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

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(sp(2)) centres can be achieved using fluoromethyl radic...

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Autores principales: Deneny, Patrick J., Kumar, Roopender, Gaunt, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494037/
https://www.ncbi.nlm.nih.gov/pubmed/34703568
http://dx.doi.org/10.1039/d1sc04554g
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author Deneny, Patrick J.
Kumar, Roopender
Gaunt, Matthew J.
author_facet Deneny, Patrick J.
Kumar, Roopender
Gaunt, Matthew J.
author_sort Deneny, Patrick J.
collection PubMed
description 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(sp(2)) 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(sp(3))–CH(2)F 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.
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spelling pubmed-84940372021-10-25 Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane Deneny, Patrick J. Kumar, Roopender Gaunt, Matthew J. Chem Sci Chemistry 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(sp(2)) 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(sp(3))–CH(2)F 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. The Royal Society of Chemistry 2021-09-08 /pmc/articles/PMC8494037/ /pubmed/34703568 http://dx.doi.org/10.1039/d1sc04554g Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Deneny, Patrick J.
Kumar, Roopender
Gaunt, Matthew J.
Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
title Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
title_full Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
title_fullStr Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
title_full_unstemmed Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
title_short Visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
title_sort visible light-mediated radical fluoromethylation via halogen atom transfer activation of fluoroiodomethane
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494037/
https://www.ncbi.nlm.nih.gov/pubmed/34703568
http://dx.doi.org/10.1039/d1sc04554g
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