Switchable Regioselectivity in Cs2CO3-Catalyzed (3 + 2) vs (3 + 4) Annulations of Aminoalkyl Esters with Azadienes: A DFT Study

Abstract Spiro and fused skeletons are particularly noteworthy for their intriguing biological properties and their prevalence in natural products and drug candidates. Although meaningful progress has been made in the synthesis of these compounds, a comprehensive mechanistic understanding remains essential. In this study, we present a theoretical investigation of the competing mechanisms in Cs2CO3-catalyzed (3 + 2) versus (3 + 4) annulations involving aminoalkyl α,β-unsaturated esters and azadienes. Our calculations reveal that for benzofuran-derived azadienes, the (3 + 2) annulation is energetically favored over the (3 + 4) pathway, leading to spirocycles. In contrast, benzothiophene-derived azadienes preferentially follow the (3 + 4) route to afford fused diazepines. The overall mechanism begins with Cs2CO3 deprotonating the relatively acidic N–H group of the aminoalkyl α,β-unsaturated ester to generate a nitrogen anion. This anion then nucleophilically attacks the azadiene, forming carbanion and nitrogen anion intermediates, which subsequently diverge into two pathways. In Pathway A, the carbanion intermediate undergoes α-regioselective (3 + 2) annulation, followed by protonation with CsHCO3 to yield spirobenzofurans. In Pathway B, the nitrogen anion intermediate undergoes γ-regioselective (3 + 4) annulation, and subsequent protonation by CsHCO3 gives the seven-membered ring benzothiophene-diazepine product. To elucidate the origin of the heteroatom-controlled regioselectivity, we employed three complementary approaches: Parr functions (Pk–) and local nucleophilicity indices (Nk) to assess the nucleophilicity of the competing reactive sites, and distortion/interaction analysis to dissect the energetic contributions. The results reveal that replacement of O by S modulates the nucleophilicity of the N1 and C2 sites in opposite directions. Moreover, the distortion/interaction analysis demonstrates that the O → S substitution selectively increases the distortion energy for the (3 + 2) pathway but decreases it for the (3 + 4) pathway, providing a quantitative physical origin for the switchable regioselectivity. Collectively, these findings establish a complete mechanistic picture of the heteroatom-controlled regiodivergence.