Copper and Nickel Catalysis for the Construction of Novel C−N and C−C Bonds

Citation

Matier, Carson Douglas (2019) Copper and Nickel Catalysis for the Construction of Novel C−N and C−C Bonds. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/G3Q9-8F81. https://resolver.caltech.edu/CaltechTHESIS:05142019-145414091

Abstract

First-row transition-metals such as nickel and copper have revolutionized cross-coupling chemistry. Their propensity to form radical intermediates from alkyl electrophiles has greatly expanded the scope of traditional cross-coupling reactions. Alkyl radicals can be recaptured by a chiral transition-metal catalyst allowing for enantioselective bond formation. In general, alkyl radicals rapidly epimerize, and thus both enantiomers of a racemic mixture of an alkyl electrophile can be processed into the same enantiomer of product, rendering the overall process enantioconvergent. Herein, the development of basic bond constructions and the development of asymmetric reactions leveraging alkyl radical intermediates for carbon-nitrogen and carbon-carbon bond formations are discussed. Reaction development is the primary focus of this work, though mechanistic insights discovered along the way are also detailed within.

Chapter 2 describes the development of an enantioconvergent alkylation of amine nucleophiles with alkyl electrophiles. Carbazole and indole derivatives are employed as nucleophiles to undergo copper-catalyzed cross-coupling with tertiary α-chloroamide electrophiles under visible light irradiation. Reaction optimization, scope of reactivity, inorganic synthesis, and mechanistic insights are described within.

Chapter 3 details the development of a non-asymmetric copper-catalyzed alkylation of aliphatic amines with unactivated alkyl electrophiles under visible light irradiation. The development of a novel catalytic system to circumvent the issues with the photophysical properties of aliphatic amine-copper complexes is discussed. Scope of reactivity and mechanistic investigations are detailed within. Additionally, our efforts to develop an asymmetric variant of this reaction are enclosed.

Chapter 4 discusses the development of a copper-catalyzed alkylation of N-heterocycles with α-halolactams in the absence of light. The scope of the reactivity is detailed within. Mechanistic studies contained in this section suggest a unique and interesting reaction pathway—one that does not proceed through a radical intermediate.

Chapter 5 presents a novel class of organosilane electrophiles employed in an enantioconvergent nickel-catalyzed cross-coupling reaction. Here, the development of the reaction, scope of reactivity, and initial mechanistic insights are discussed.

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