Engineering Nickel-Catalyzed Cross-Electrophile Couplings for Drug Discovery Leveraging Industry–Academia Collaborations

Abstract

Nickel-catalyzed reductive cross-electrophile couplings offer powerful access to C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds from readily available electrophiles, yet their use in drug discovery has been hampered by difficult optimization, narrow scope, and limited tolerance of complex functionality. Through collaborations between MSD Discovery Chemistry and the Watson, Hazari, and Sevov groups, we established deaminative couplings of diverse alkyl pyridinium electrophiles with a wide range of aryl halides, dual Ni/Co and Ni/Ti catalysis that engages challenging primary and secondary alkyl and aryl halides using tunable homogeneous organic reductants, and isolable Ni(aryl)/Ni(alkyl) oxidative addition complexes as persistent organonickel platforms that accommodate both aryl and alkyl halide partners. Together, these complementary strategies improve control over key elementary steps, broaden substrate scope to challenging secondary and peptide-like partners, and enable late-stage functionalization of complex, drug-like scaffolds under high-throughput experimentation-compatible conditions.