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Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability
[Image: see text] Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on r...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204094/ https://www.ncbi.nlm.nih.gov/pubmed/36868184 http://dx.doi.org/10.1021/acs.joc.3c00083 |
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author | Dubois, Maryne A. J. Rojas, Juan J. Sterling, Alistair J. Broderick, Hannah C. Smith, Milo A. White, Andrew J. P. Miller, Philip W. Choi, Chulho Mousseau, James J. Duarte, Fernanda Bull, James A. |
author_facet | Dubois, Maryne A. J. Rojas, Juan J. Sterling, Alistair J. Broderick, Hannah C. Smith, Milo A. White, Andrew J. P. Miller, Philip W. Choi, Chulho Mousseau, James J. Duarte, Fernanda Bull, James A. |
author_sort | Dubois, Maryne A. J. |
collection | PubMed |
description | [Image: see text] Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible. |
format | Online Article Text |
id | pubmed-10204094 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-102040942023-05-24 Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability Dubois, Maryne A. J. Rojas, Juan J. Sterling, Alistair J. Broderick, Hannah C. Smith, Milo A. White, Andrew J. P. Miller, Philip W. Choi, Chulho Mousseau, James J. Duarte, Fernanda Bull, James A. J Org Chem [Image: see text] Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible. American Chemical Society 2023-03-03 /pmc/articles/PMC10204094/ /pubmed/36868184 http://dx.doi.org/10.1021/acs.joc.3c00083 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Dubois, Maryne A. J. Rojas, Juan J. Sterling, Alistair J. Broderick, Hannah C. Smith, Milo A. White, Andrew J. P. Miller, Philip W. Choi, Chulho Mousseau, James J. Duarte, Fernanda Bull, James A. Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability |
title | Visible Light Photoredox-Catalyzed
Decarboxylative
Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary
Radicals and Implications of Benzylic Radical Stability |
title_full | Visible Light Photoredox-Catalyzed
Decarboxylative
Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary
Radicals and Implications of Benzylic Radical Stability |
title_fullStr | Visible Light Photoredox-Catalyzed
Decarboxylative
Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary
Radicals and Implications of Benzylic Radical Stability |
title_full_unstemmed | Visible Light Photoredox-Catalyzed
Decarboxylative
Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary
Radicals and Implications of Benzylic Radical Stability |
title_short | Visible Light Photoredox-Catalyzed
Decarboxylative
Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary
Radicals and Implications of Benzylic Radical Stability |
title_sort | visible light photoredox-catalyzed
decarboxylative
alkylation of 3-aryl-oxetanes and azetidines via benzylic tertiary
radicals and implications of benzylic radical stability |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204094/ https://www.ncbi.nlm.nih.gov/pubmed/36868184 http://dx.doi.org/10.1021/acs.joc.3c00083 |
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