Synthetic Studies of Photochemical Radical Generation from N-(acyloxy)pyridinium Salts

Abstract

Energy supplied in the form of photons can interact with organic chromophores, enabling challenging bond formation and fragmentation reactions that could not otherwise be accessed. With an array of unique reactivity, photochemistry has the potential to revolutionize approaches to the synthesis of pharmaceutical and natural products targets alike. Over the past decade, coinciding with the emergence of photoredox catalysis, there has been a renewed interest in the study and development of photochemical methods for selective radical generation promoted by visible light. Importantly, these developments provide access to high energy radical intermediates under benign conditions, circumventing the need for hazardous, toxic reagents such as AIBN, tributyltin hydride, or UV light. Herein we describe the study of N-(acyloxy)pyridinium reagents as novel radical precursors, the development of new reactivity modes to leverage visible light for photochemical radical generation, and their application to aromatic C–H alkylation and perfluoroalkylation reactions. Chapter 1 provides an overview of photochemical methods for radical generation. Starting with a brief synopsis of photochemistry and its application to organic synthesis, the proceeding sections cover recent developments in photoredox catalysis, EDA complex photochemistry, and photocleavable auxiliaries for photochemical radical generation, with specific attention directed to highlighting their applications for arene alkylation reactions. Chapter 2 describes the development of a formal fragment coupling approach to the Minisci alkylation reaction. The developed reaction leverages a low cost, easily handled reagent mixture of heteroaromatic N-oxide with acyl chlorides for the in-situ generation of redox active esters. Photochemical radical generation is enabled by a photoinduced electron transfer from employed polypyridyl iridium photosensitizer, leading to fragmentation of the redox active ester and subsequent decarboxylative radical generation. Reaction optimization, exploration of the scope of reactivity, adaptation of the reaction to flow processing, and demonstration of late-stage functionalization efforts are discussed. Chapter 3 describes the development of a novel EDA complex, and its application as a catalyst for the radical trifluoromethylation of electron rich arenes. A historical overview of EDA complex photochemistry and its applications to organic synthesis is provided. Detailed studies of the designed EDA complex, reaction optimization, flow processing, and exploration of the scope of reactivity are each discussed. Chapter 4 describes the discovery and development of methyl 2-phenylquinoline-4-carboxylate N-oxide (PQCNO) as an auxiliary for efficient photoinduced radical generation. Design, optimization, and study of the auxiliary, as well as application towards a photoinduced Minisci alkylation reaction are described.