Mechanistic Investigation on NHC‐Catalyzed Switchable Annulation Reactions: Polarity Controlled Chemoselective Pathways

ABSTRACT Despite significant progress in switchable synthesis via catalytic regiodivergent procedures, the underlying mechanisms governing stereoselectivity and chemoselectivity remain elusive. In this study, we present a theoretical investigation into the origins of these selectivities for NHC‐catalyzed annulation reactions between enals and ketimines. Our calculations identify the Michael addition between the Breslow intermediate and ketimine as the stereoselectivity‐determining step, whereas the subsequent proton transfer determines the chemoselectivity. Notably, both pathways share a common initial formation of an enol intermediate before diverging. In DCE solvent, the spirocyclopentane oxindole product arises through a sequential mechanism comprising [1,3]‐proton transfer, aza‐Dieckmann cyclization, and tautomerization. Conversely, in MeCN solvent, the reaction proceeds via [1,6]‐proton transfer, Mannich reaction, and lactamization to yield the β‐lactam fused spirocyclopentane oxindole. NCI and AIM analyses identify C─H⋯π, π⋯π, LP⋯π, and hydrogen bond interactions as critical factors stabilizing the SR ‐configured isomer. Furthermore, our solvent–solute interaction model indicates that the polarity differences of key transition states in distinct solvents are the predominant drivers of chemoselectivity switching. This work deepens the understanding of switchable reactions in NHC catalysis, offering valuable insights for designing solvent‐controlled synthetic strategies.