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Development of Nickel-Catalyzed Cross-Coupling Reactions

  • Author(s): Hie, Liana
  • Advisor(s): Gary, Neil K
  • et al.

Transition metal-catalyzed cross-couplings provide a powerful means to assemble carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds. Although Pd catalysis is most commonly used in these transformations, Ni catalysis offers a valuable alternative due to the low cost and high reactivity of Ni. More importantly, Ni catalysis has proven effective for the activation of traditionally inert carbon–heteroatom bonds and therefore provides exciting opportunities with regard to chemical reactivity and synthetic applications.

Chapter one, two, and three describe the development of practical cross-coupling methodologies. Chapter one explains the amination of aryl sulfamates and carbamates that relies on an air-stable Ni(II) precatalyst. Chapter two introduces the development of green cross-couplings of phenolic derivatives and aryl halides to form biaryls. Subsequently, the couplings of heterocycles, which are commonly encountered in natural product synthesis and in the pharmaceutical sector, are described. Chapter three describes the development of green cross-couplings of aryl sulfamates and chlorides to form aryl amines.

Chapter four and seven concern the utility of amides as electrophilic cross-coupling partners. These traditionally unreactive moieties are activated by nickel and coupled to alcohols to form acyl C–O bonds. This study suggests that amides may serve as useful building blocks to construct carbon–carbon and carbon–heteroatom bonds. Chapter four describes the development of nickel-catalyzed activation of benzamides and chapter seven introduces the development of nickel-catalyzed activation of aliphatic amide derivatives.

Chapter five describes the nickel-catalyzed activation of the acyl carbon–oxygen bonds of methyl esters through an oxidative addition process. The oxidative addition adducts, formed using nickel catalysis, undergo in situ trapping to provide anilide products. DFT calculations are used to support the proposed reaction mechanism, understand why decarbonylation does not occur competitively, and to elucidate the beneficial role of the substrate structure and Al(OtBu)3 additive on the kinetics and thermodynamics of the reaction.

Chapter six focus on the nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in bioactive molecules.

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