DFT Investigation\non Palladium-Catalyzed [2 + 2 +\n1] Spiroannulation between Aryl Halides and Alkynes: Mechanism, Base\nAdditive Role, and Solvent and Ligand Effects

Transition metal-catalyzed spiroannulations are practical\nstrategies\nfor constructing spirocyclic skeletons of pharmaceutical and biological\nsignificance, yet the microscopic mechanism still lacks in-depth explorations.\nHere, the palladium-catalyzed [2 + 2 + 1] spiroannulation between\naryl halides and alkynes was studied by employing the density functional\ntheory (DFT) method. Based on comprehensive explorations on a couple\nof possible reaction pathways, it is found that the reaction probably\nexperiences C–I oxidative addition, alkyne migration insertion,\nCs<sub>2</sub>CO<sub>3</sub>-assisted aryl C–H activation,\nC–Br bond oxidative addition, C–C coupling, arene dearomatization\nand reductive elimination in sequence and leads to the formation of\nthe spiro[4,5]decane pentacyclic product (<b>P</b>) ultimately.\nAmong these, the C–Br bond oxidative addition step acts as\nthe rate-determining step (RDS) of the whole reaction, featuring a\npractical free energy barrier of 32.4 kcal·mol<sup>–1</sup> at 130 °C. Computationally predicted kinetics such as half-life\ntransferred from the RDS step’s barrier on the optimal reaction\npathway (1.2 × 10<sup>1</sup> h) coincides well with corresponding\nexperimental results (91% yield of the spiro[4,5]decane pentacyclic\nproduct <b>P</b> after reacting 10 h at 130 °C). In addition,\ntheoretical predictions regarding the solvent/ligand effects and base\nadditive role in the reaction, rationalized by distortion–interaction/natural\npopulation/noncovalent interaction analyses, are also in good agreement\nwith experimental data and trend. This good agreement between experiment\nand theory makes sense for new designations and further experimental\nimprovements of such Pd-catalyzed transformations.