Unstabilized Radical Generation via Beta-Scission for Nickel-Catalyzed Cross-Coupling Reactions

Abstract

Transition metal-catalyzed cross-coupling reactions are among the most impactful methods for constructing C–C bonds. Recently, the development of reactions that selectively enable cross-coupling of two electrophiles (“cross-electrophile coupling”) has broadened the range of chemical structures that can be prepared using two abundant, stable, and functional group-tolerant coupling partners. The ability of Ni to activate electrophiles, in addition to its proclivity to both generate and accept reactive radical intermediates, has rendered Ni catalysis highly privileged for enabling these coupling reactions. At the same time, photoredox catalysis has emerged as a mild method for generating radical species through visible light-promoted single electron transfer events. The synergistic merger of Ni and photoredox catalysis thus has revolutionized the way that chemists approach cross-coupling, particularly for constructing C(sp2)–C(sp3) scaffolds. This dissertation describes the development of novel methodologies that form highly unstabilized radical species, including methyl radicals, under Ni/photoredox catalysis.In drug development, the installation of a methyl group is an established strategy for rendering compounds with improved binding affinity, bioavailability, and metabolic stability (the “magic methyl effect”). Chapter 2 describes the development of a methylation reaction of (hetero)aryl and acyl chlorides using trimethyl orthoformate, a common laboratory solvent, as a source of methyl radicals. In this method, photocatalytically generated chlorine radicals undergo hydrogen atom transfer with trimethyl orthoformate, with liberation of high-energy methyl radicals proceeding upon beta-scission of the resulting tertiary radical. The mild nature of this reaction is demonstrated in the methylation of a variety of late-stage and biologically relevant targets. More generally, access to other low molecular weight aliphatic radicals can be enabled by coupling their production with an energetically favorable beta-scission process. Chapter 3 describes a general and broad C(sp2)–C(sp3) coupling of aryl halides and benzaldehyde di(alkyl) acetals. The use of acetals as radical precursors produces (deutero)methyl, primary aliphatic, and secondary aliphatic radicals for cross-coupling upon bromine radical-mediated hydrogen atom transfer and beta-scission. In conducting scope studies, a new tool is reported for the design of diverse and representative substrate scope tables through the integration of data science techniques, including DFT featurization, dimensionality reduction, and hierarchical clustering.