Expanding the medicinal chemistry toolbox: development of new pyridine and piperidine functionalization strategies
Date
2022
Authors
Greenwood, Jacob W., author
McNally, Andrew, advisor
Bandar, Jeffrey, committee member
Sambur, Justin, committee member
Chatterjee, Delphi, committee member
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Abstract
Nitrogen-containing heterocycles, such as pyridine, are ubiquitous in pharmaceuticals, agrochemicals, ligands, and materials. Therefore, robust methods for their direct functionalization are highly desired. Chapter one focuses on the importance of pyridine-containing molecules, the reactivity of pyridine, and challenges associated with functionalization of such compounds. In chapter two, a method for bipyridine synthesis is discussed that uses pyridylphosphonium salts as radical precursors. Other radical precursors failed to provide the desired products, highlighting the unique reactivity imparted by the phosphonium group. In chapter three, pyridylphosphonium salts are explored as alternatives to cyanopyridines in photoredox-catalyzed radical coupling reactions. This work expands the scope of the reaction manifold to complex pyridine substrates where installation of the cyano group can be challenging. Chapter four introduces the value of piperidines and challenges associated with their synthesis. A strategy is described to address these limitations using isolable, cyclic iminium salts as a general platform to elaborate the piperidine scaffold with several medicinally relevant functional groups. An alternative piperidine synthesis is presented in chapter five, where the mild transformation of a range of pyridines into pyridinium salts is achieved, followed by mild hydrogenation to the desired piperidine products. This method operates under mild conditions and can tolerate substitution at the 2-position of the pyridine substrate. As a result, a large amount of pyridine starting materials can now be engaged to form piperidines that are challenging to make with other technologies.
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Subject
organic chemistry
piperidine
single electron
photoredox
medicinal chemistry
pyridine