The Preparation and Systematic Evaluation of Ligated Ni(II) Pre-Catalysts (NiPC) in Common Single Electron Cross-Coupling Reactions

Abstract The advent of single-electron, nickel-mediated cross-coupling reactions has fundamentally transformed how carbon bonds can be forged and is now a mainstay of modern synthesis and medicinal chemistry. Nickel is a prevailing transition metal that facilitates these innovations, and yet despite its obvious competence, standardized practices regarding Ni/ligand preparation and administration, as separate entities or as a single precomplex or catalyst, have not been systematically established. This study investigates the synthesis, isolation, and efficacy of simple, ligated Ni(II) precatalysts (NiPCs) to expedite and standardize protocols for contemporary single-electron nickel-mediated cross-coupling reactions. We demonstrate the effectiveness of a library of isolated NiPCs in commonly used singleton transformations and high-throughput experimentation (HTE) setups with broad application to pharmaceutical chemistry. By illuminating the practical rules that govern NiPC synthesis and administration, this work equips the community with an actionable understanding to enable wide, normalized adoption of simple NiPC methods.