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Abstract
This dissertation explores single-atom editing of azaarene substrates enabled by a common mode of skeletal activation: photochemical generation of 3,1-benzoxazepines. Chapter 1 presents selected case studies of high-impact design elements and the corresponding synthetic practices, eventually leading to the motivation for pursuing skeletal editing transformations in drug discovery. Then, the definitions and classification schemes of single-atom editing are introduced, and the prior art of carbon deletion and carbon-to-nitrogen exchanges of azaarenes are discussed in detail, highlighting key reactive intermediates and mechanisms. The last section of Chapter 1 focuses on classical photochemistry of quinoline N-oxide, which contains various pathways to secondary photoproducts and hydrolysis products due to the harsh, broadband irradiation of mercury lamps. Chapter 2 reports a process of wavelength optimization using LEDs to achieve selective excitations of azaarene N-oxides substrates, and subsequent in situ acidolysis accomplished net C2-selective carbon deletion. Chapter 3 explores a direct replacement of carbon with a nitrogen atom that bypasses deletion-insertion heuristics of transmutation. Inducing oxidative cleavage on the enol ether moiety of 3,1-benzoxazepines generates “sticky end” intermediates that incorporate the nitrogen atom and simultaneously excise the replaced carbon atom as labile leaving groups. Finally, Chapter 4 reports the serendipitous discovery of HFIP-promoted, reagent-controlled selective deletion of C3 or C2 carbon atom of azaarenes, enabling divergent single-atom editing. Distinctive kinds of skeletal editing discussed throughout Chapters 2-4 are unified under a common activation strategy; in this way, a rapid diversification of the parent azaarene skeleton is achieved through parallel synthesis.