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Heterocycles Old and New: Carbonylazoles as Chemoselective Acylation Reagents and the Synthesis and Applications of Benzindolizinones


Carbonylazole derivatives have been shown to be chemoselective and efficient acylating reagents under a variety of conditions. Catalysis with pyridinium salts, as well as with DBU or DABCO are discussed, as is the thermal reaction of imidazole carbamates with carboxylic acids to provide esters. The application of a protic solvent-mediated cycloisomerization approach to two isomers of benzindolizinone - a relatively unstudied heterocyclic system - and the syntheses of two Erythrina alkaloids are also discussed.

Chapter 1 provides an overview of the fundamental importance of the carbonyl group in the chemistry of life, as well as in the service of man. Key processes through which these versatile groups react are illustrated with an emphasis on the chemistry of esters. The chapter concludes with a survey of the application of carbonylimidazoles as acyl donors from their first development by Staab to the present.

Through another line of inquiry, it was discovered that imidazole carbamates and ureas are chemoselective esterification and amidation reagents. The optimization, substrate scope, and mechanism of esterification and amidation of carboxylic acids mediated by imidazole-based reagents are discussed in Chapter 2. The innate reactivity of carbonyl imidazole reagents with a range of nucleophiles is also explored.

Following this initial discovery, it was found that pyridinium salts greatly enhance the reactivity of carbonylimidazole derivatives as acylation reargents for esterification and amidation. Chapter 3 details the development of this mode of catalysis and outlines a mechanistic proposal in which pyridinium salts act as both Brønsted acid and nucleophilic catalysts. Finally, the scope of this technology in the synthesis of difficult to access oxazolidinones, as well as esters and amides, is discussed. This work was executed in partnership with Tingting Fu.

Drawing on the possibility that carbonylazole acyl donors could be potentiated through nucleophilic catalysis, a DBU-catalyzed N-acylation of indoles and oxazolidinones was devised. Chapter 4 covers the development of this reaction, as well as the subsequent finding that this acylation was chemoselective even in the presence of more reactive amine and alcohol functional groups. This work was performed in collaboration with Erica Schultz.

The solvent-promoted cycloisomerization of quinoline and isoquinoline propargylic carbinols to benz[e]- and benz[g]indolizinones, respectively, is described in Chapter 5. The study of the fundamental reactivity of these new heterocyclic motifs is discussed. The formal synthesis of 3-demethoxyerythratidinone using this cycloisomerization strategy, as well as its application in studies toward the synthesis of cocculidine are also detailed.

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