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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8625577 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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