Mechanistic Basis for Efficient, Site-Selective, Aerobic Catalytic Turnover in Pd-Catalyzed C–H Imidoylation of Heterocycle-Containing Molecules

A recently
reported Pd-catalyzed method for oxidative imidoylation
of C–H bonds exhibits unique features that have important implications
for Pd-catalyzed aerobic oxidation catalysis: (1) The reaction tolerates
heterocycles that commonly poison Pd catalysts. (2) The site selectivity
of C–H activation is controlled by an N-methoxyamide
group rather than a suitably positioned heterocycle. (3) A Pd0 source, Pd2(dba)3 (dba = dibenzylideneacetone),
is superior to Pd­(OAc)2 as a precatalyst, and other PdII sources are ineffective. (4) The reaction performs better
with air, rather than pure O2. The present study elucidates
the origin of these features. Kinetic, mechanistic, and in situ spectroscopic
studies establish that PdII-mediated C–H activation
is the turnover-limiting step. The tBuNC substrate is shown
to coordinate more strongly to PdII than pyridine, thereby
contributing to the lack of heterocycle catalyst poisoning. A well-defined
PdII–peroxo complex is a competent intermediate
that promotes substrate coordination via proton-coupled ligand exchange.
The effectiveness of this substrate coordination step correlates with
the basicity of the anionic ligands coordinated to PdII, and Pd0 catalyst precursors are most effective because
they selectively afford the PdII–peroxo in situ.
Finally, elevated O2 pressures are shown to contribute
to background oxidation of the isonitrile, thereby explaining the
improved performance of reactions conducted with air rather than 1
atm O2. These collective results explain the unique features
of the aerobic C–H imidoylation of N-methoxybenzamides
and have important implications for other Pd-catalyzed aerobic C–H
oxidation reactions.