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Int. J. Mol. Sci. 2013, 14(6), 12484-12495; doi:10.3390/ijms140612484

Facile Synthesis of 5-Arylidene Thiohydantoin by Sequential Sulfonylation/Desulfination Reaction
Jintao Han 1, Hongbo Dong 1, Zhihong Xu 1,2, Jianping Lei 1 and Mingan Wang 1,*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
College of Agriculture, Yangtze University, Jingzhou 434025, Hubei, China
Author to whom correspondence should be addressed; Tel.: +86-10-6273-4093.
Received: 6 May 2013; in revised form: 28 May 2013 / Accepted: 29 May 2013 / Published: 13 June 2013


: The sequential sulfonylation/desulfination reactions of 5-benzylthiohydantoin with excess arylsulfonyl chlorides in the presence of triethylamine have been developed to afford a wide range of 5-arylidene thiohydantoin derivatives in moderate to excellent yields. A plausible sulfonylation/desulfination mechanism was proposed. The bioassay showed that these compounds exhibit certain fungicidal activities with the 71.9% inhibition rate of 2K against B. cinerea, and 57.6% inhibition rate of 2m against A. solani, respectively.
5-arylidene thiohydantoin; sulfonylation; desulfination; arylsulfonyl chloride

1. Introduction

5-Arylidene hydantoins and thiohydantoins are key structural motifs of numerous natural and unnatural products that display a wide range of biological activity. Among them, hydantoin A has exhibited comparable anticonvulsant activity to phenytoin [1], B showed antimycobacterial activity against Mycobacterium tuberculosis with IC50 of 4.5 μg/mL [2], and C and D exhibited fungicidal activity with 95%–100% inhibition against Erysiphe graminis, Uromyceis appendiculatus, and Botrytis cinerea [3], E had been investigated as antitumor agent (Scheme 1). In addition, these 5-arylidene derivatives are very useful building blocks for the synthesis of various heterocycles such as 5-arylidene derivatives of imidazoline-4-one, imidazothiazine, diazinone, and diazepinone [48]. In 5-arylidene hydantoins and thiohydantoins, the arylidene carbon-carbon double bond at 5-position are as important as hydantoin or thiohydantoin moiety to the biological effect [13]. Therefore, there has been great demand for highly efficient synthetic methods for the introduction of arylidene carbon-carbon double bond at the 5-position of the hydantoin or thiohydantoin ring [1,2]. So far, several typical synthetic strategies of 5-arylidene derivatives of hydantoin and thiohydantoin have been reported, including a traditional base-catalyzed aldol condensation of hydantoin and thiohydantoin with substituted benzaldehydes [1,3,5,6,9], improved aldol condensation such as one-pot multicomponent reaction of substituted benzaldehydes, glycine and potassium thiocyanate [10], microwave-assisted condensation of thiohydantoin/hydantoin with substituted benzaldehyde Schiff bases [11], Wittig-Horner Reaction [1214], and Mn-catalyzed reactions of terminal alkynes with isocyanates [15]. Herein, we report a new protocol via sequential sulfonylation/desulfination to construct the 5-arylidene thiohydantoin.

2. Results and Discussion

In our laboratory, we needed to prepare 5-aryl derivatives of hydantoin and thiohydantoin as the key intermediate to develop the novel inhibitor of Adenylosuccinate Synthetase (AdSS) [1618], which plays a key role in the two-step conversion of IMP to AMP in the de novo pathway of purine biosynthesis [1921]. In order to prepare 5-aryl derivatives of thiohydantoin, 5-(4-hydroxylbenzyl)-thiohydantoin was treated with phenylsulfonyl chloride in acetone at 30 °C in the presence of one equivalent of triethyl amine (entry 1, Table 1). The target product 3a was obtained in 84% yield. In addition, unexpectedly, a new product 2a was isolated in 15% yield. We established the structure of the new product 2a to be that from sequential sulfonylation/desulfination at the 5-position of thiohydantoin, using NMR spectroscopy and X-ray crystallography of the homologous 2k obtained from the reaction of 1 with the p-tert-butyl-phenylsulfonyl chloride 4k (Figure 1, see more in supplementary Figures S1 and S2, Tables S1–S3), and natural occurring compound 5-(4-hydroxy phenylidene)-2-thiohydantoin [22]. The reaction provided the trisubstituted exocyclic alkylidene as a single Z isomer [23]. Next, we examined the sulfonylation/desulfination reaction in detail. Table 1 presents the results of screening for appropriate reaction conditions for the model reaction between 1 and phenylsulfonyl chloride 4a. When the amount of phenylsulfonyl chloride was increased to 1.2, 1.5, 2 and 3 equation, the corresponding product 2a was obtained in 29%, 69% and 81%, 80% yields, respectively (entries 2–5, Table 1). Therefore, the best quantity of phenylsulfonyl chloride was 2 equivalents for this reaction. When the reaction times were shortened, the yields decreased from 81% to 38% (entry 4,6,7,8, Table 1). As the temperature was decreased to 0 °C, the yield decreased to 53%, while as the temperature was increased to 60 °C, the yield was kept 81% (entry 9,10, Table 1). When the reaction solvents and the bases were canged, the yields decreased greatly (entry 11–15, Table 1). If we added 3–5 equivalents of Et3N, the yields also decreased (entry 16–18, Table 1). The following reactions were then performed for 8h in 1:2:2 ratios for 5-(4-hydroxylbenzyl)-thiohydantoin, phenylsulfonyl chloride and Et3N in acetone solution at 30 °C.

Under the optimized reaction conditions, we examined a range of arylsulfonyl chlorides in the sequential sulfonylation/desulfination of 5-(4-hydroxybenzyl)-2-thioxoimidazolidin-4-one (1). As shown in Table 2, a variety of arylsulfonyl chlorides underwent the sulfonylation/desulfination at the 5-position of thiohydantoin, providing the anticipated 5-arylidene thiohydantoin 2 in moderate to excellent yields (entries 1–14, Table 2). Arylsulfonyl chlorides featuring phenyl groups with either electron-withdrawing or -donating substituents worked well as substrates under the given conditions.

Considering that the sulfonyl is a strong electron-withdrawing group, we assumed that 5-aryl-2-thioxoimidazolidin-4-ones having another electron-withdrawing group on the benzene ring will also work. As indicated in Table 3, 5-benzylthiohydantoins were synthesized and treated with phenylsulfonyl chloride under the optimized conditions. We were pleased to observe that the anticipated products 5-phenylidene-thiohydantoin were obtained in 38%–86% yields (entries 1–9, Table 3). In a sharp contrast with these substrates, 5-(4-aminobenzyl)-thiohydantoin having a strong electron-donating NH2 group on the benzene ring did not carry out the reaction (entries 10, Table 3). In addition, the reaction of 5-aryl derivatives of hydantoin 3a had been explored to give 2a in 91% yield under the given conditions with one equivalent molar of phenylsulfonyl chloride (4a). Interestingly, 5-benzylthiohydantoins undertook a similar reaction using phenylsulfonyl chloride and N,N-diisopropylethylamine (DIPEA) without changing the other reaction conditions (entries 11–13, Table 3). It should be stated that all of the prepared compounds 2 and 6 exhibit similar Z selectivity based on the 1H NMR analysis of significant methine proton chemical shifts (Figure S1) and comparison with the data in the references [16].

Based on the above results, we proposed a sequential proton leaving-phenylsulfone formation-phenylsulfinic acid elimination mechanism for the reaction (Figure 2). After the sulfonylation of the starting material 1, the acidity of proton at the 5-postion of thiohydantoin was enhanced. Consequent deprotonation in the presence of base afforded the carbon anion, which was captured by phenylsulfonyl chloride to give intermediate II. Then, the sulfone intermediate II lost one molar of phenylsulfinic acid to give 5-arylidene thiohydantoin. This mechanism was very similar to Ei elimination observed by Jenks in the sulfone chemistry, in which sulfone groups act simultaneously as base and leaving group [25,26], an enone and conjugated olefin preparation via phenylsulfinic acid elimination of β-sulfone developed by Trost and Procopiou groups [2729], and thermal decomposition pathway for polysulfones found by Wudl [30].

The data in Table 4 showed that these compounds exhibit certain inhibition rates against Botrytis cinerea, Alternaria solani, Fusarium oxysporum and Dothiorella gregaria at the concentration of 100 μg/mL. In general, the fungicidal activities against B. cinerea and A. solani were better than that of against F. oxysporum and D. gregaria. The inhibition rate of 2k against B. cinerea was 71.9%, and the inhibition rate of 2m against A. solani was 57.6%, respectively. They are much better than that of carbendazim (the positive control) against B. cinerea and A. solani.

3. Experimental Section

3.1. General Information

All reactions were performed under an air atmosphere with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Flash column chromatography was performed using Qingdao Haiyang flash silica gel (200–300 mesh). Meting points were measured on a Yanagimoto apparatus and uncorrected. Infrared spectra were recorded using a Shimadzu IR-435 instrument with KBr plates. 1H and 13C NMR spectra were obtained on Bruker DPX 300 spectrometer with DMSO-d6 as a solvent and TMS as an internal standard. Elemental analysis was performed on a Vario EL instrument (Elementar Vario Micro Cube, Hanau, Germany). X-ray crystallographic data were collected using a Bruker SMART CCD-based diffractometer operated at 293 K. Crystallographic for compound 2K have been deposited at the Cambridge Crystallographic data center, CCDC No. 831811. Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CB2, 1EZ, UK.

3.2. Synthesis

3.2.1. The Synthesis of 5-(4-Hydroxybenzyl)-Thiohydantoin (1)

A 1:3 mixture of tyrosine (5.4 g, 30 mmol) and thiourea (6.9 g, 90 mmol) was placed in a flask and heated under stirring. Control the oil bath temperature to 180–190 °C, about 5 min later the homogenous liquid started to fume. After 15 min, the reaction was completed as monitored by TLC. The flask was allowed to cool down and 20 mL water was added while the flask was still warm. The solution was reheated to dissolve all the solids and allowed to cool to room temperature, then placed in a refrigerator for 4 h. The crystal of compound 1 was removed by vacuum filtration, and the mother liquid was extracted with ethyl acetate and further purified by flash column chromatography. Finally, 5.3 g yellow product was obtained. Yield: 83%. m.p. 208–209 °C (Literature: 211 °C [32]).1H NMR (DMSO-d6, 300 MHz) δ: 11.39 (s, 1H), 10.04 (s, 1H), 9.25 (s, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 4.45 (dd, J = 4.8, 3.9 Hz, 1H), 2.85 (d, J = 4.8 Hz, 2H).

3.2.2. General Procedure for the Synthesis of Compounds 2 and 6

To a stirred solution of 5-(4-hydroxybenzyl)-2-thiohydantoin or 5-substitutedbenzyl-2-thiohydantoin (2 mmol) and Et3N or DIPEA(4 mmol) in acetone (15 mL), substituted phenylsulfonyl chloride (2–6 mmol) was added dropwise at 0 °C, then the temperature was allowed to 0, 30, 60 °C. The reaction was monitored by TLC. After 2–8 h, stop the reaction, and filtered. The products were purified by column chromatography on silica gel (petrolem ether-EtOAc, 1.5:1) to give the product 2 and 6. The 1H and 13C NMR spectra for new compounds could be found in supplementary Figure S1.

5-(Phenylsulfonyloxy) phenylidene thiohydantoin 2a, yellow solid, m.p. 199–200 °C. 1H NMR (DMSO-d6, 300 MHz) δ: 12.42 (s, 1H), 12.17 (s, 1H), 7.91–7.04 (m, 9H), 6.45 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.62, 165.78, 149.08, 135.26, 134.44, 131.83, 129.96, 128.47, 128.33, 122.41, 109.68; IR (KBr) ν: 3470, 3329, 1780, 1725, 1649 cm−1. Anal calcd for C16H12N2O4S2: C 53.32, H 3.36, N 7.77; Found: C 53.26, H 3.19, N 7.72.

5-(Phenylsulfonyloxy) benzyl thiohydantoin 3a, white solid, m.p. 158–160 °C. 1H NMR (DMSO-d6, 300 MHz) δ: 11.51 (s, 1H), 10.05 (s, 1H), 7.84–7.64 (m, 5H), 7.17–7.14 (m, 2H), 6.93–6.88 (m, 2H), 4.54 (dd, J = 4.4, 5.3 Hz, 1H), 2.96 (d, J = 5.3 Hz, 1H). IR (KBr) ν: 3123, 2869, 1746, 1544, 1502, 1377, 1177, 1154, 1090, 823 cm−1.

5-(4-Flurophenylsulfonyloxy) phenylidene thiohydantoin 2b, yellow solid, m.p. 227–228 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.41 (s, 1H), 12.15 (s, 1H), 7.99–7.06 (m, 8H), 6.45 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ:179.69, 165.86, 165.84 (JCF = 254.9 Hz), 149.01, 131.98, 131.92 (JCF = 13.0 Hz), 131.74, 130.69, 128.61, 122.53, 117.41 (JCF = 23.1 Hz), 109.69; IR (KBr) ν: 3465, 3262, 1780, 1730, 1653cm−1. Anal calcd for C16H11FN2O4S2: C 50.79, H 2.93, N 7.40; Found: C 50.79, H 2.76, N 7.28.

5-(4-Chlorophenylsulfonyloxy) phenylidene thiohydantoin 2c, yellow solid, m.p.206–208 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.43 (s, 1H), 12.18 (s, 1H), 7.93–7.08 (m, 8H), 6.45 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.65, 165.76, 148.93, 140.34, 133.19, 131.98, 131.91, 130.30, 130.19, 128.55, 122.47, 109.62; IR (KBr) ν: 3448, 3179, 1776, 1733, 1648 cm−1; Anal calcd for C16H11ClN2O4S2: C 48.67, H 7.09, N 2.81; Found: C 48.58, H 7.06, N 2.53.

5-(4-Chlorophenylsulfonyloxy) benzyl thiohydantoin 3c, white solid, m.p. 168–170 °C. 1H NMR (DMSO-d6, 300 MHz) δ: 11.52 (s, 1H), 10.04 (s, 1H), 7.79–7.72 (m, 4H), 7.20–7.16 (m, 2H), 6.96–6.92 (m, 2H), 4.55 (dd, J = 4.4, 5.3 Hz, 1H), 2.97 (d, J =5.0 Hz, 1H). IR (KBr) ν: 3212, 2881, 1743, 1548, 1504, 1477, 1379, 1154, 1094, 825 cm−1.

5-(4-Methoxyphenylsulfonyloxy) phenylidene thiohydantoin 2d, yellow solid, m.p. 208–210 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.41 (s, 1H), 12.16 (s, 1H), 7.82–7.03 (m, 8H), 6.45 (s, 1H), 3.87 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.67, 165.87, 164.32, 149.30, 131.87, 131.73, 130.86, 128.50, 125.66, 115.23, 115.23, 109.87, 56.16; IR (KBr) ν: 3420, 3257, 1768, 1652 cm−1; Anal calcd for C17H14N2O5S2: C 52.30, H 3.61, N 7.17; Found: C 52.16, H 3.40, N 7.18.

5-(4-Methoxyphenylsulfonyloxy) benzyl thiohydantoin 3d, white solid, m.p. 181–183 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 11.50 (s, 1H), 10.04 (s, 1H), 7.70–7.65 (m, 2H), 7.17–7.13 (m, 4H), 6.91–6.88 (m, 2H), 4.54 (dd, J = 4.4, 5.3 Hz, 1H), 3.87 (s, 3H), 2.96 (d, 1H, J = 5.0 Hz). IR (KBr) ν: 3150, 3024, 2928, 1742, 1592, 1502, 1372, 1268, 1151, 1092, 862, 844 cm−1.

5-(4-Methylphenylsulfonyloxy) phenylidene thiohydantoin 2e, yellow solid, m.p. 184–185 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.42 (s, 1H), 12.17 (s, 1H), 7.78–7.04 (m, 8H), 6.45 (s, 1H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.62, 165.78, 149.17, 146.06, 131.83, 131.73, 131.57, 130.42, 128.45, 128.36, 122.41, 109.74, 21.31; IR (KBr) ν: 3472, 3387, 1785, 1730, 1649 cm−1; Anal calcd for C17H14N2O4S2: C 54.53, H 3.77, N 7.48; Found: C 54.46, H 3.87, N 7.52.

5-(4-Nitrophenylsulfonyloxy) phenylidene thiohydantoin 2f, yellow solid, m.p. 258–260 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.43 (s, 1H), 12.18 (s, 1H), 8.48–7.11 (m, 8H), 6.45 (s,1H); 13C NMR (DMSO-d6, 75 MHz) δ:179.68, 165.77, 151.25, 148.76, 139.63, 132.22, 132.01, 130.19, 128.66, 125.19, 122.46, 109.53; IR (KBr) ν: 3468, 3284, 1775, 1736, 1651 cm−1; Anal calcd for C16H11N3O6S2: C 47.70, H 2.73, N 10.36; Found: C 47.70, H 2.59, N 10.23.

5-(4-Bromophenylsulfonyloxy) phenylidene thiohydantoin 2g, yellow solid, m.p. 230–232 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.43 (s, 1H), 12.19 (s, 1H), 7.93–7.90 (d, J = 8.8 Hz, 2H), 7.83–7.80 (d, J = 8.8 Hz, 2H), 7.77–7.74 (d, J = 8.7 Hz, 2H), 7.10–7.07 (d, J = 8.7 Hz, 2H), 6.46(s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.68, 165.82, 148.96, 133.63, 133.18, 132.03, 131.96, 130.33, 129.56, 128.58, 122.52, 109.68; IR (KBr) ν: 3414, 3246, 3181, 1734, 1650 cm−1; Anal calcd for C16H11BrN2O4S2: C 43.74, H 2.52, N 6.38; Found: C 43.76, H 2.57, N 6.40.

5-(2-Methylphenylsulfonyloxy) phenylidene thiohydantoin 2h, yellow solid, m.p. 160–162 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.42 (s, 1H), 12.16 (s, 1H), 7.79–7.69 (m, 5H), 7.46–7.02 (m, 3H), 6.46 (s, 1H); 2.72 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.63, 165.80, 149.05, 138.34, 135.24, 133.23, 131.89, 131.79, 130.44, 130.24, 128.47, 127.04, 122.16, 109.69, 19.99; IR (KBr) ν: 3382, 3155, 1760, 1606 cm−1; Anal calcd for C17H14N2O4S2: C 54.53, H 3.77, N 7.48; Found: C 54.48, H 3.68, N 7.38.

5-(3-Trifluromethylphenylsulfonyloxy) phenylidene thiohydantoin 2i, yellow solid, m.p. 196–198 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.44 (s, 1H), 12.18 (s, 1H), 8.28–8.16 (m, 3H), 7.98–7.95 (d, J = 7.9 Hz, 1H), 7.78–7.75 (d, J = 8.7 Hz, 2H), 7.73–7.11 (d, J = 8.7 Hz, 2H), 6.46 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.68, 165.80, 148.79, 135.58, 132.58, 132.15, 131.96, 131.77, 128.61, 124.97, 122.52, 109.56; Anal calcd for C17H11F3N2O4S2: C 43.74, H 2.52, N 6.38; Found: C 43.76, H 2.57, N 6.40.

5-(4-Iodophenylsulfonyloxy) phenylidene thiohydantoin 2j, yellow solid, m.p. 210–212 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.43 (s, 1H), 12.18 (s,1H), 8.10–8.07 (d, J = 8.9 Hz, 2H), 7.77–7.74 (d, J = 8.8 Hz, 2H), 7.64–7.61 (d, J = 8.7 Hz, 2H), 7.10–7.07 (d, J = 8.7 Hz, 2H), 6.46 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.65, 165.80, 148.96, 138.95, 133.97, 131.97, 131.93, 129.97, 128.55, 122.47, 109.68, 104.41; IR (KBr) ν: Anal calcd forC16H11IN2O4S2: C 39.52, H 2.28, N 5.76; Found: C 39.73, H 2.49, N 5.76.

5-(4-tert-Butylphenylsulfonyloxy) phenylidene thiohydantoin 2k, yellow solid, m.p. 210–212 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.42 (s, 1H), 12.17 (s,1H), 7.85–7.82 (d, J = 8.8 Hz, 2H), 7.77–7.70 (m, 4H), 7.10–7.07 (d, J = 8.9 Hz, 2H), 6.46 (s, 1H), 1.32 (s, 9H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.62, 165.80, 158.53, 149.16, 131.87, 131.82, 131.73, 128.46, 128.21, 126.85, 122.35, 109.76, 35.29, 30.78; IR (KBr) ν: Anal calcd for C20H20N2O4S2: C 57.67, H 4.84, N 6.73; Found: C 57.56, H 4.92, N 6.73.

5-(4-tert-Butylphenylsulfonyloxy) benzyl thiohydantoin 3k, white solid, m.p. 161–163 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 11.50 (s, 1H), 10.04 (s, 1H), 7.74–7.67 (m, 4H), 7.19–7.15 (m, 2H), 6.95–6.90 (m, 2H), 4.55 (dd, J = 4.4, 5.3 Hz, 1H), 2.96 (d, J = 5.3 Hz, 1H), 1.32 (s, 9H). IR (KBr) ν: 3167, 3042, 2962, 1740, 1596, 1547, 1403, 1373, 1184, 1089, 889, 825 cm−1.

5-(4-Acetylaminophenylsulfonyloxy) phenylidene thiohydantoin 2l, yellow solid, m.p. 262–264 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.41 (s, 1H), 12.17 (s, 1H), 10.50 (s, 1H), 7.86–7.72 (m, 6H), 7.04–7.01 (d, J = 8.8 Hz, 2H), 6.44 (s, 1H), 2.11 (3H, s); 13C NMR (DMSO-d6, 75 MHz) δ: 179.61, 169.49, 165.79, 149.20, 145.15, 131.81, 131.69, 129.86, 128.42, 127.30, 122.50, 118.86, 109.77, 24.34; IR (KBr) ν: Anal calcd for C18H15N3O5S2: C 51.79, H 3.62, N 10.07; Found: C 51.80, H 3.76, N 9.97.

5-(2,5-Dichlorophenylsulfonyloxy) phenylidene thiohydantoin 2m, yellow solid, m.p. 226–228 °C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.44 (s, 1H), 12.19 (s, 1H), 7.95–7.92 (m, 3H), 7.79–7.75 (d, J = 8.9 Hz, 2H), 7.18–7.15 (d, J = 8.9 Hz, 2H), 6.46 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.70, 165.79, 148.68, 136.61, 134.51, 133.93, 132.31, 132.41, 130.89, 128.73, 122.05, 109.52; IR (KBr) ν: Anal calcd for C16H10Cl2N2O4S2: C 44.76, H 2.35, N 6.53; Found: C 44.82, H 2.57, N 6.42.

5-(3,4-Dichlorophenylsulfonyloxy) phenylidene thiohydantoin 2n, yellow solid, m.p. 220–222°C, 1H NMR (DMSO-d6, 300 MHz) δ: 12.42 (s, 1H), 12.15 (s, 1H), 8.19 (s, 1H), 7.98–7.95 (d, J = 8.5 Hz, 1H), 7.85–7.77 (m, 3H), 7.17–7.14 (d, J = 8.9 Hz, 2H), 6.47 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) δ: 179.68, 165.80, 148.81, 138.68, 134.51, 133.14, 132.29, 131.98, 129.98, 128.67, 128.48, 122.54, 109.58; IR (KBr) ν: Anal calcd for C16H10Cl2N2O4S2: C 44.76, H 2.35, N 6.53; Found: C 45.01, H 2.60, N 6.52.

3.3. Bioassay of Fungicidal Activity

Fungicidal activities of compounds 2 against B. cinerea, A.solani, F. oxysporurm, and D. gregaria were evaluated using the mycelium growth rate test [33]. The culture media with known concentration of the test compounds were obtained by mixing the solution of 2 in acetone with potato dextrose agar (PDA), on which fungus cakes were placed. The blank test was made using acetone and carbendazin was used as positive control. The culture was incubated at 25 ± 0.5 °C. Three replicates were performed. After the mycelium in the blank grew completely, the diameter of the mycelium was measured and the inhibition rate calculated according to the formula in reference [33]. In which I is the inhibition rate, P0 is the average diameter of the mycelium in the blank, and P1 is the average diameter of the mycelium in the presence of the test samples. Mean measurements were calculated from the three replicates.

4. Conclusions

In conclusion, we have investigated the sequential sulfonylation/desulfination reaction of 5-(4-hydroxylbenzyl)-thiohydantoin with excess arylsulfonyl chloride in the presence of triethylamine. These reactions are operationally simple and proceed smoothly under very mild reaction conditions, providing a broad range of 5-arylidene thiohydantoin derivatives in moderate to excellent yields. The further applications of the reaction in the synthesis of biologically relevant molecules are ongoing in our laboratory. The bioassay showed that these compounds exhibit certain fungicidal activities with the 71.9% inhibition rate of 2K against B. cinerea, and 57.6% inhibition rate of 2m against A. solani, respectively.

Supplementary Information



This project was founded by National Natural Science Foundation of China (Nos. 21172254 and 20772150), the 12th Five-year National Key Technologies R&D Program of China (No. 2011BAE06B03) and National Key Laboratory of Elemento-Organic Chemistry in Nankai University (201003).

Conflict of Interest

The authors declare no conflict of interest.

References and Notes

  1. Thenmozhiyal, J.C.; Wong, P.T.-H.; Chui, W.K. Anticonvulsant activity of phenylmethylene-hydantoins: A structure-activity relationship study. J. Med. Chem 2004, 47, 1527–1535. [Google Scholar]
  2. Kiec-Kononowicz, K.; Szymanska, E. Antimycobacterial activity of 5-arylidene derivatives of hydantoin. II Farmaco 2002, 57, 909–916. [Google Scholar]
  3. Marton, J.; Enisz, J.; Hosztafi, S.; Timar, T. Preparation and fungicidal activity of 5-substituted hydantoins and their 2-thio analogs. J. Agric. Food Chem 1993, 41, 148–152. [Google Scholar]
  4. Kiec-Kononowicz, K.; Karolak-Wojicechowska, J.; Muller, C.E.; Schumacher, B.; Pekela, E.; Szymanska, E. Imidazo-thiazine, -diazinone and -diazepinone derivatives. Synthesis, structure and benzodiazepine receptor binding. Eur. J. Med. Chem 2001, 36, 407–419. [Google Scholar]
  5. Szymanska, E.; Kiec-Kononowicz, K.; Bialecka, E.; Kasprowicz, A. Antimicrobial activity of 5-arylidene aromatic derivatives of hydantoin. II Farmaco 2002, 57, 39–44. [Google Scholar]
  6. Szymanska, E.; Kiec-Kononowicz, K. Antimycobacterial activity of 5-arylidene aromatic derivatives of hydantoin. II Farmaco 2002, 57, 355–362. [Google Scholar]
  7. Kumar, R.; Chauhan, P.M.S. A one-pot chemoselective S-alkylation and acetylation of thiohydantoins using the alkyl orthoformate-ZnCl2-Ac2O reagent system. Tetrahedron Lett 2008, 49, 5475–5479. [Google Scholar]
  8. Bourahla, K.; Paquin, L.; Lozach, O.; Meijer, L.; Carreaux, F.; Bazureau, J.P. A practical approach to new (5Z) 2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one derivatives. Molecules 2011, 16, 7377–7390. [Google Scholar]
  9. Shalaby, A.F.A.; Daboun, H.A.; Moghdadi, S.S.M. Reactions with 1-phenyl-4-thiohydantoin. Preparation of 5-arylazo-1-phenyl-4-thiohydantoin, their reactions towards alkylating agents and Mannich reaction. Z. Naturforsch 1976, B31, 865–869. [Google Scholar]
  10. Porwal, S.; Kumar, R.; Maulik, P.R.; Chauhan, P.M.S. A multicomponent reaction efficiently producing arylmethylene 2-thiohydantoins. Tetrahedron Lett 2006, 47, 5863–5866. [Google Scholar]
  11. Tripathy, P.K. Microwave assisted rapid condensation of 2-thiohydantoin/hydantoin with Schiff bases. Asian J. Chem 2005, 17, 1207–1210. [Google Scholar]
  12. Meanwell, N.A.; Herbert, R.R.; Edward, C.R. 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-onesinhibitors of blood platelet cAMP phosphodiesterase and induced aggregation. J. Med. Chem 1991, 34, 2906–2916. [Google Scholar]
  13. Zhu, Z.J.; Lippa, B.S.; Townsend, L.B. A novel photo-assisted annulation reaction for the synthesis of 6,7-dichloroimidazo[4,5-b]quinolin-2-one. Tetrahedron Lett 1996, 37, 1937–1940. [Google Scholar]
  14. Pedro, M.; Alberto, T.; David, C. Synthesis of imidazo[1,5-c][1,3]benzodiazepines via an aza-Wittig/carbodiimide-mediated annulation process. Tetrahedron 1997, 53, 15895–15902. [Google Scholar]
  15. Kuninobu, Y.; Kikuchi, K.; Takai, K. Manganese-catalyzed synthesis of hydantoin derivatives from terminal alkynes and isocyanates. Chem. Lett 2008, 37, 740–741. [Google Scholar]
  16. Han, J.T.; Wang, J.M.; Dong, H.B.; Xu, Z.H.; Liu, B.; Wang, M.A. Synthesis and biological activity of novel phosphoramidate with hydantoin. Chin. J. Org. Chem 2013, 33, 596–601. [Google Scholar]
  17. Xu, Z.H.; Wang, J.M.; Han, J.T.; Liu, B.; Wang, M.A. Synthesis and biological activity of novel (thio)phosphates with hydantoin. Chin. J. Org. Chem 2012, 32, 2134–2140. [Google Scholar]
  18. Han, J.T.; Wang, J.M.; Dong, H.B.; Lei, J.P.; Wang, M.A.; Fang, J.X. Synthesis and herbicidal activity of 5-(4-hydroxybenzyl)-2-thioxoimidazolidin-4-one esters. Molecules 2011, 16, 2833–2845. [Google Scholar]
  19. Walters, E.W.; Lee, S.F.; Niderman, T.; Bemasconi, P.; Subramanian, M.V.; Siehl, D.L. Adenylosuccinate synthetase from maize. Purification, properties, and mechanism of inhibition by 5′-phosphohydantocidin. Plant Physiol 1997, 114, 549–555. [Google Scholar]
  20. Cseke, C.; Gerwick, B.C.; Crouse, G.D.; Murdoch, M.G.; Green, S.B.; Heim, D.R. 2-Phosphohydantocidin: The in vivo adenylosuccinate synthetase inhibitor responsible for hydantocidin phytotoxicity. Pestic. Biochem. Physiol 1996, 55, 210–217. [Google Scholar]
  21. Fonne-Pfister, R.; Chemla, P.; Ward, E.; Girardet, M.; Kreuz, K.E.; Hinzatko, R.B.; Fromm, H.; Schar, H.P.; Grutter, M.G.; Cowan-Jacob, S.W. The mode of action and the structure of a herbicide in complex with its target: binding of activated hydantocidin to the feedback regulation site of adenylosuccinate synthetase. Proc. Natl. Acad. Sci. USA 1996, 93, 9431–9436. [Google Scholar]
  22. Brady, S.F.; Bauer, J.D.; Clarke-Pearson, M.F.; Daniels, R. Natural products from isnA-containing biosynthetic gene clusters recovered from the genomes of cultured and uncultured bacteria. J. Am. Chem. Soc 2007, 129, 12102–12103. [Google Scholar]
  23. The quantum chemical calculation results showed that the molecular energy for Z-isomers are lower 6–10 Kcal/mol than that of E-isomers, which indicated the Z-isomers are much stable.
  24. The similar results were obtained with the other substituted phenylsulfonyl chloride such as 4c, 4d, and 4k. For example, the yields for 3k were 86%, 65%, 14%, <5%, the yields for 2k were 10%, 16%, 74%, 82% when 4k was used with 1, 1.2, 1.5, 2.0 equivalents, respectively.
  25. Cubbage, J.W.; Vos, B.W.; Jenks, W.S. Ei elimination: An unprecedented facet of sulfone chemistry. J. Am. Chem. Soc 2000, 122, 4968–4971. [Google Scholar]
  26. Cubbage, J.W.; Guo, Y.; McCulla, R.D.; Jenks, W.S. Thermolysis of alkyl sulfoxides and derivatives: A comparison of experiment and theory. J. Org. Chem 2001, 66, 8722–8736. [Google Scholar]
  27. Trost, B.M.; Seoane, P.; Mignani, S.; Acemoglu, M. Stereocontrolled cyclopentenone synthesis via cycloaddition. J. Am. Chem. Soc 1989, 111, 7487–7500. [Google Scholar]
  28. Baker-Glenn, C.A.G.; Barrett, A.G.M.; Gray, A.A.; Procopiou, P.A.; Ruston, M. Alkene synthesis: Elimination of arenesulfinic acid from alkyl aryl sulfones using potassium trimethylsilanolate as base. Tetrahedron Lett 2005, 46, 7427–7430. [Google Scholar]
  29. Barrett, A.G.M.; Cramp, S.M.; Hennessy, A.J.; Procopiou, P.A.; Roberts, R.S. Oxazole synthesis with minimal purification: Synthesis and application of a rompgel tosmic reagent. Org. Lett 2001, 3, 271–273. [Google Scholar]
  30. Schmidt-Winkel, P.; Wudl, F. A remarkably thermally stable, polar aliphatic polysulfone. Macromolecules 1998, 31, 2911–2917. [Google Scholar]
  31. Kiec-Kononowicz, K.; Szymanska, E.; Motyl, M.; Kasprowicz, A.; Bialecka, A.; Holzer, W. Synthesis, spectral, and antimicrobial properties of 5-chloroarylidene aromatic derivatives of imidazolin-4-one. Pharmazie 1998, 53, 680–684. [Google Scholar]
  32. Wang, Z.D.; Sheikh, S.O.; Zhang, Y.A. Simple synthesis of 2-thiohydantoins. Molecules 2006, 11, 739–750. [Google Scholar]
  33. Chen, N.C. The Bioassay Technologies for Pesticides; Beijing Agricultural University Press: Beijing, China, 1991; pp. 161–162. [Google Scholar]
Figure 1. X-ray structure of compound 2k.
Figure 1. X-ray structure of compound 2k.
Ijms 14 12484f1 1024
Figure 2. The proposed reaction mechanism of 5-arylidene thiohydantoin.
Figure 2. The proposed reaction mechanism of 5-arylidene thiohydantoin.
Ijms 14 12484f2 1024
Scheme 1. The biological active 5-arylidene hydantoin and thiohydantoin compounds.
Scheme 1. The biological active 5-arylidene hydantoin and thiohydantoin compounds.
Ijms 14 12484f3 1024
Table 1. The reaction of 1 and phenylsulfonyl chloride (4a).
Table 1. The reaction of 1 and phenylsulfonyl chloride (4a).
Ijms 14 12484f4

EntryRatio (1:4a)Temp (°C)Time (h)SolventBase2a Yields (%) a3a yield (%) a
11:1308acetoneEt3N1584 [24]
21:1.2308acetoneEt3N2958 [24]
31:1.5308acetoneEt3N6923 [24]
41:2308acetoneEt3N81<5 [24]
51:3308acetoneEt3N80- b
61:2306acetoneEt3N76- b
71:2304acetoneEt3N49- b
81:2302acetoneEt3N38- b
91:208acetoneEt3N53- b
101:2608acetoneEt3N81- b
111:2308CH2Cl2Et3N41- b
121:2308CHCl3Et3N63- b
131:2308THFEt3N66- b
141:2308acetonePyridine34- b
151:2308acetoneNa2CO328- b
16 c1:2308acetoneEt3N63- b
17 d1:2308acetoneEt3N64- b
18 e1:2308acetoneEt3N65- b

aIsolated yield;bThe side-product 3a hadn’t been isolated;c–eThe 3–5 equivalents of Et3N were used, respectively.

Table 2. The reaction of 1 and arylsulfonyl chloride (4).
Table 2. The reaction of 1 and arylsulfonyl chloride (4).
Ijms 14 12484f5
EntryArProductYield (%)
1Ph (4a)2a81
24-FC6H4 (4b)2b78
34-ClC6H4 (4c)2c77
44-MeOC6H4 (4d)2d40
54-MeC6H4 (4e)2e46
64-NO2C6H4 (4f)2f84
74-BrC6H4 (4g)2g49
82-MeC6H4 (4h)2h42
93-CF3C6H4 (4i)2i80
104-IC6H4 (4j)2j49
114-t-ButC6H4 (4k)2k80
124-AcNHC6H4 (4l)2l48
132,5-Cl2C6H4 (4m)2m52
143,4-Cl2C6H4 (4n)2n54
Table 3. The reaction of analogues 5 and arylsulfonyl chloride (4a).
Table 3. The reaction of analogues 5 and arylsulfonyl chloride (4a).
Ijms 14 12484f6
EntryRProduct aYield (%)
1H (5a)6a38
24-F (5b)6b77
34-Cl (5c)6c74
44-Br (5d)6d65
54-Me (5e)6e48
64-NO2 (5f)6f76
74-MeO (5g)6g49
84-CF3 (5h)6h86
92,4-Cl2 (5i)6i75
104-NH2 (5j)6j0
11H (5a)6a52
124-NO2 (5f)6f84
134-CF3 (5h)6h88

aThe products were identified by 1H NMR and MS data [2,31].

Table 4. The fungicidal activities (inhibition rate, %) of compounds 2 against several plant fungi.
Table 4. The fungicidal activities (inhibition rate, %) of compounds 2 against several plant fungi.
Compd.Botrytis cinereaAlternaria solaniFusarium oxysporumDothiorella gregaria
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