Mechanism, regioselectivity and stereoselectivity of NHC-catalyzed [12+2] annulation of 5H-benzo[a]-pyrrolizine-3-carbaldehydes and cyclic sulfonic imines: a DFT study

The mechanism, regioselectivity and enantioselectivity of the [12+2] cyclization reaction between 5H-benzo[a]-pyrrolizine-3-carbaldehydes and cyclic sulfonic imines catalyzed by triazolium-derived N-heterocyclic carbene (NHC) have been elucidated by density functional theory calculations. The optimal reaction pathway occurs in seven steps: nucleophilic addition, proton transfer assisted by HOAc, oxidation, deprotonation, Michael addition leading to the formation of a new C–C bond, ring closure leading to the formation of a new C–N bond, and catalyst regeneration yielding the target product. The DFT results indicate that the fifth step is the stereo-controlling step, and SR-piperazin-2-one is the dominant product. The calculated enantiomeric excess (93.4% ee) agrees well with the experimental findings (95% ee). Analysis of the distortion-interaction shows that the stronger interaction energy and smaller distortion energy are the main factors determining the reaction's stereoselectivity. Analysis of the global reactivity index suggests that the role of NHC is to enhance the nucleophilicity of the substrate 5H-benzo[a]pyrrolizine-3-carboxaldehydes, thereby facilitating further reactions.