Ligand design overcomes bottlenecks in Ni(I)-catalyzed C(sp²)–heteroatom couplings

The formation of C(sp2)–heteroatom bonds is a cornerstone of modern organic synthesis and key for the preparation of pharmaceuticals, agrochemicals, and functional materials. Traditionally, such bond formations have relied on palladium-catalyzed cross-couplings operating through canonical Pd0/PdII cycles, which require complex ligand architectures to control the orthogonal steric and electronic ligand demands for the initial electrophile activation and final bond forming event.Cross-coupling catalysis via paramagnetic Niᴵ and Niᴵᴵᴵ species is an appealing alternative because the bond-forming step is energetically favorable. However, this approach is confined to activated starting materials and requires high catalyst loadings, due to the insufficient catalytic activity and stability of state-of-the-art NiI catalysts. Here, we show that mechanistically guided ligand design overcomes these intrinsic bottlenecks by achieving a well-balanced equilibrium between a highly reactive NiI species and a stabilized ligand-centered radical. Use of a non-nucleophilic base additive promotes visible-light generation of Niᴵ from a bench-stable precatalyst and facilitates reactions with a broad range of nucleophiles. Our results show that this platform provides a highly general set of conditions for coupling challenging aryl halides with N-, O-, S-, and P-based nucleophiles at nickel loadings as low as 100 ppm. Further, this is the first NiI/NiIII catalysis method that couples sterically encumbered nucleophiles. Gram-scale synthesis of pharmaceuticals and late-stage couplings of complex molecules underscore the potential of this approach for medicinal chemistry applications.