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

Štefan, Leo; Čikoš, Ana; Vianello, Robert; Đilović, Ivica; Matković-Čalogović, Dubravka; Dumić, Miljenko (2021) Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane. Molecules, 26 (22). ISSN 1420-3049

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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 intermediatethiiranium 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 21/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 AgBF4. 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 21/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 21/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.

Item Type: Article
Uncontrolled Keywords: 1, 2-Bis[(1-methyl-1H-imidazole-2-yl)thio]ethane ; methimazole ; 7-methyl-2H, 3H, 7H-imidazo[2, 1-b]thiazol-4-ium salts ; thiiranium ion ; single-crystal X-ray study ; isomerization kinetics ; time-dependent NMR spectroscopy ; computational methods ; bis-{; ; 2-[(chloroethyl)thio]-1-methyl-1H-imidazole}; ; -silver(I)tetrafluoroborate ; 2, 3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
NMR Center
Depositing User: Kristina Ciglar
Date Deposited: 07 Apr 2022 13:33
DOI: 10.3390/molecules26227032

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