A DFT Study on the NHC-Catalyzed Reaction of Enals with Aminoacrylates: Mechanism, Regioselectivity, and Stereoselectivity

DFT (M06-2X) calculations were used to study the NHC-catalyzed [3 + 3] cycloaddition of enals with aminoacrylates. The catalytic cycle begins with the binding of the NHC to enal. Subsequent intramolecular proton transfer generates the Breslow intermediate. This intermediate undergoes an oxidative reaction, leading to the formation of an acyl azolium intermediate, which further reacts with the other substrate aminoacrylate via a new C-C bond formation. This step determines the stereoselectivity of the current reaction, and re-face addition mode leading to the formation of the intermediate with an S-configuration is predominant. Afterward, sequential protonation, deprotonation, and cyclization form the six-membered cyclic intermediate, which upon elimination of the NHC affords the final cycloaddition product dihydropyridinone. The computed enantiomeric excess (99.1% ee) is in very good agreement with the experimentally reported value (99% ee). The origin of enantioselectivity is traced to the stronger LP<middle dot><middle dot><middle dot>pi interactions between the acyl azolium intermediate and aminoacrylate in the favored S-congurational transition state.