Metallaphotoredox Decarboxylative Arylation of Natural Amino Acids via an Elusive Mechanistic Pathway

The merger of photoredox and nickel
catalysis for the
decarboxylative
arylation of carboxylic acids has evolved into an effective strategy
to forge C–C bonds from readily available feedstock. Despite
its rapid industrial adoption, the mechanism of this dual-catalyzed
cross-coupling reaction has remained unclear and under-studied. Here,
we propose an alternative mechanism for the photoredox–Ni dual-catalyzed
decarboxylative arylation of α-amino acids based on control
experiments with NiIIArBr complexes, cyclic voltammetry
(CV), and computational studies. Our mechanistic studies revealed
that a Ni0–NiII–NiI–NiII–Ni0 cycle is feasible in
the dual-catalyzed Csp2–Csp3 cross-coupling. Distinct from previous mechanism proposals,
we show with a series of CV studies and density functional theory
(DFT) calculations that a single electron transfer reduction of NiIIArBr to NiIAr by IrII is thermodynamically
favorable. Reductive elimination via a NiII-species rather
than via a NiIII-species is also supported by DFT calculations.
Those mechanistic insights allowed for the reaction scope to be extended
to encompass α-amino acids bearing pharmacophoric elements,
which were previously unexplored coupling partners. α-Amino
acids bearing broad functional groups, including heterocycles, successfully
underwent decarboxylative arylation with a diverse set of aryl bromides.
This strategy represents an advance in photoredox and Ni-catalysis
and broadens its industrial applicability as well as mechanistic understanding.