Metallacycle-Based Nickel-Catalyzed Reductive Couplings and Reductive Cross-Electrophile Couplings

Abstract

The development of nickel catalysis has become more prominent over the years for organic transformations due to its low cost and widespread availability. This thesis discusses the impact of nickel catalysis in organic transformations such as metallacycle–based nickel-catalyzed reductive couplings and reductive cross–electrophile couplings. Chapter 1 provides background literature to the various strategies developed by the Montgomery lab to control regioselectivity and enantioselectivity of stereodefined silyl–protected allylic alcohol products in the reductive couplings of aldehydes and alkynes. Chapter 2 discusses the challenges associated with synthesizing small, chiral BAC ligands along with the challenges faced with developing a strategy using small, chiral ligands to control regioselectivity and enantioselectivity in the reductive couplings of aldehydes and alkynes. During the strategy development process, an endo product in the ynal cyclizations was serendipitously discovered. However, the formation of endo product was only observed for one privileged substrate. With obtaining moderate regioselectivity and low enantioselectivity using small, chiral ligands, future work will need to investigate the synthesis of other novel BAC ligands to simultaneously obtain great regioselectivity and high enantioselectivity. Chapter 3 provides background literature to the design, synthesis and reactivity of novel, well–defined NHC–Ni(0) complexes to avoid the use of unstable Ni(0) precursors and in–situ protocols to generate the Ni(0) catalyst. Chapter 4 discusses the synthesis of novel BAC–Ni(0) complexes with fumarate ligands, which were the first of this class to be synthesized. Although these novel BAC–Ni(0) complexes showed to be inactive in the reductive coupling of aldehydes and alkynes compared to the IMes–Ni(0) complexes, it was shown computationally that the BAC–Ni(0) complexes prefer to undergo the ketene first pathway for catalyst activation. This pathway leads to a nickel hydride species that is too endergonic and not capable of forming an active catalyst. Future work will need to consist of determining what pi–acidic additives can allow for BAC–Ni(0) to be stable, yet active in the reductive coupling of aldehydes and alkynes. Chapter 5 provides background literature to the recent metallacycle–based reductive cross-electrophile coupling method developed by the Montgomery to synthesize tetrasubstituted olefins. Chapter 6 discusses the challenges in preventing oligomerization and / or polymerization from occurring in the metallacycle–based reductive cross-electrophile coupling method when utilizing electron–deficient substrates such as alkynyl enamides, alkynyl enals, alkynyl enones and alkynyl enoates. Moderate yields were obtained after optimization with an alkynyl enamide. Future work would consist of looking at various primary alkyl halides to generate a potential substrate scope with alkynyl enamides. Additionally, there is the potential to synthesize bipyridine–Ni(0) complexes using pi–acidic additives, such as fumarates and acrylates. This would limit the reduction step needed to reduce the Ni(II) complex to the active Ni(0) complex and potentially increase the yield of product formation.