Competing Reaction Mechanisms and Origin of Selectivity in Base-Controlled (4 + 1) versus (2 + 1)/(4 + 2) Annulations of o -Aminochalcones with γ-Bromocrotonates

Base-controlled reactions represent a cornerstone of modern organic synthesis. Despite significant advances, a comprehensive mechanistic understanding of the role of the base, particularly its influence on the reaction pathway selectivity, remains incomplete. In this study, we present a theoretical investigation of the competing mechanisms in Cs 2 CO 3 -catalyzed (4 + 1) versus (2 + 1)/(4 + 2) annulations involving γ-bromocrotonates and o -aminochalcones. Our calculations demonstrate that the (4 + 1) annulation is energetically favored over the (2 + 1)/(4 + 2) annulation. In the (4 + 1) annulation mechanism, the base catalyst Cs 2 CO 3 deprotonates the relatively acidic N–H group of o -aminochalcone, generating a resonance-stabilized amino anion, which undergoes nucleophilic attack on γ-bromocrotonate via an S N 2 mechanism to form a diene intermediate. This intermediate is subsequently deprotonated by Cs 2 CO 3 to yield a carbanion that participates in an intramolecular vinylogous Michael addition, followed by protonation, to afford the cis -2,3-disubstituted indolines. In the overall pathway, the base Cs 2 CO 3 acts as a non-nucleophilic strong base that deprotonates acidic substrates to generate reactive anionic intermediates for the subsequent Michael addition. To elucidate the origin of chemoselectivity, we employed the POCV method to evaluate the atomic reactivity vectors F ⃗ for the hydrogen atoms at the N–H group o f o -aminochalcone and at the γ-carbon of γ-bromocrotonate. This analysis was complemented by p K a calculations to provide a quantitative thermodynamic perspective. To further probe the origin of diastereoselectivity, we performed noncovalent interaction (NCI), atoms in molecules (AIM), and natural bond orbital (NBO) second-order perturbation analyses. Collectively, these results offer mechanistic insights into the fundamental principles governing base-mediated reactions of γ-bromocrotonates, revealing key electronic and steric factors that dictate both chemoselectivity and diastereoselectivity.