Reactions of thiiranes with NH-heterocycles 1. An investigation of the reaction of 2-chloromethylthiirane with 3,5-dibro
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Reactions of thiiranes with NH-heterocycles 1. An investigation of the reaction of 2-chloromethylthiirane with 3,5-dibromo-4-nitropyrazole Ferkat А. Khaliullin1, Elena E. Klen1*, Nadezhda N. Makarova1, Svetlana O. Shepilova1, Irina P. Baikova2 1
Bashkir State Medical University, 3 Lenina St., Ufa 450008, Russia; е-mail: [email protected] 2 Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 71 Oktyabrya Ave., Ufa 450054, Russia; e-mail: [email protected] Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(9), 1213–1217
Submitted March 4, 2020 Accepted March 23, 2020
S KOH, H2O
N N
45–50°C Br 40%
Br NO2
N NH
Cl Br
Br
S
NO2
S
N N
K2CO3 MeCN 50°C 0.24–5.2%
Br
Br NO2
N NH Br
Br NO2 K2CO3
N N
MeCN 33–45% Br
NO2
N N S
Br
Br
NO2
The reaction of 2-chloromethylthiirane with 3,5-dibromo-4-nitropyrazole in H2O and the aprotic solvent MeCN in the presence of bases was investigated. It was found that thiirane-thietane rearrangement occurs in an aqueous medium with the formation of 3,5-dibromo4-nitro-1-(thietan-3-yl)-1H-pyrazole. In MeCN, 3,5-dibromo-4-nitro-1-(thiiran-2-ylmethyl)-1H-pyrazole and the product of its reaction with the starting pyrazole, 6-bromo-2-[(3,5-dibromo-4-nitro-1H-pyrazol-1-yl)methyl]-7-nitro-2,3-dihydropyrazolo[5,1-b]thiazole, are formed, the yields of which depend on the molar ratio of the reactants. Keywords: 2,3-dihydropyrazolo[5,1-b]thiazole, pyrazole, thietane, thiirane, alkylation, thiirane-thietane rearrangement.
Pyrazole belongs to the privileged structures of medicinal chemistry and is used in the targeted design of new drugs1 due to the variety of its chemical properties and diverse pharmacological activity.2–4 Pyrazole-containing drugs exhibit antitumor (crizotinib), anticoagulant (apixaban), anorexigenic (rimonabant), anti-inflammatory (celecoxib, lonazolac), antidepressant (fezolamine), hypoglycemic (teneligliptin), anxiolytic (mepiprazole) activity (Fig. 1). A universal method for the preparation of pyrazole derivatives is alkylation with haloalkanes,5,6 halo ketones,7,8 halogenated carboxylic acids.9,10 Alcohols,11,12 3-iodoazetidine,13 1,3-dehydroadamantane,14 oxiranes15 etc. are 0009-3122/20/56(9)-1213©2020 Springer Science+Business Media, LLC
also used for the synthesis of N-substituted pyrazoles. Reactions of pyrazoles with thiiranes have not yet been studied. This article discusses the reaction of 2-chloromethylthiirane with 3,5-dibromo-4-nitropyrazole. 2-Chloromethylthiirane is a bielectrophilic reagent and can react with nucleophiles both at the carbon–chlorine bond and at the carbon–sulfur bond with the opening of the thiirane ring.16 The structure of the products of its reactions with nucleophiles is influenced by the nature of the nucleophile and the polarity of the solvent.17 Earlier studies18–21 showed that azoles react with 2-chloromethylthiirane in polar aprotic solvents to form N-(thiiran-
1213
Chemistry of Heterocyclic Compounds 2020, 56(9), 1213–1217 OMe H2N
NH
N N O
O
S
Cl
NH
N N N Me N
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