Exploring Ligand-Enabled Nickel-Catalyzed Cross-Coupling of Sulfur-Based Nucleophiles

Abstract

The catalytic synthesis of C(sp2)-N linkages is of utmost significance in modern synthetic chemistry, predominantly due to their prevalence in active pharmaceutical ingredients and natural products. Pd-catalyzed cross-couplings of this type, known colloquially as Buchwald-Hartwig amination (BHA), represent a tremendously important class of reactions in research and industrial settings. The success achieved by BHA can largely be attributed to the rational design of ancillary ligands specifically configured to exploit the natural electronic characteristics of the Pd metal centre. Research efforts surrounding the BHA reaction have enabled the scope of suitable coupling partners to grow rapidly, encompassing a vast array of (hetero)aryl (pseudo)halides and NH couplings partners. Notwithstanding the value of the BHA reaction, concerns over the rising costs of Pd and subsequent sustainability issues have prompted researchers to seek economical methods for accessing these linkages. One of the most promising alternatives to Pd-catalysis is the developing field of its 3d congener, Ni. However, given the relatively underdeveloped nature of Ni-catalyzed C-N bond formation, many questions regarding the mechanistic underpinnings and scope limitations remain unanswered. In this thesis, my contributions include experimental investigations into the elementary steps of a successful Ni-catalyzed cross-coupling. The successful synthesis and characterization of primary Ni-NHR catalytic intermediates reveal previously undocumented C-N bond-forming pathways, and the implementation of the mechanistic lessons learned from these studies allow for the discovery of new ligand-enabled Ni-catalyzed C-N cross-couplings.