Investigating the Design of Bisphosphine Ligands for use in Nickel-catalyzed C(sp2)-N Cross-Coupling

Abstract

Notwithstanding the matured protocol of palladium-catalyzed C(sp2)-N cross-coupling (Buchwald Hartwig Amination, BHA), the development of nickel-based catalysts that carry out analogous transformations is motivated both by the benefits of employing Earth-abundant, cost-effective first-row transition-metals, and the potential for nickel catalysts to unveil new modes of reactivity. Over the past five years, significant advances in nickel-catalyzed amination chemistry have led to a widespread interest and expansion of this methodology. Although nickel catalysts are highly effective in the cross-coupling of ammonia, alkylamine, indole, and primary amide nucleophiles with (hetero)aryl electrophiles, these catalytic systems have yet to contend with palladium analogs in terms of exceedingly low catalyst loadings and the turnover of increasingly challenging substrate classes. Whereas BHA benefits from an unambiguous set of criteria that defines optimal ancillary ligand properties for this palladium-catalyzed transformation, structure-reactivity trends for nickel counterparts are ill-defined. Additionally, complex mechanistic details exist for nickel-catalyzed C(sp2)-N cross-coupling, which may be responsible for the vague guidelines for optimizing ancillary ligands, and the need for higher catalyst loadings. My thesis work explores ancillary ligand design criteria for nickel-catalyzed C(sp2)-N cross-coupling by cross-examining top-tier bisphosphine ligand classes with aims of clarifying the apparently divergent properties that exist among state-of-the-art ancillary ligands. Information gathered from the systematic comparisons of these ligand classes results in the development of the new bisphosphine ligand, PAd2-DalPhos, which enables the hitherto unknown nickel-catalyzed C(sp2)-N cross-coupling of primary heteroarylamines with (hetero)aryl chlorides. This chemical transformation is highly sought-after by pharmaceutical chemists for the synthesis of heteroatom-dense molecular structures, and reveals a new mode of reactivity involving challenging substrates in the context of nickel catalysis.