Nickel-Catalyzed Reactions of Amides and New Methods for the Synthesis of Nitrogen-Containing Heterocycles

This dissertation is divided into two main themes concerning transition metal-mediatedmethodologies and the synthesis of nitrogen-containing heterocycles. The first part of thisdissertation focuses on the development of three new reaction pathways utilizing nickel andpalladium. The impact of transition metals in the field of synthetic organic chemistry cannot beoverstated, with the 2010 Nobel Prize being awarded for the use of palladium cross-coupling inorganic synthesis. The second part of this dissertation aims to expand the synthetic toolboxtowards the generation of nitrogen-containing heterocycles. With over 100 FDA-approved drugscontaining a nitrogen atom, new methodologies toward these scaffolds remain highly soughtafter.Chapters One, Two, and Three focus on the development of new methodologies utilizingnickel and palladium catalysis. Chapters One and Two describe our efforts towards thefunctionalization of the amide moiety. Although amides were once thought to be unreactive dueto their resonance stabilization, we sought to probe the utility of amides as a functional grouphandle. Chapter One focuses on the alkylation of amides using nickel and an organozinc sourceto generate sp2–sp3 C–C bonds. Chapter Two showcases a methodology to convert secondaryand tertiary amides to their corresponding amines using a silane reducing agent and nickelcatalysis. Chapter Three discusses an academic and industrial collaboration towards the synthesisof tetra-ortho-substituted biaryls using palladium catalysis. These studies culminated in anextensive computational analysis of the reaction mechanism and the synthesis of numerousatropisomeric biaryls.Chapters Four, Five, and Six detail new methodologies towards the generation ofnitrogen-containing heterocycles. With the nitrogen atom being prevalent in numerous FDA-approveddrugs, facile routes towards their incorporation remain highly valued. Chapter Fourillustrates the elusive 3,4-piperidyne’s use in a variety of cycloaddition reactions. This study ledto the formation of numerous annulated piperidines and exemplifies the utility of ourmethodology. Chapters Five and Six utilize the interrupted Fischer indolization reaction toproduce an assortment of furanoindoline and pyrrolidinoindoline products. Chapter Five centerson the synthesis of the aza-analogues of these products by employing pyridylhydrazines. Acomputational study was undertaken to determine the cause of success or failure in thistransformation. Chapter Six describes a variation of interrupted Fischer indolizationmethodology performed in a microfluidic device, which should enable its use in medicinalchemistry