Nickel-mediated aerobic C(sp2)-nucleophile coupling reactions for late-stage diversification of aryl electrophiles

The structural diversification of pharmaceutically relevant compounds presents unique challenges to catalytic methodologies that have been developed and optimized on simpler substrates that lack drug-like complexity. Herein, we report a general strategy for carbon-heteroatom (C-X) bond formation through reactions between a wide range of nucleophiles and Ni-based oxidative addition complexes (OACs) of drug-like aryl and heteroaryl electrophiles. These organonickel complexes are easily synthesized by oxidative addition of the corresponding electrophiles under electroreductive conditions using an inexpensive Ni precursor. Redox-induced oxidative coupling from these persistent complexes proved challenging, but mechanistic studies guided the development of a simple aerobic oxidation procedure to rapidly form C-X coupled products. Exposure of the organonickel complexes to ambient air forms a high-valent (peroxo)Ni^(III)Ar complex intermediate that can undergo substitution with a variety of N-, O-, S-, C-, P- or halide-based nucleophiles, which are incorporated into the product. The breadth of this methodology was demonstrated by reactions with unreactive electrophiles, such as aryl chlorides, drug-like (hetero)aryl electrophiles, and small peptides. Finally, the aerobic chemistry was miniaturized to allow for high-throughput exploration of substrate diversity with an equally complex set of nucleophilic partners.