Hybrid Pincer (PNN)Ni(II) Complex Catalyzed Selective C–H Alkylation of Pyridones Using Unactivated Alkyl Chlorides

The use of readily accessible unactivated alkyl chlorides
in the
alkylation reaction to install valuable alkyl and methyl motifs into
privileged heterocycles is an underdeveloped area. Herein, we report
the regioselective C–H alkylation of diverse pyridones employing
challenging unactivated alkyl chlorides as coupling partners, enabled
by a strategically developed quinolinyl-based pincer (Ph2PNNQ)Ni(II) complex. The air-stable nickel catalyst is
highly effective for the selective alkylation of functionalized 2-pyridones
with both primary and secondary alkyl chlorides as well as for the
unexpected C6 methylation, furnishing a wide range of 6-alkyl-2-pyridone
scaffolds (78 examples). Remarkably, the alkyls bearing biologically
and pharmacologically significant motifs, such as pterostilbene, nonyl
phenol, sesamol, estrone, vitamin E, stigmasterol, cholesterol, and
diosgenin, were compatible under this catalytic approach. The insights
into the mechanism suggest that the alkylation reaction follows a
Ni(II)/Ni(III)/Ni(IV) pathway involving the crucial two-step, one-electron
oxidative addition of alkyl chloride. Several control studies, kinetics,
and EPR analyses were performed to understand the detailed reaction
pathway, further supported by density functional theory calculations.