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Open Access Publications from the University of California

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

  • Author(s): Simmons, Bryan Joseph
  • Advisor(s): Garg, Neil K
  • et al.

This dissertation is divided into two main themes concerning transition metal-mediated

methodologies and the synthesis of nitrogen-containing heterocycles. The first part of this

dissertation focuses on the development of three new reaction pathways utilizing nickel and

palladium. The impact of transition metals in the field of synthetic organic chemistry cannot be

overstated, with the 2010 Nobel Prize being awarded for the use of palladium cross-coupling in

organic synthesis. The second part of this dissertation aims to expand the synthetic toolbox

towards the generation of nitrogen-containing heterocycles. With over 100 FDA-approved drugs

containing a nitrogen atom, new methodologies toward these scaffolds remain highly sought


Chapters One, Two, and Three focus on the development of new methodologies utilizing

nickel and palladium catalysis. Chapters One and Two describe our efforts towards the

functionalization of the amide moiety. Although amides were once thought to be unreactive due

to their resonance stabilization, we sought to probe the utility of amides as a functional group

handle. Chapter One focuses on the alkylation of amides using nickel and an organozinc source

to generate sp2–sp3 C–C bonds. Chapter Two showcases a methodology to convert secondary

and tertiary amides to their corresponding amines using a silane reducing agent and nickel

catalysis. Chapter Three discusses an academic and industrial collaboration towards the synthesis

of tetra-ortho-substituted biaryls using palladium catalysis. These studies culminated in an

extensive computational analysis of the reaction mechanism and the synthesis of numerous

atropisomeric biaryls.

Chapters Four, Five, and Six detail new methodologies towards the generation of

nitrogen-containing heterocycles. With the nitrogen atom being prevalent in numerous FDA-approved

drugs, facile routes towards their incorporation remain highly valued. Chapter Four

illustrates the elusive 3,4-piperidyne’s use in a variety of cycloaddition reactions. This study led

to the formation of numerous annulated piperidines and exemplifies the utility of our

methodology. Chapters Five and Six utilize the interrupted Fischer indolization reaction to

produce an assortment of furanoindoline and pyrrolidinoindoline products. Chapter Five centers

on the synthesis of the aza-analogues of these products by employing pyridylhydrazines. A

computational study was undertaken to determine the cause of success or failure in this

transformation. Chapter Six describes a variation of interrupted Fischer indolization

methodology performed in a microfluidic device, which should enable its use in medicinal


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