A DFT study of NHC-catalyzed reactions between 2-bromo-2-enals and acylhydrazones: mechanisms, and chemo- and stereoselectivities

The mechanistic features, and chemo- and stereoselectivities of the [4 + 2] cycloaddition between 2-bromo-2-enal and acylhydrazone catalyzed by a chiral N-heterocyclic carbene (NHC) catalyst were derived from density functional theory calculations. In the energetically most favored pathway, the activation of 2-bromo-2-enal by the NHC catalyst occurs first, followed by a proton transfer promoted by HCO₃⁻, and the resulting Breslow intermediate then undergoes successive debromination and HCO₃⁻-mediated proton transfer leading to an acylazolium ion, which in turn undergoes γ-deprotonation to yield the vinyl enolate intermediate. The next crucial step is the [4 + 2] cycloaddition and affords the six-membered zwitterionic intermediate, which upon expulsion of NHC provides access to (R)-δ-lactam. The computational results are in good agreement with the experimental observations. Distortion/interaction and non-covalent interaction (NCI) analyses were conducted to disclose the origins of the stereoselectivity. Furthermore, global reactivity indexes (GRIs) analysis was also performed to investigate the role of NHC.