Microwave-assisted solid-state synthesis and characterization of thiohydantoin derivatives

Article abstract of DOI:10.1081/SCC-200054778

A new and efficient solid-state method for the preparation of thiohydantoins is reported. With this method, twelve thiohydantoin compounds have been synthesized in good to excellent yields (81-92%). In addition, this method has the advantages of high yields, a cleaner reaction, simple methodology, and short reaction times. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054778

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Microwave‐Assisted Solid‐State
Synthesis and Characterization
of Thiohydantoin Derivatives
Jian‐Ping Li a , Chun‐Ming Ma a & Gui‐Rong Qu a
a College of Chemistry & Environmental Science,
Henan Normal University, Xinxiang, China
Published online: 16 Aug 2006.
To cite this article: Jian‐Ping Li , Chun‐Ming Ma & Gui‐Rong Qu (2005):
Microwave‐Assisted Solid‐State Synthesis and Characterization of Thiohydantoin
Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:9, 1203-1208
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Synthetic Communicationsw, 35: 1203–1208, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054778
Microwave-Assisted Solid-State Synthesis
and Characterization of Thiohydantoin
Derivatives
Jian-Ping Li, Chun-Ming Ma, and Gui-Rong Qu
College of Chemistry & Environmental Science, Henan Normal
University, Xinxiang, China
Abstract: A new and efficient solid-state method for the preparation of thiohydantoins
is reported. With this method, twelve thiohydantoin compounds have been synthesized
in good to excellent yields (81–92%). In addition, this method has the advantages of
high yields, a cleaner reaction, simple methodology, and short reaction times.
Keywords: Microwave activation, solid-state synthesis, thiohydantoin derivatives
In recent years, the use of microwave technology in organic synthesis has
received considerable attention.[1–3] It has many advantages, such as high effi-
ciency and selectivity, easy separation and purification, and environmental
acceptability.[4–6] All these merits are in accord with the green production’s
requests of energy-savings and high efficiency. Today, it has been widely
used in a variety of organic reactions.[7–10] However, the solvent-free
synthesis of thiohydantoins by the reaction of arylisothiocyanates with free
amino acids has not been reported.
It is well known that thiohydantion derivatives display a wide range
of biological properties, including anticonvulsant,[11] antiviral,[12] and
antitumor[13] activities, and can act as herbicidal and fungicidal regeants.[14]
Meanwhile, some were used to synthesize novel optically active
poly(amide-imide)s using microwave irradiation.[15] Therefore, particularly
Received in Japan October 16, 2004
Address correspondence to Jian-Ping Li, College of Chemistry & Environmental
Science, Henan Normal University, Xinxiang, 453007, China. E-mail: jplig@163.com

1204
J.-P. Li, C.-M. Ma, and G.-R. Qu
intense interest has been directed toward the synthesis of them.[16–18]
Generally, these reactions were carried out in solution. All these methods
have their merits. However, they also have drawbacks, such as using large
amounts of volatile and poisonous solvents and needing a long reaction time.
To overcome these disadvantages, avoid the use of a solvent, and syn-
thesize these valuable compounds rapidly and with a high efficiently, a new,
rapid, solvent-free synthesis of thiohydantoins with microwave activation
was studied. It was found that the addition reaction of aryl isothiocyanates
and DL-amino acid in the presence of sodium hydroxide and the cyclizative
condensation of adduct in the presence of sodium hydrogen sulphate in a
microwave oven takes place quickly. In the reaction, we have found that the
substrates containing electron-withdrawing groups can make the reaction
time shorter. However, there is no inevitable relationship between the yields
and the electron-withdrawing and electron-donating groups in the substrates.
It was also worthy of note that the thiohydantoins were formed via a conden-
sation reaction in which the amino acids underwent nucleophilic addition
followed by ring closure, and the asymmetric center of amino acid was not
involved in the reaction and the configuration had not been changed in this
Microwave irradiation (MWI) reaction.
Using this new method, we synthesized twelve thiohydantoins in
excellent yield (81–92%). This method has significant advantages, such as
operational simplicity, shorter reaction time, higher yields, and environmental
acceptability. The structures of the products were characterized by IR, MS,
1H NMR, 13C NMR, and elemental analysis. And more detailed work about
the application of the thiohydantoins in analytical chemistry and physiological
activitiy is in progress in our laboratory.
EXPERIMENTAL
Melting points were determined with a Kofler micro melting point apparatus
and are uncorrected. IR spectra were recorded on a FTS-40 spectrophotometer
using KBr pellets. 1H NMR and 13C NMR spectra were measured on a Bruker
DPX-400 spectrometer at 400 and 100 MHz, respectively, using TMS as
internal standard and CDCl3 or DMSO-d6 as solvent. Chemical shifts (d)
were expressed in ppm downfield from internal standard TMS and coupling
constants J are given in Hz. Mass spectra were recorded on a HP-5 6890/
5973 GC-MS spectrometer. Elemental analyses were performed on PE-2400
CHN elemental analyzer. We used a Galanz microwave oven (750 W).
General Procedure for the Preparation of Thiohydantoins (4a-l)
Synthesis of the aryl isothiocyanates (2) were described in detail elsewhere
(Scheme 1).[19]

Synthesis of Thiohydantoin Derivatives
1205
Scheme 1. Synthesis of aryl thiohydantoins (4a-1).
Aryl isothiocyanate (1 mmol), DL-amino acid (1 mmol), and sodium
hydroxide (1 mmol) were mixed well in a mortar, then irradiated in a
microwave oven with 495 W for the specified time, 6–10 min, under solvent-
free conditions. Then sodium hydrogen sulphate (1 mmol) was added and
mixed well, and irradiated again with 495 W for 2 min. The reaction was
traced with TLC. After the reaction was completed, the mixture was cooled
to room temperature. A small amount of ethanol was dropped into
the mortar and then cool water was poured into the mortar slowly, and the
precipitate was filtrated and the filtrate was condensed. The crude products
were collected, dried and recrystallized from ethanol. Drying in vacuum
gave the pure products. All the compounds gave satisfactory analytical and
spectra data.
Physical and Spectra Data of Compounds 4a-l
3-(p-Chlorophenyl)-2-thiohydantoin 4a: Yellow crystals. Yields: 87%; Mp
229.5–2318C IR (KBr): 3214 (N-H), 3051, 2955, 2900, 1756 (C55O), 1598,
1530, 1276 (C55S), 827 cm21 1H NMR (400 MHz, DMSO-d6): d 10.13
;
(s, 1H, N-H), 7.57 (d, 2H, J ¼ 8.4 Hz, ArH), 7.34 (d, 2H, J ¼ 8.4 Hz, ArH),
4.29 (s, 2H, N-CH2). Anal. calcd. for C9H7ClN2OS: C, 47.69; H, 3.11; N,
12.36. Found: C, 47.80; H, 3.02; N, 12.44.
5-Methyl-3-(p-chlorophenyl)-2-thiohydantoin 4b: White
Yields: 86%; Mp 209–210.58C; IR (KBr): 3175 (N-H), 3077, 2940, 1757
(C55O), 1530, 1497, 1264 (C55S), 821 cm21 1H NMR (400 MHz,
CDCl3): d 7.71 (s, 1H, N-H), 7.51 (d, 2H, J ¼ 8.2 Hz, ArH), 7.33 (d, 2H,
crystals.
;

1206
J.-P. Li, C.-M. Ma, and G.-R. Qu
J ¼ 8.2 Hz, ArH), 4.38 (q, 1H, J ¼ 7.0 Hz, N-CH), 1.63 (d, 3H, J ¼ 7.0 Hz,
CH3); MS (m/z): 240 (Mþ),169 (B), 111, 86, 75, 28. Anal. calcd. for
C10H9ClN2OS: C, 49.90; H, 3.77; N, 11.64. Found: C, 49.88; H, 3.69; N,
11.72.
5-Isopropyl-3-(p-chlorophenyl)-2-thiohydantoin 4c: White crystals.
Yields: 88%; Mp 192–193.58C; IR (KBr): 3177 (N-H), 3076, 966, 2873,
1759 (C55O), 1520, 1496, 1268 (C55S), 830 cm21 1H NMR (400 MHz,
;
CDCl3): 7.81 (s, 1H, N-H), 7.50 (d, 2H, J ¼ 8.8 Hz, ArH), 7.28 (d, 2H,
J ¼ 8.8 Hz, ArH), 4.21 (d, 1H, J ¼ 3.6 Hz, N-CH), 2.41 (m, 1H, CH), 1.16
(d, 3H, J ¼ 6.8 Hz, CH3), 1.06 (d, 3H, J ¼ 6.8 Hz, CH3); 13C NMR
(100 MHz, CDCl3):d 184.38 (C55S), 173.24 (C55O), 135.86, 131.58,
130.13, 130.03, 65.58 (N-CH), 31.77, 19.33, 16.82; MS (m/z): 268 (Mþ,B),
226, 169, 111, 75. Anal. calcd. for C12H13ClN2OS: C, 53.53; H, 4.88; N,
10.42. Found: C, 53.59; H, 4.78; N, 10.47.
5-Isobutyl-3-(p-chlorophenyl)-2-thiohydantoin 4d: White crystals.
Yields: 85%; Mp 173–174 8C; IR (KBr): 3166 (N-H), 3031, 2956, 2872,
1760 (C55O), 1603, 1539, 1280 (C55S), 825 m21 1H NMR (400 MHz,
;
CDCl3): d 8.00 (s, 1H, N-H), 7.49 (d, 2H, J ¼ 8.8 Hz, ArH), 7.29 (d, 2H,
J ¼ 8.8 Hz, ArH), 4.33 (dd, 1H, J ¼ 2.8, 9.2 Hz, N-CH), 1.90 (m, 2H,
CH2), 1.74 (m, 1H, CH), 1.03 (t, 6H, J ¼ 6.4 Hz, 2CH3); 13C
NMR(100 MHz, CDCl3): d 183.85 (C55S), 174.19 (C55O), 135.83,
131.58, 130.13, 130.03, 59.02 (N-CH), 25.79, 41.01, 23.60, 22.09; MS
(m/z): 282 (Mþ), 253, 226, 169 (B), 111, 75. Anal. calcd. for
C13H15ClN2OS: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.30; H, 5.20;
N, 9.95.
3-(p-Bromophenyl)-2-thiohydantoin 4e: Yellow crystals. Yields: 91%;
Mp 247–249 8C; IR (KBr): 141 (N-H), 3041, 2928, 1765 (C55O), 1590,
1517, 1269 (C55S), 821 cm21 1H NMR (400 MHz, DMSO-d6): d10.40
;
(s, 1H, N-H), 7.71 (d, 2H, J ¼ 8.8 Hz, ArH), 7.28 (d, 2H, J ¼ 8.8 Hz, ArH),
4.30 (s, 2H, N-CH2). Anal. calcd. for C9H7BrN2OS: C, 39.87; H, 2.60; N,
10.33. Found: C, 39.98; H, 2.50; N, 10.49.
5-Methyl-3-(p-bromophenyl)-2-thiohydantoin 4f: White crystals. Yields:
88%; Mp 210–2128C; IR (KBr): 174 (N-H), 3075, 2938, 1758 (C ¼ O), 1597,
1
1529, 1275 (C55S), 823 cm21; H NMR (400 MHz, CDCl3): d 7.77 (s, 1H,
N-H), 7.66 (d, 2H, J ¼ 8.4 Hz, ArH), 7.24 (d, 2H, J ¼ 8.4 Hz, ArH), 4.38
(q, 1H, J ¼ 7.2 Hz, N-CH), 1.62 (d, 3H, J ¼ 7.2 Hz, CH3); MS (m/z): 286
(Mþ þ 2), 215 (B), 157, 86; Anal. calcd. for C10H9BrN2OS: C, 42.12; H,
3.18; N, 9.82. Found: C, 42.28; H, 3.25; N, 9.97.
5-Isopropyl-3-(p-bromophenyl)-2-thiohydantoin 4g: White crystals,
Yields: 81%; Mp 205–206.58C; IR (KBr): 3180 (N-H), 3083, 2966, 2873,
1762 (C55O), 1560, 1521, 1270 (C ¼ S), 830 cm21
;
1H NMR(400 MHz,
CDCl3): d 7.99 (s, 1H, N-H), 7.64 (d, 2H, J ¼ 8.8 Hz, ArH), 7.20 (d, 2H,
J ¼ 8.8 Hz, ArH), 4.20 (d, 1H, J ¼ 3.6 Hz, N-CH), 2.41 (m, 1H, CH), 1.17
(d, 3H, J ¼ 6.8 Hz, CH3), 1.07 (d, 3H, J ¼ 6.8 Hz, CH3); MS (m/z): 312

Synthesis of Thiohydantoin Derivatives
1207
(Mþ,B), 272, 213, 184, 155, 28. Anal. calcd. for C12H13BrN2OS: C, 46.02; H,
4.18; N, 8.94. Found: C, 46.14; H, 4.20; N, 8.90.
5-Isobutyl-3-(p-promophenyl)-2-thiohydantoin 4h: White crystals.
Yields: 91%; Mp 192–193.58C; IR (KBr): 3256 (N-H), 3060, 2957, 2871,
1758 (C55O), 1587, 1528, 1280 (C55S), 825 cm21 1H NMR (400 MHz,
;
CDCl3): d 8.03 (s, 1H, N-H), 7.64 (d, 2H, J ¼ 8.4 Hz, ArH), 7.22 (d, 2H,
J ¼ 8.4 Hz, ArH), 4.33 (dd, 1H, J ¼ 3.2, 9.2 Hz, N-CH), 1.91 (m, 2H, CH2),
1.76 (m, 1H, CH), 1.04 (t, 6H, J ¼ 6.4 Hz, 2CH3); MS (m/z): 328
(Mþ þ 2,B), 270, 215, 175, 155, 134, 86, 43. Anal. calcd. for
C13H15BrN2OS: C, 47.71; H, 4.62; N, 8.56. Found: C, 47.55; H, 4.64;
N, 8.66.
3-(p-Ethoxylphenyl)-2-thiohydantoin 4i: Yellow crystals. Yields: 90%;
Mp 202–2048C; IR (KBr): 3160 (N-H), 3079, 2986, 2888, 1770 (C55O),
1
1600, 1580, 1281 (C55S), 842 cm21; H NMR (400 MHz, CDCl3): d 7.31
(s, 1H, N-H), 7.22 (d, 2H, J ¼ 8.8 Hz, ArH), 7.01 (d, 2H, J ¼ 8.8 Hz, ArH),
4.26 (s, 2H, N-CH), 4.08 (q, 2H, J ¼ 6.8 Hz, CH2), 1.44 (t, 3H, J ¼ 6.8 Hz,
CH3); Anal. calcd. for C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86. Found:
C, 56.04; H, 5.08; N, 11.75.
5-Methyl-3-(p-bromophenyl)-2-thiohydantoin 4j: White crystals. Yields:
89%; Mp 192.5–1948C; IR (KBr): 3220 (N-H), 3061, 2990, 2878, 1720
1
(C55O), 1608, 1597, 1285 (C55S), 843 cm21; H NMR (400 MHz, CDCl3):
d 7.81 (s, 1H, N-H), 7.24 (d, 2H, J ¼ 8.8 Hz, ArH), 7.02 (d, 2H, J ¼ 8.8 Hz,
ArH), 4.35 (q, 1H, J ¼ 6.8 Hz, N-CH), 4.10 (q, 2H, J ¼ 6.8 Hz, CH2), 1.61
(d, 3H, J ¼ 6.8 Hz, CH3), 1.45 (d, 3H, J ¼ 6.8 Hz, CH3); MS (m/z): 250
(Mþ, B), 179, 151, 122. Anal. calcd. for C12H14N2O2S: C, 57.58; H, 5.64;
N, 11.19. Found: C, 57.75; H, 5.58; N, 11.25.
5-Isopropyl-3-(p-ethoxylphenyl)-2-thiohydantoin 4k: White crystals.
Yields: 90%; Mp 201–2038C; IR (KBr): 3175 (N-H), 3059, 2988, 2877,
1763 (C55O), 1606, 1590, 1272 (C55S), 845 cm21 1H NMR (400 MHz,
;
CDCl3): d 8.02 (s, 1H, N-H), 7.22 (d, 2H, J ¼ 8.8 Hz, ArH), 7.02 (d, 2H,
J ¼ 8.8 Hz, ArH), 4.19 (d, 1H, J ¼ 3.6 Hz, N-CH), 4.10 (q, 2H, J ¼ 6.8 Hz,
CH2), 2.40 (m, 1H, CH), 1.46 (t, 3H, J ¼ 6.8 Hz, CH3), 1.15 (d, 3H,
J ¼ 6.8 Hz, CH3), 1.05 (d, 3H, J ¼ 6.8 Hz, CH3); MS (m/z): 278 (Mþ, B),
235, 179, 151, 122. Anal. calcd. for C14H18N2O2S: C, 60.41; H, 6.52; N,
10.06. Found: C, 60.61; H, 6.45; N, 10.00.
5-Isobutyl-3-(p-ethoxylphenyl)-2-thiohydantoin 4l: White crystals.
Yields: 92%; Mp 168.5–1708C; IR(KBr): 3176 (N-H), 3075, 2969, 2873,
1764 (C55O), 1612, 1525, 1281 (C55S), 827 cm21 1H NMR (400 MHz,
;
CDCl3):d 7.90 (s, 1H, N-H), 7.22 (d, 2H, J ¼ 8.8 Hz, ArH), 7.02 (d, 2H,
J ¼ 8.8 Hz, ArH), 4.31 (dd, 1H, J ¼ 2.8, 9.2 Hz, N-CH), 4.09 (q, 2H,
J ¼ 6.4 Hz, CH2), 1.91 (m, 2H, CH2), 1.75 (m, 2H, CH2), 1.45 (t, 3H,
J ¼ 6.8 Hz, CH3), 1.04 (t, 6H, J ¼ 6.4 Hz, 2CH3); MS (m/z): 292 (Mþ, B),
263, 236, 179, 151. Anal. calcd. for C15H20N2O2S: C, 61.62; H, 6.89; N,
9.58. Found: C, 61.83; H, 6.85; N, 9.64.

1208
J.-P. Li, C.-M. Ma, and G.-R. Qu
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the Natural
Science Foundation of China (Project No. 20372018).
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