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 Cs2CO3-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 Cs2CO3 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 SN2 mechanism to form a diene intermediate. This intermediate is subsequently deprotonated by Cs2CO3 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 Cs2CO3 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 F⃗ for the hydrogen atoms at the N-H group of o-aminochalcone and at the γ-carbon of γ-bromocrotonate. This analysis was complemented by pKa 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.