THE CARBOCATION IN MODERN ORGANIC SYNTHESIS: PHOTOCATALYTIC METHODOLOGIES FOR NUCLEOPHILIC C(sp3)–H FUNCTIONALIZATION AND THE GENERAL SYNTHESIS OF SATURATED HETEROCYCLES

Abstract

Reactive intermediates in organic synthesis are powerful species. Either polar or radical in nature, reactive intermediates are the lynchpin of organic transformations, effecting swift, selective, and even predictable bond formations across diverse reactivity platforms. In the works described herein, the reactive intermediate of premier relevance is the carbocation, a polar intermediate bearing positive charge at the carbon center. Highly reactive and versatile, the carbocation is uniquely poised for functionalization by nucleophiles, which represent an expansive class of coupling partners that—when combined with carbocations—provide access to a wealth of valuable bond formations. The works in this thesis describe the development of carbocation-mediated methodologies for C(sp3)–H functionalization (with an emphasis towards C(sp3)–H fluorination) and saturated heterocycle synthesis. Chapter One provides historical context regarding the importance of nucleophilic C(sp3)–H fluorination chemistry in organic synthesis and society, with an emphasis towards the four main categories of research that define this field: 1) leveraging functional groups for fluorination, 2) C(sp3)–H fluorination, 3) asymmetric fluorination, and 4) radiofluorination. Recent developments across these four categories of research are discussed, with an emphasis towards research from leading experts in the field of nucleophilic C(sp3)–H fluorination.Chapter Two describes the development of a photocatalytic C(sp3)–H functionalization strategy with nucleophiles to achieve nucleophilic C(sp3)–H fluorination. In this work, C(sp3)–H bonds are transformed into carbocations through a hydrogen atom transfer–oxidative radical-polar crossover (HAT-ORPC) sequence, wherein mechanistic studies revealed HAT to be mediated by methyl radical. Chapter Three provides historical context regarding the importance of annulation chemistry and heterocycle synthesis, with an emphasis towards the synthesis of pyrrolidine fragments. Finally, Chapter Four describes the development of a photocatalytic, radical redox approach to the diverse synthesis of saturated heterocycles. Founded on the principles of carbocation-mediated functionalization explored in Chapter Two, the methodology described herein leverages principles of reductive radical generation and ORPC to provide the versatile carbocation intermediate for broad nucleophilic cyclization from N- and O-centered tethered nucleophiles.