Role of Electron-Deficient Olefin Ligands in a Ni-Catalyzed Aziridine Cross-Coupling To Generate Quaternary Carbons

We previously reported
the development of an electron-deficient
olefin (EDO) ligand, Fro-DO, that promotes the generation of quaternary
carbon centers via Ni-catalyzed Csp3–Csp3 cross-coupling with aziridines. By contrast, electronically and
structurally similar EDO ligands such as dimethyl fumarate and electron-deficient
styrenes afford primarily β-hydride elimination side reactivity.
Only a few catalyst systems have been identified that promote the
formation of quaternary carbons via Ni-catalyzed Csp3–Csp3 cross-coupling. Although Fro-DO represents a promising ligand
in this regard, the basis for its superior performance is not well
understood. Here we describe a detailed mechanistic study of the aziridine
cross-coupling reaction and the role of EDO ligands in facilitating
Csp3–Csp3 bond formation. This analysis
reveals that cross-coupling proceeds by a Ni0/II cycle
with a NiII azametalla­cyclobutane catalyst resting
state. Turnover-limiting C–C reductive elimination occurs from
a spectroscopically observable NiII-dialkyl intermediate
bound to the EDO. Computational analysis shows that Fro-DO accelerates
turnover limiting reductive elimination via LUMO lowering. However,
it is no more effective than dimethyl fumarate at reducing the barrier
to Csp3–Csp3 reductive elimination. Instead,
Fro-DO’s unique reactivity arises from its ability to associate
favorably to NiII intermediates. Natural bond order second-order
perturbation theory analysis of the catalytically relevant NiII intermediate indicates that Fro-DO binds to NiII through an additional stabilizing donor–acceptor interaction
between its sulfonyl group and NiII. Design of new ligands
to evaluate this proposal supports this model and has led to the development
of a new and tunable ligand framework.