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    Site-selective pyridine functionalization via nucleophilic additions to activated pyridiniums
    (Colorado State University. Libraries, 2024) Nguyen, Hillary M. H., author; McNally, Andrew, advisor; Bandar, Jeff, committee member; Chung, Jean, committee member; Shoemaker, Mark, committee member
    Pyridines and diazines are important heterocycles commonly found in pharmaceuticals, agrochemicals, ligands, and various other organic molecules. Pyridines existing in these molecules usually have multiple bonds connected to them that contribute to their reactivity and characteristics. Therefore, there are ongoing efforts l to find new methods to functionalize these heterocycles. Our lab has contributed to this field by developing methods to functionalize pyridines directly from the C–H bond through phosphonium salts or Zincke imines. Chapter One gives an overview of the current methods for pyridine functionalization and their limitations. Chapter Two describes the synthesis of N-Tf Zincke imines and their use for regioselective 3-position pyridine functionalization. Bipyridines and pyridine-piperidine coupled products are accessed through this method. Chapter Three discusses using N-Tf Zincke imines to form 15N pyridines and coupled with deuteration forms higher mass isotopologues. Chapter Four describes the formation of N-alkyl pyridinium salts from N-Tf Zincke imines. This chapter focuses on optimizing the ring-opening of 2-ester pyridines and ring-closing them with amino esters to access pipecolic esters for macrocyclization. Chapter Five highlights direct nucleophile additions to the 4-position of N-Tf pyridinium salts for pyridine functionalization. 4-aminated pyridines are formed with both aliphatic amines and anilines from the C–H bond. The regioselectivity of this amination is controlled by the basicity of the reaction. In addition, 4-NH2 pyridines are achieved through this method by adding benzophenone imine, an ammonia surrogate. This reaction extends to adding in heteroatom nucleophiles including alcohols, thioesters, amides, and sulfonamides.