Issue 38, 2021

Visible light-mediated radical fluoromethylation via 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 via 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 via 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 via 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 via radical addition to in situ-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 via previously reported methods, may serve as useful building blocks or fragments in synthetic and medicinal chemistry both in academia and industry.

Graphical abstract: Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane

Supplementary files

Article information

Article type
Edge Article
Submitted
17 aug 2021
Accepted
30 aug 2021
First published
08 sep 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 12812-12818

Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane

P. J. Deneny, R. Kumar and M. J. Gaunt, Chem. Sci., 2021, 12, 12812 DOI: 10.1039/D1SC04554G

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