A Role for Pd(IV) in Catalytic Enantioselective C–H Functionalization with Monoprotected Amino Acid Ligands under Mild Conditions

Journal of the American Chemical Society

5 years ago

A Role for Pd(IV) in Catalytic Enantioselective C–H Functionalization with Monoprotected Amino Acid Ligands under Mild Conditions

Ling Chu, R. Erik Plata, Donna G. Blackmond, Jin-Quan Yu, Brandon E. Haines, David P. Hickey, Matthew S. Sigman, Djamaladdin G. Musaev, David E. Hill

Kinetic and mechanistic studies of the desymmetrization of benzhydrylamine using Pd/monoprotected amino acid ligands (Pd/MPAA) via C–H functionalization with molecular iodine provide mechanistic insight into the rate-determining step and the oxidation state of Pd in the C–H functionalization step. Enantiomeric excess is strikingly insensitive to temperature from ambient temperature up to over 70 °C, and reaction rate is insensitive to the electronic characteristics of the ligand’s benzoyl protecting group. The reaction is highly robust with no evidence of catalyst deactivation. Intriguingly, C–H bond breaking does not occur prior to the addition of I₂ to the reaction mixture. Electrochemical experiments demonstrate the viability of oxidative addition of I₂ to Pd(II). Together with ¹⁹F NMR studies, these observations suggest that iodine oxidizes Pd prior to addition of the amine substrate. This work may lead to a better general understanding of the subtle variations in the reaction mechanisms for C–H functionalization reactions that may be extant for this ligand class depending on substrate, amino acid ligand and protecting group, and reaction conditions.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b03716

DOI: 10.1021/jacs.7b03716