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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
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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. |
format | Online Article Text |
id | pubmed-8494037 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
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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