Computational insights into the synergistic interplay of ligand and fluorine effects in palladium-catalyzed regiodivergent decarboxylative allylic alkylation

Abstract

Palladium-catalyzed regiodivergent decarboxylative allylic alkylation of allyl difluoro-β-ketoesters provides a versatile approach for accessing a variety of α,α-difluoroketones. In this report, density functional theory calculations have been performed to investigate the detailed reaction mechanisms and elucidate the origins of regioselectivity. These computations reveal that the reaction is initiated by C–O bond cleavage via the S_N2 back-side attack pathway to give η³-allyl Pd(II) ion pair species. Subsequent CO₂ extrusion is identified as the rate-determining step of the overall reaction. Regioselectivity is dictated by the final C–C bond formation, involving both an outer-sphere nucleophilic attack and inner-sphere sigmatropic rearrangement. A notable influence on both CO₂ extrusion and C–C bond formation is observed with the ligand. The electron-rich and bulky ligand ^tBuBrettPhos undergoes CO₂ extrusion directly through the outer-sphere pathway, leading to subsequent C–C bond formation via an outer-sphere nucleophilic attack, resulting in linear regioselectivity. This preference is primarily attributed to non-covalent interactions, specifically C–H⋯O hydrogen bonding and C–H⋯π interactions. Conversely, with the more electron-deficient and small ligand PhXPhos, CO₂ extrusion is determined to proceed through the inner-sphere pathway, aided by favorable Pd⋯O coordination. Subsequent C–C bond formation involves inner-sphere sigmatropic rearrangement and outer-sphere nucleophilic attack, yielding branched and linear products, respectively. The excellent branched regioselectivity results from the synergistic effects of both the ligand and fluorine substituents. The fluorine substituents, owing to p⋯π conjugation and their electron-withdrawing properties, are observed to reduce the HOMO–LUMO gap. Coupled with lone pair⋯π interactions, inner-sphere sigmatropic rearrangement via a seven-membered pericyclic transition state is facilitated.