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Nickel-Catalyzed Reactions of Amides and New Methods for the Synthesis of Nitrogen-Containing Heterocycles
- Simmons, Bryan Joseph
- Advisor(s): Garg, Neil K
Abstract
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
after.
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
chemistry.
Main Content
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