A Systematic Investigation into Bisphosphine Ligands for Nickel-Catalyzed C(sp2)–N Cross-Coupling

Abstract

Research into transition metal-catalyzed C–N cross-coupling reactions has been driven by a need for robust and facile synthetic routes towards bioactive molecules which are rich in C–N linkages. The use of Pd-based catalysts in Buchwald-Hartwig Amination (BHA) protocols are the most well studied and utilized within industry. The choice of Pd source, ancillary ligand, base, solvent, and the use of additives have been thoroughly investigated aiding in the selection and optimization of reaction conditions. However, research has refocused towards finding more Earth-abundant and cost-effective transition metals capable of comparable reactivity. Ni has proven to be a competitor with the development of new ancillary ligands after efforts to repurpose well-known ligands in Pd-catalysis had limited success. In particular, bisphosphines within the DalPhos ligand family have enabled the Ni-catalyzed N-arylation of challenging substrates including ammonia, alkylamines, heteroarylamines, indole, and amides with (hetero)aryl electrophiles prompting the commercialization of several ligand variants. The effects of varying experimental parameters within these ligand/Ni systems are less established and prompt further investigation in order to determine trends in reactivity and limitations. A systematic evaluation of selected bases and solvents on the effectiveness of leading DalPhos ligand variants in the C–N cross-coupling of structurally varied (hetero)aryl electrophiles with primary and secondary amines is reported herein.