Challenging Nickel-Catalyzed Cross-Couplings Enabled by Ligand Design

Abstract

Carbon-nitrogen linkages are highly prevalent in bioactive molecules, and as such, the development of sustainable methodologies for their formation is of immense importance to both the pharmaceutical and agricultural industries. Within this realm, the advent of homogeneous transition metal catalysis has allowed significant progress to be made in the development of routes toward the formation of these linkages, encompassing a wide range of different carbon and nitrogen-containing organic reagents. Specifically, the development of Pd-catalyzed C(sp2)-N (herein, C-N) cross-coupling (i.e. Buchwald-Hartwig-Amination, BHA) has transformed the way chemists approach solving synthetic problems. Indeed, research efforts in BHA over the past 25 years have allowed for the development of several catalytic systems, encompassing a large array of both (hetero)aryl (pseudo)halide and NH-bearing substrates. Successes in BHA can be largely attributed to the rational design of ancillary ligands, which are able to dramatically influence the reactive properties of Pd through a combination of steric and electronic effects. Despite the utility of BHA, researchers have now turned to more Earth-abundant sources for effecting these transformations, including the implementation of Cu for improved versions of well-known Ullmann-coupling, and the implementation of Ni, both as alternatives to precious Pd. In this thesis, my contributions toward the rational design, syntheses and use of appropriate ancillary ligands for enabling Ni-catalyzed C-N cross-coupling are described. Included are the development of new phosphonite/phosphine ligands such as Phen-DalPhos and related variants, along with the application of Ni-based pre-catalysts for the cross-coupling of ammonia, (hetero)anilines, indoles, sulfonamides, fluoroalkylamines and amides with (hetero)aryl (pseudo)halides under unprecedently mild conditions in Ni-based catalysis.