DFT Investigation on Palladium-Catalyzed [2 + 2 + 1] Spiroannulation between Aryl Halides and Alkynes: Mechanism, Base Additive Role, and Solvent and Ligand Effects

Transition metal-catalyzed spiroannulations are practical
strategies
for constructing spirocyclic skeletons of pharmaceutical and biological
significance, yet the microscopic mechanism still lacks in-depth explorations.
Here, the palladium-catalyzed [2 + 2 + 1] spiroannulation between
aryl halides and alkynes was studied by employing the density functional
theory (DFT) method. Based on comprehensive explorations on a couple
of possible reaction pathways, it is found that the reaction probably
experiences C–I oxidative addition, alkyne migration insertion,
Cs2CO3-assisted aryl C–H activation,
C–Br bond oxidative addition, C–C coupling, arene dearomatization
and reductive elimination in sequence and leads to the formation of
the spiro[4,5]decane pentacyclic product (P) ultimately.
Among these, the C–Br bond oxidative addition step acts as
the rate-determining step (RDS) of the whole reaction, featuring a
practical free energy barrier of 32.4 kcal·mol–1 at 130 °C. Computationally predicted kinetics such as half-life
transferred from the RDS step’s barrier on the optimal reaction
pathway (1.2 × 101 h) coincides well with corresponding
experimental results (91% yield of the spiro[4,5]decane pentacyclic
product P after reacting 10 h at 130 °C). In addition,
theoretical predictions regarding the solvent/ligand effects and base
additive role in the reaction, rationalized by distortion–interaction/natural
population/noncovalent interaction analyses, are also in good agreement
with experimental data and trend. This good agreement between experiment
and theory makes sense for new designations and further experimental
improvements of such Pd-catalyzed transformations.