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Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow

The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselecti...

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Autores principales: Sanjosé-Orduna, Jesús, Silva, Rodrigo C., Raymenants, Fabian, Reus, Bente, Thaens, Jannik, de Oliveira, Kleber T., Noël, Timothy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629060/
https://www.ncbi.nlm.nih.gov/pubmed/36382292
http://dx.doi.org/10.1039/d2sc04990b
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author Sanjosé-Orduna, Jesús
Silva, Rodrigo C.
Raymenants, Fabian
Reus, Bente
Thaens, Jannik
de Oliveira, Kleber T.
Noël, Timothy
author_facet Sanjosé-Orduna, Jesús
Silva, Rodrigo C.
Raymenants, Fabian
Reus, Bente
Thaens, Jannik
de Oliveira, Kleber T.
Noël, Timothy
author_sort Sanjosé-Orduna, Jesús
collection PubMed
description The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselectivity, safety and/or scalability. Herein, we describe a fast, safe and scalable flow process which allows preparation of said C-4 alkylated pyridines. The process involves a photochemical hydrogen atom transfer (HAT) event to generate the carbon-centered radicals needed to alkylate the C-2 blocked pyridine. In a two-step streamlined flow process, this light-mediated alkylation step is combined with a nearly instantaneous inline removal of the blocking group. Notably, cheap benzophenone plays a dual role in the pyridine alkylation mechanism by activating the hydrocarbon feedstock reagents via a HAT mechanism, and by acting as a benign, terminal oxidant. The key role of benzophenone in the operative reaction mechanism has also been revealed through a combination of experimental and computational studies.
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spelling pubmed-96290602022-11-14 Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow Sanjosé-Orduna, Jesús Silva, Rodrigo C. Raymenants, Fabian Reus, Bente Thaens, Jannik de Oliveira, Kleber T. Noël, Timothy Chem Sci Chemistry The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselectivity, safety and/or scalability. Herein, we describe a fast, safe and scalable flow process which allows preparation of said C-4 alkylated pyridines. The process involves a photochemical hydrogen atom transfer (HAT) event to generate the carbon-centered radicals needed to alkylate the C-2 blocked pyridine. In a two-step streamlined flow process, this light-mediated alkylation step is combined with a nearly instantaneous inline removal of the blocking group. Notably, cheap benzophenone plays a dual role in the pyridine alkylation mechanism by activating the hydrocarbon feedstock reagents via a HAT mechanism, and by acting as a benign, terminal oxidant. The key role of benzophenone in the operative reaction mechanism has also been revealed through a combination of experimental and computational studies. The Royal Society of Chemistry 2022-10-10 /pmc/articles/PMC9629060/ /pubmed/36382292 http://dx.doi.org/10.1039/d2sc04990b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Sanjosé-Orduna, Jesús
Silva, Rodrigo C.
Raymenants, Fabian
Reus, Bente
Thaens, Jannik
de Oliveira, Kleber T.
Noël, Timothy
Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow
title Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow
title_full Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow
title_fullStr Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow
title_full_unstemmed Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow
title_short Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow
title_sort dual role of benzophenone enables a fast and scalable c-4 selective alkylation of pyridines in flow
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629060/
https://www.ncbi.nlm.nih.gov/pubmed/36382292
http://dx.doi.org/10.1039/d2sc04990b
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