Russian Chemical Bulletin, International Edition, Vol. 66, No. 3, pp. 506—510, March, 2017 506 Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0506—0510, March, 2017. 1066-5285/17/6603-0506 © 2017 Springer Science+Business Media, Inc. Synthesis 5-(pyrazolin-3-ylmethylidene)-2-thiohydantoins and 2-alkylsulfanyl-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro- 4H-imidazol-4-ones N. I. Vorozhtsov, a L. A. Sviridova, a O. S. Grigorkevich, a D. D. Korablina, b E. K. Beloglazkina, a A. G. Majouga, a and N. V. Zyk a a M. V. Lomonosov Moscow State University, Department of Chemistry, Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation. E-mail: bel@org.chem.msu.ru b M. V. Lomonosov Moscow State University, Department of Fundamental Medicine, Build. 1, 27 Lomonosovsky prosp., 119991 Moscow, Russian Federation A reaction of 3-allyl- and 3-phenylthiohydantoins with 1,5-diphenyl- and 1-phenyl-substi- tuted 3-formyl-2-pyrazolines was used to obtain a series of 5-(pyrazolin-3-ylmethylidene)-2- thioxotetrahydro-4H-imidazol-4-ones, the subsequent alkylation of which with methyl iodide or ethyl chloroacetate gave the corresponding 2-alkylthio-5-(pyrazolin-3-ylmethylidene)-3,5- dihydro-4H-imidazol-4-ones in the yields from 30 to 77%. The oxidation of (5Z)-3-phenyl-5- [(1,5-diphenylpyrazolin-3-yl)methylidene]-2-methylsulfanyl-4,5-dihydroimidazol-4-one with lead tetraacetate led to the corresponding pyrazole in 48% yield. Key words: thiohydantoins, 2-alkylthioimidazol-4-ones, pyrazolines, pyrazoles. 2-Thioxotetrahydro-4H-imidazol-4-ones (thiohydan- toins) and their derivatives attract attention of researchers already during more than a hundred of years, 1,2 which is explained by their biphilic reactivity and a wide range of pharmacological activity: anticonvulsant, antibacterial, antiviral, antihypertensive, antidiabetic. 3—7 Starting from 1950 (see Ref. 8) and to the present time, 7—11 the reac- tions leading to the preparation of thiohydantoin cycles are widely used for analytical purposes in determination of polypeptide structures by Edman degradation. Complexes based on 2-thiohydantoins and their derivatives with tran- sition metals can serve as efficient models of the active centers of some metalloenzymes 12 and act as the catalysts of redox reactions, for example, the epoxidation reac- tion 13—18 and reduction of nitrite anion. 19 In continuation of our studies of 5-hetarylmethylidene- substituted 2-thioxoimidazol-4-ones and their S-alkylated derivatives, 12—32 in the present work we used 3-allyl- and 3-phenyl-2-thiohydantoins 1a,b and 3-formyl-4,5-di- hydro-1H-pyrazoles (3-formyl-2-pyrazolines) 2a,b in a two- step sequence of reactions with the intermediate forma- tion of 5-(pyrazolin-3-ylmethylidene)-2-thioxotetrahy- dro-4H-imidazol-4-ones 3a—d to synthesize new organic ligand of the series of 5-hetaryl-substituted 2-alkylthiodi- hydroimidazolones, namely, 2-alkylthio-5-(pyrazolin-3- ylmethylidene)-3,5-dihydro-4H-imidazol-4-ones 4 and 5. The starting formyl-2-pyrazolines 2a,b were synthe- sized according to a modified procedure (see Experimen- tal section) by the addition of the corresponding pyrazo- line to a cooled solution of the Vilsmeier reagent. This procedure allowed us to avoid side reactions of the pyrazo- line ring opening and the formylation of the benzene ring and to obtain reproducible yields of target aldehydes. Note that though compounds 2a,b were described earlier, we for the first time characterized them by 1 H NMR spectro- scopy data. Thus, the 1 H NMR spectrum of compound 2a exhibits characteristic multiplets for the protons HC(4) of the pyrazoline ring in the region of δ 3.02—3.05 and 3.64—3.66, a multiplet for the pyrazoline proton HC(5) at δ 5.50—5.52, as well as multiplets for the aromatic pro- tons at δ 6.96—7.85 and a singlet at δ 9.89 corresponding to the proton of the aldehyde group. The literature describes two methods for the prepara- tion of 5-arylidene-substituted thiohydantoins from the corresponding 5-unsubstituted 2-thioxotetrahydro-4H- imidazol-4-ones: the condensation of 2-thiohydantoin and an aldehyde in the presence of an equimolar amount of anhydrous sodium acetate in acetic acid 33 and a simi- lar condensation in the alcoholic solution of KOH. 34 In the case of 3-allylthiohydantoin 1a, acetic acid was shown to be the optimal for carrying out the reaction (Scheme 1). In the case of the condensation of 3-phenyl- thiohydantoin 1b with pyrazolines 2a and 2b, the prepara- tive yields of the products were obtained when the con- densation was carried out in 2% ethanolic solution of KOH (Scheme 1).