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Functionalization of pyridines and other azines via phosphorus ligand-coupling reactions




Hilton, Michael C., author
McNally, Andrew, advisor
Reynolds, Melissa, committee member
Crans, Debbie, committee member
Montgomery, Tai, committee member

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Nitrogen heterocycles are ubiquitous in pharmaceutical compounds with pyridine being one of the most frequently occurring examples. The discovery and development of new drugs rely heavily on our ability to modify these commonly occurring structures. The functionalization of pyridine has a long history but despite this, there remain some deficiencies in this area of synthesis. Reactions which expand upon the known methodologies are of tremendous value to medicinal chemists who frequently work with pyridines and similar azines. Chapter one will cover the relevance of pyridines in pharmaceuticals and will explain how structural features contribute to their presence in drugs. Conventional and newer methods to functionalize pyridine are also addressed. Chapter two will describe the work of the McNally lab in the development of heterocyclic phosphonium salts as reagents to selectively functionalize pyridines. An application of these salts is as precursors to form C−O bonds from alkoxide nucleophiles. Chapter three presents the development of a strategy to construct bis-heterobiaryls using phosphorus ligand-coupling. This method offers an alternative to the widely used metal-catalyzed approaches which often struggle in the synthesis of bis-heterobiaryls. Lastly, chapter four will expand upon this work showing a new approach to prepare bis-heterobiaryls using heteroaryl halides. This route enables easy access to 2,2'-bipyridines which are difficult to synthesize using conventional methods.


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