Visible light-mediated radical fluoromethylation <i>via</i> halogen atom transfer activation of fluoroiodomethane

Abstract

Incorporation of the fluoromethyl group can profoundly influence the physicochemical properties of organic molecules, offering a promising strategy for the discovery of novel pharmaceutical agents. Direct fluoromethylation of unfunctionalized C(sp²) centres can be achieved using fluoromethyl radicals, but current methods for their generation usually rely on the activation of non-commercial or expensive radical precursors <i>via</i> inefficient single electron transfer pathways, which limits their synthetic application. Here we report the development of a fluoromethylation strategy based on the generation of fluoromethyl radicals from commercially available fluoroiodomethane <i>via</i> halogen atom transfer. This mode of activation is orchestrated by visible light and tris(trimethylsilyl)silane, which serves as both a hydrogen- and halogen atom transfer reagent to facilitate the formation of C(sp³)-CH₂F bonds <i>via</i> a radical chain process. The utility of this metal- and photocatalyst-free transformation is demonstrated through the multicomponent synthesis of complex α-fluoromethyl amines and amino acid derivatives <i>via</i> radical addition to <i>in situ</i>-formed iminium ions, and the construction of β-fluoromethyl esters and amides from electron-deficient alkene acceptors. These complex fluoromethylated products, many of which are inaccessible <i>via</i> previously reported methods, may serve as useful building blocks or fragments in synthetic and medicinal chemistry both in academia and industry.