Alkyne-Dependent Chemoselective [2 + 2 + 1] Spiroannulation of 4-Bromocoumarin: Mechanistic Basis for the Divergent Formation of Indane-Fused Spiropentadiene Chromanones versus Spiropentadiene Chromanone

Abstract

To unravel the chemoselectivity of the palladium-catalyzed [2 + 2 + 1] spiroannulation of 4-bromocoumarin with alkynes, this work presents a comprehensive density functional theory (DFT) investigation on its reaction mechanism, substituent effects, and ligand effects. The reaction can proceed via C–Br oxidative addition, sequential alkyne insertions, carbopalladation, C–H activation, and reductive elimination (Path_I), and leading finally to the Indane-fused spiropentadiene chromanones (P1a/b/c). It can also occur along Path_II, which comprises C–Br oxidative addition, sequential alkyne insertions, carbopalladation, and protonation, and ultimately affording the spiropentadiene chromanone (P2d). The first alkyne insertion is rate-determining on both pathways, with computed free-energy barriers of 28.4–28.9 kcal·mol–1 and 29.7 kcal·mol–1, respectively. Theoretically predicted half-lives (8–16 and 49 h) match well with experiments, where the spirocyclic P1a/b/c were obtained in 78–82% yield or P2d in 63% yield after reacting 8 h at 85 °C. Analyses based on electrostatic potential (ESP) maps, natural population analysis (NPA) and distortion–interaction models indicate that the chemoselectivity toward P1 versus P2 is predominantly governed by the electronic effects of the alkyne substituents, while the overall reactivity depends on both electronic and steric distortion factors. These elucidations provide valuable mechanistic insights for future design, optimization, and selectivity-controlling of analogous palladium-catalyzed transformations.