Electronic and Steric Effects of the ProPhos Ligand Family for Nickel-Catalyzed Suzuki–Miyaura Coupling of Heteroaromatics

Abstract

Nickel-catalyzed Suzuki–Miyaura coupling (Ni-SMC) reactions offer a cost-effective approach for active pharmaceutical ingredient (API) synthesis but remain constrained by their limited compatibility with heteroaromatic substrates and the need for high catalyst loadings. Our laboratory recently developed the ProPhos ligand, which significantly addresses these challenges. In this study, we systematically investigate the electronic and steric effects of the ProPhos ligand framework. Evaluation of over 20 ProPhos derivatives, alongside representative monodentate and bidentate phosphine ligands, reveals that the beneficial influence of the tethered hydroxyl group is general. Other nucleophilic substituents were less effective, and variations in the three-carbon linker length compromised the catalytic efficiency. Increased steric bulk on phosphorus decreased reactivity, whereas electron-donating substituents such as para-tolyl enhanced performance; in contrast, replacing aryl groups with cyclohexyl groups proved detrimental. Finally, the application of the optimized ligand, ProPhos*, to a range of previously challenging substrates demonstrated the robustness and efficiency of Ni-SMC at low catalyst loading.