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Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational stu...

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Autores principales: Štefan, Leo, Čikoš, Ana, Vianello, Robert, Đilović, Ivica, Matković-Čalogović, Dubravka, Dumić, Miljenko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625577/
https://www.ncbi.nlm.nih.gov/pubmed/34834123
http://dx.doi.org/10.3390/molecules26227032
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author Štefan, Leo
Čikoš, Ana
Vianello, Robert
Đilović, Ivica
Matković-Čalogović, Dubravka
Dumić, Miljenko
author_facet Štefan, Leo
Čikoš, Ana
Vianello, Robert
Đilović, Ivica
Matković-Čalogović, Dubravka
Dumić, Miljenko
author_sort Štefan, Leo
collection PubMed
description Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 2(1)/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF(4). However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6(,) monoclinic, space group P 2(1)/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 2(1)/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.
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spelling pubmed-86255772021-11-27 Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane Štefan, Leo Čikoš, Ana Vianello, Robert Đilović, Ivica Matković-Čalogović, Dubravka Dumić, Miljenko Molecules Article Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 2(1)/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF(4). However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6(,) monoclinic, space group P 2(1)/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 2(1)/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures. MDPI 2021-11-21 /pmc/articles/PMC8625577/ /pubmed/34834123 http://dx.doi.org/10.3390/molecules26227032 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
Štefan, Leo
Čikoš, Ana
Vianello, Robert
Đilović, Ivica
Matković-Čalogović, Dubravka
Dumić, Miljenko
Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane
title Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane
title_full Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane
title_fullStr Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane
title_full_unstemmed Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane
title_short Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane
title_sort chemistry of spontaneous alkylation of methimazole with 1,2-dichloroethane
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625577/
https://www.ncbi.nlm.nih.gov/pubmed/34834123
http://dx.doi.org/10.3390/molecules26227032
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