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

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.