Novel Platforms for Cross-Coupling and Decarboxylative Functionalization via Metallaphotocatalysis

Abstract

Access to novel molecular scaffolds in organic synthesis relies on the exploration of new chemical space. Consequently, the development of new methods to rapidly construct diverse, complex molecules has become of increasing importance in the field of synthetic organic chemistry in recent decades. To address these needs, our group leverages the merger of transition metal catalysis and photocatalysis (i.e., metallaphotocatalysis) toward the development of new coupling and activation platforms. The ability of photocatalysis to selectively activate organic substrates via single electron transfer pathways to generate open-shell species under mild conditions, coupled with transition metal cross-coupling, has led to the development of a diverse and powerful array of synthetic manifolds that enable previously elusive bond disconnections and streamline the synthesis of molecules. Although this field has advanced rapidly in the past decade, the development of novel metallaphotocatalytic methods that broadly enable the coupling of diverse fragments continues to be in high demand. This thesis details several efforts that employ metallaphotocatalysis in the development of novel cross-coupling methods and activation modes. First, Chapter 2 describes a new approach for nickel/photoredox-catalyzed cross-electrophile coupling of activated alkyl chlorides and aryl halides, facilitated by silyl radical-mediated halogen atom abstraction as a key design element. Chapter 3 extends this design element to the activation of C(sp2)–Br bonds which, in combination with dual copper/photoredox catalysis, enables a general protocol for trifluoromethylation of aryl bromides. Finally, Chapter 4 describes a novel ligand-to-copper charge transfer platform that promotes the decarboxylative functionalization of aryl carboxylic acids (a modular and abundant yet recalcitrant class of substrates), rendering a previously inaccessible range of aryl carboxylic acids broadly accessible as adaptive functional handles.