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Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines

[Image: see text] 1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-...

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Autores principales: Wu, Zhi-Chen, Houk, K. N., Boger, Dale L., Svatunek, Dennis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228069/
https://www.ncbi.nlm.nih.gov/pubmed/35666564
http://dx.doi.org/10.1021/jacs.2c03726
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author Wu, Zhi-Chen
Houk, K. N.
Boger, Dale L.
Svatunek, Dennis
author_facet Wu, Zhi-Chen
Houk, K. N.
Boger, Dale L.
Svatunek, Dennis
author_sort Wu, Zhi-Chen
collection PubMed
description [Image: see text] 1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism of the 1,2,3-triazine/1,2,3,5-tetrazine–amidine reaction as well as its intrinsic reactivity remains underexplored. By using (15)N-labeling, kinetic investigations, and kinetic isotope effect studies, complemented by extensive computational investigations, we show that this reaction proceeds through an addition/N(2) elimination/cyclization pathway, rather than the generally expected concerted or stepwise Diels–Alder/retro Diels–Alder sequence. The rate-limiting step in this transformation is the initial nucleophilic attack of an amidine on azine C4, with a subsequent energetically favored N(2) elimination step compared with a disfavored stepwise formation of a Diels–Alder cycloadduct. The proposed reaction mechanism is in agreement with experimental and computational results, which explains the observed reactivity of 1,2,3-triazines and 1,2,3,5-tetrazines with amidines.
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spelling pubmed-92280692022-06-25 Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines Wu, Zhi-Chen Houk, K. N. Boger, Dale L. Svatunek, Dennis J Am Chem Soc [Image: see text] 1,2,3-Triazines and 1,2,3,5-tetrazines react rapidly, efficiently, and selectively with amidines to form pyrimidines/1,3,5-triazines, exhibiting an orthogonal reactivity with 1,2,4,5-tetrazine-based conjugation chemistry. Whereas the mechanism of the reaction of the isomeric 1,2,4-triazines and 1,2,4,5-tetrazines with alkenes is well understood, the mechanism of the 1,2,3-triazine/1,2,3,5-tetrazine–amidine reaction as well as its intrinsic reactivity remains underexplored. By using (15)N-labeling, kinetic investigations, and kinetic isotope effect studies, complemented by extensive computational investigations, we show that this reaction proceeds through an addition/N(2) elimination/cyclization pathway, rather than the generally expected concerted or stepwise Diels–Alder/retro Diels–Alder sequence. The rate-limiting step in this transformation is the initial nucleophilic attack of an amidine on azine C4, with a subsequent energetically favored N(2) elimination step compared with a disfavored stepwise formation of a Diels–Alder cycloadduct. The proposed reaction mechanism is in agreement with experimental and computational results, which explains the observed reactivity of 1,2,3-triazines and 1,2,3,5-tetrazines with amidines. American Chemical Society 2022-06-06 2022-06-22 /pmc/articles/PMC9228069/ /pubmed/35666564 http://dx.doi.org/10.1021/jacs.2c03726 Text en © 2022 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 Wu, Zhi-Chen
Houk, K. N.
Boger, Dale L.
Svatunek, Dennis
Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines
title Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines
title_full Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines
title_fullStr Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines
title_full_unstemmed Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines
title_short Mechanistic Insights into the Reaction of Amidines with 1,2,3-Triazines and 1,2,3,5-Tetrazines
title_sort mechanistic insights into the reaction of amidines with 1,2,3-triazines and 1,2,3,5-tetrazines
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9228069/
https://www.ncbi.nlm.nih.gov/pubmed/35666564
http://dx.doi.org/10.1021/jacs.2c03726
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