Mechanistic Investigations of the Palladium-Catalyzed Aerobic Oxidative Kinetic Resolution of Secondary Alcohols Using (−)-Sparteine

Abstract

The mechanistic details of the Pd(II)/(−)-sparteine-catalyzed aerobic oxidative kinetic resolution of secondary alcohols were elucidated, and the origin of asymmetric induction was determined. Saturation kinetics were observed for rate dependence on [(−)-sparteine]. First-order rate dependencies were observed for both the Pd((−)-sparteine)Cl₂ concentration and the alcohol concentration at high and low [(−)-sparteine]. The oxidation rate was inhibited by addition of (−)-sparteine HCl. At low [(−)-sparteine], Pd-alkoxide formation is proposed to be rate limiting, while at high [(−)-sparteine], β-hydride elimination is proposed to be rate determining. These conclusions are consistent with the measured kinetic isotope effect of k_H/k_D = 1.31 ± 0.04 and a Hammett ρ value of −1.41 ± 0.15 at high [(−)-sparteine]. Calculated activation parameters agree with the change in the rate-limiting step by increasing [(−)-sparteine] with ΔH^⧧ = 11.55 ± 0.65 kcal/mol, ΔS^⧧ = −24.5 ± 2.0 eu at low [(−)-sparteine], and ΔH^⧧ = 20.25 ± 0.89 kcal/mol, ΔS^⧧ = −5.4 ± 2.7 eu at high [(−)-sparteine]. At high [(−)-sparteine], the selectivity is influenced by both a thermodynamic difference in the stability of the diastereomeric Pd-alkoxides formed and a kinetic β-hydride elimination to maximize asymmetric induction. At low [(−)-sparteine], the selectivity is influenced by kinetic deprotonation, resulting in lower k_rel values. A key, nonintuitive discovery is that (−)-sparteine plays a dual role in this oxidative kinetic resolution of secondary alcohols as a chiral ligand on palladium and as an exogenous chiral base.