Advances in Nickel-Catalyzed C–O Cross-Coupling Reactions Enabled by Ancillary Ligand Design

Abstract

The ubiquity of C(sp2)–N and C(sp2)–O linkages in active pharmaceutical ingredients, agrochemicals, and other biologically active compounds generates motivation for developing effective avenues for the formation of such moieties. Transition-metal catalysis has been consequential in enabling carbon-heteroatom bond-forming reactions. Recent breakthroughs in Ni-catalyzed cross-couplings have offered competitive, and in some cases superior, reactivity to Pd- or Cu-based processes. Amidst the ongoing renaissance in this field, Ni-catalyzed C–O cross-coupling of alcohols and (hetero)aryl (pseudo)halides has surfaced as an effective strategy for the synthesis of (hetero)aryl ethers. While tunable bisphosphine ligands have proven effective in enabling such reactions, they remain largely underexplored and their application is arguably still in its infancy. Presented herein is a summary of my contributions to the field of Ni-catalyzed C(sp2)–O cross-coupling. Inspired by previous work by our group, this Thesis establishes new protocols and reactivity in such C–O bond forming processes. Chapter 2 details the Ni-catalyzed O-arylation of tertiary aliphatic alcohols, achieved by the newly developed ligand, CgPhen-DalPhos (2-L4). Using a derived Ni pre-catalyst, a substrate scope not previously demonstrated by any base-metal catalyst system was achieved. In addition to addressing an unmet synthetic challenge, this work also highlights selectivity differences between Ni catalysts supported by DalPhos ligands. Such findings motivated the systematic evaluation of competitive bisphosphine/Ni catalyzed C–O versus C–N cross-couplings reported in Chapter 3. Mapping these selectivity differences enabled the development of otherwise unknown chemoselective O- and N-arylation of amino alcohols using pre-catalyst 2-C1, featuring CyPAd-DalPhos (2-L1), without the use of protecting group chemistry. Chapter 4 examines the functionality of Ni(I) and Ni(II) pre-catalysts in C–O cross-couplings, with DFT calculations suggesting that such reactions occur within a Ni(0/II) manifold. Finally, Chapter 5 details a new protocol using pre-catalyst 3-C2, incorporating PAd2-DalPhos (3-L2), for the synthesis of (hetero)aryl ethers via Ni catalysis under organic base conditions. It is my hope that the concepts of ancillary ligand design and advances in Ni-catalyzed C–O cross-coupling presented herein will inspire further development of efficient Ni-based catalytic systems. It is imperative that we continue to pioneer environmentally benign synthetic methods for both C–N and C–O bond forming reactions that can be translatable to industrial settings.