C═C bonds to promote the γ-C(sp3)-H deprotonation. The NHC catalyst acts as a Lewis base, and the hydrogen-bond network between the NHC and the substrate formed in the key Michael addition step is responsible for the origin of the stereoselectivity. Further DFT calculations reveal that the nonpolar solvent can stabilize the nonpolar R isomer but destabilize the polar S isomer for the stereoselectivity-determining transition states, thus improving the stereoselectivity.