Insights into N-heterocyclic carbene and Lewis acid cooperatively catalyzed oxidative [3 + 3] annulation reactions of α,β-unsaturated aldehyde with 1,3-dicarbonyl compounds

Abstract

Unravelling the origin of stereoselectivity and chemoselectivity is one of the most challenging questions in the field of N-heterocyclic carbene (NHC) catalysis. Recently, Lewis acid (LA) additives were found to be key additives for improving the stereoselectivity in many NHC-catalyzed annulation reactions (especially [3 + 3] annulation) of dicarbonyl compounds; however, the reason for this general phenomenon remains unclear so far. In order to solve this issue, a universal model has been suggested for NHC and Lewis acid cooperatively catalyzed oxidative [3 + 3] annulation reactions between α,β-unsaturated aldehyde and 1,3-dicarbonyl compounds to explore the origin of the improved stereoselectivity. The computed results indicate that the Lewis acid can increase the free energy difference (ΔΔG^‡) between the transition states involved in the stereoselectivity-determining step to improve stereoselectivity, which is mainly due to the stronger non-covalent interactions between the LA-coordinated substrate and the chiral NHC catalyst in the favorable R-isomer transition state. Furthermore, two new reactivity indices, i.e. electrophilic and nucleophilic atom energies (denoted E_a⁺ and E_a⁻), were proposed to measure the electrophilicity and nucleophilicity of possible reactive sites, which could be used to predict the chemoselective products in the [3 + 3] and [3 + 2] annulations. The obtained insights will be helpful for the rational design of organocatalytic reactions with excellent stereoselectivity and special chemoselectivity.