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Stereoelectronic Features of a Complex Ketene Dimerization Reaction

The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) i...

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Autores principales: Barrows, Robert D., Dresel, Mark J., Emge, Thomas J., Rablen, Paul R., Knapp, Spencer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746406/
https://www.ncbi.nlm.nih.gov/pubmed/35011298
http://dx.doi.org/10.3390/molecules27010066
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author Barrows, Robert D.
Dresel, Mark J.
Emge, Thomas J.
Rablen, Paul R.
Knapp, Spencer
author_facet Barrows, Robert D.
Dresel, Mark J.
Emge, Thomas J.
Rablen, Paul R.
Knapp, Spencer
author_sort Barrows, Robert D.
collection PubMed
description The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.
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spelling pubmed-87464062022-01-11 Stereoelectronic Features of a Complex Ketene Dimerization Reaction Barrows, Robert D. Dresel, Mark J. Emge, Thomas J. Rablen, Paul R. Knapp, Spencer Molecules Article The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed. MDPI 2021-12-23 /pmc/articles/PMC8746406/ /pubmed/35011298 http://dx.doi.org/10.3390/molecules27010066 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barrows, Robert D.
Dresel, Mark J.
Emge, Thomas J.
Rablen, Paul R.
Knapp, Spencer
Stereoelectronic Features of a Complex Ketene Dimerization Reaction
title Stereoelectronic Features of a Complex Ketene Dimerization Reaction
title_full Stereoelectronic Features of a Complex Ketene Dimerization Reaction
title_fullStr Stereoelectronic Features of a Complex Ketene Dimerization Reaction
title_full_unstemmed Stereoelectronic Features of a Complex Ketene Dimerization Reaction
title_short Stereoelectronic Features of a Complex Ketene Dimerization Reaction
title_sort stereoelectronic features of a complex ketene dimerization reaction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746406/
https://www.ncbi.nlm.nih.gov/pubmed/35011298
http://dx.doi.org/10.3390/molecules27010066
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