New Photoredox Reactions Enabled By Unique Applications Of Base Metal Catalysis

Abstract

New synthetic technologies, particularly those that employ abundant reagents to execute challenging transformations, have the capacity to dramatically impact research efforts across both academic and industrial settings. In particular, light-driven radical generation via photoredox catalysis has emerged as a powerful approach for engaging bench-stable feedstock chemicals as versatile reagents for synthesis. This approach can also be enhanced through a synergistic merger with transition metal cross-coupling steps, termed metallaphotoredox catalysis, to rapidly generate various pharmaceutically-relevant small molecule products. To further accelerate drug discovery efforts, new mechanistic principles and elementary steps applicable to metallaphotoredox catalysis must be discovered, as these unique approaches may be critical for enabling novel, advantageous and historically elusive reactions to occur.This thesis describes four separate photoredox or metallaphotoredox platforms which can address outstanding challenges in synthesis, particularly those relevant to medicinal chemistry, by exploiting the unique elementary steps performed by base metal catalysts. Chapter 2 describes the discovery of a copper metallaphotoredox alternative to SN2-type N-alkylation between N- heterocyclic nucleophiles and alkyl halides, achieved by radical formation via silyl radical activation and C–N reductive elimination from Cu(III) intermediates. The third chapter describes a near-UV, copper-LMCT approach to the previously elusive catalytic decarboxylation of (hetero)aryl acids, enabling the unified development of halogenation and borylation reactions as well as one-pot decarboxylative cross-coupling protocols. The fourth chapter describes ongoing efforts to exploit a novel metallaphotoredox step, manganese-catalyzed hydrogen atom transfer to unactivated olefins, for triple catalytic olefin-acid cross-coupling (i.e. decarboxylative hydroalkylation) via nickel-catalyzed radical sorting and homolytic substitution-based bond-forming pathways. Lastly, the final chapter details advances in the photoredox generation and catalytic applications of metal carbenes furnished from benign aldehyde, acid and alcohol feedstocks, enabled by inducing iron porphyrin intermediates to undergo a-elimination with non- conventional leaving groups under single-electron activation.