An efficient method for synthesis of thiohydantoins with α-amino esters under microwave irradiation

Article abstract of DOI:10.14233/ajchem.2014.16119

An efficient and simple way for synthesis of thiohydantoins is reported. In the absence of any additional catalysts, a series of thiohydantoins were synthesized with amino esters and isothiocyanates in aqueous medium under microwave irradiation. Excellent isolated yields (up to 98 %) were obtained under mild conditions.

Full text of DOI:10.14233/ajchem.2014.16119

Asian Journal of Chemistry; Vol. 26, No. 4 (2014), 1171-1173
http://dx.doi.org/10.14233/ajchem.2014.16119
An Efficient Method for Synthesis of Thiohydantoins with
α-Amino Esters Under Microwave Irradiation
*
*
YANMEI ZHAO, ZHOUYU WANG , ZHENJU JIANG , HUALIN FENG, LI LIU and JU WANG
Department of Pharmaceutics Engineering, Xihua University, Chengdu, 610039, P.R. China
*Corresponding authors: Tel: +86 028 7729643; E-mail: zhouyuwang@mail.xhu.edu.cn; zhenjujiang@sina.com
Received: 30 July 2013; Accepted: 6 October 2013; Published online: 15 February 2014;
AJC-14722
An efficient and simple way for synthesis of thiohydantoins is reported. In the absence of any additional catalysts, a series of thiohydantoins
were synthesized with amino esters and isothiocyanates in aqueous medium under microwave irradiation. Excellent isolated yields (up to
98 %) were obtained under mild conditions.
Keywords: Thiohydantoin, Microwave irradiation, Amino esters, Isothiocyanates.
(TMS) with the solvent resonance employed as the internal
standard (CDCl3, δ 7.26 ppm). 13C NMR chemical shifts are
reported in ppm from tetramethylsilane (TMS) with the
solvent resonance as the internal standard (CDCl3, δ 77.0 ppm).
IR spectra were recorded on NICONET-380 spectrophoto-
meter using KBr pellets. ESIMS spectra were recorded on
BioTOF Q.
INTRODUCTION
Thiohydantoins are the ultimate reaction products of the
Edman degradation for peptide sequencing while their derivatives
have been found to exist in many nature products and medi-
cines1,2. Recent research results showed that thiohydantoins
and their derivatives have a wide range of biological activities
such as antiviral, antitumor, anticancer, anticonvulsant, anti-
ulcer and antibacterial activities3-9. In addition, thiohydantoins
are traditionally being considered as useful intermediates in
peptide and heterocycles synthesis. For this reason, the
synthesis of thiohydantoins is valuable for drug discovery and
lots of efficient methods have been reported9-20. However, the
present methods suffer from drawbacks such as long reaction
times, use of corrosive reagents and tedious work-up procedures.
Therefore, the development of a simple and efficient method
for synthesis of thiohydantoins is still necessary. Herein, we
reported a fast and simple way for synthesis of thiohydantoins
with α-amino esters and isothiocyanates in aqueous medium
under the microwave irradiation.
General procedure for the synthesis of thiohydantoins :
A mixture of isothiocyanate (2 mmol) and DL-amino ester (2
mmol) were stirred under microwave (400 w) at 400 °C in
DMF/ H2O (3:1) (8 mL).After 5 min, the solvent was removed
under reduced pressure and the residue purified through col-
umn chromatography on silica gel (hexane/EtOAc) to give
pure product thiohydantoins.
Spectral data of the products: 5-Benzyl-3-phenyl-2-
thioxoimidazolidin-4-one (3a): White solid; yield: 98 %; m.p.
189-190 °C; 1H NMR (300 MHz, CDCl3): δ = 3.06-3.14 (m,
1H), 3.32-3.38 (m, 1H), 4.51-4.54 (m, 1H), 7.07 (d, J = 9.60
Hz, 2H), 7.25-7.51 (m, 8H), 7.52 (brs, 1H); 13C NMR (150
MHz, CDCl3): δ = 37.7, 60.8, 127.9, 128.1, 129.1, 129.3, 132.5,
134.3, 172.5, 183.7; IR (KBr, νmax, cm-1): 3172, 1754, 1518,
1408, 1337, 1269, 1189, 1108; ESI HRMS exact mass calcd.
for (C16H14N2OS + Na)+ requires m/z 305.0719, found m/z
305.0719.
EXPERIMENTAL
All starting materials were of the commercially available
(analytical grade) and used without further purification. All
solvents used in the reactions were distilled from appropriate
drying agents prior to use. Reactions were monitored by thin
layer chromatography using silica gel HSGF254 plates. Flash
chromatography was performed using silica gel HG/T2354-
92. Melting poits were measured with SGW X-4 melting point
apparatus. H and 13C NMR (300 or 600 and 75 or 150 Hz,
respectively) spectra were recorded in CDCl3. 1H NMR chemical
shifts are reported in ppm (δ) relative to tetramethylsilane
5-Benzyl-3-(4-chlorophenyl)-2-thioxoimidazolidin-4-
one (3b): White solid; yield: 89 %; m.p. 225-227 °C; 1H NMR
(300 MHz, CDCl3): δ = 3.06-3.13 (m, 1H), 3.35-3.38 (m,
1H), 4.50-4.54 (m, 1H), 7.01 (d, J = 7.23 Hz, 2H), 7.26
- 7.43 (m, 8H); 13C NMR (150 MHz, CDCl3): δ = 37.7, 60.8,
127.9, 129.1, 129.3, 129.4, 129.5, 130.9, 134.1, 135.3, 172.2,
183.2; IR (KBr, νmax, cm-1): 3167, 1754, 1516, 1494, 1409,
1

1172 Zhao et al.
Asian J. Chem.
1273, 1188, 1092; ESI HRMS exact mass calcd. for
(C16H13N2OSCl + Na)+ requires m/z 339.0329, found m/z
339.0341.
Hz, 3H), 2.36-2.40 (m, 1H), 4.11-4.17 (m, 1H) 7.25-7.30 (m,
2H) 7.46-7.54 (m, 3H), 7.82 (brs, 1H); 13C NMR (150 MHz,
CDCl3): δ = 16.2, 18.7, 31.6, 64.9, 128.3, 129.2, 129.3, 132.7,
172.9, 184.3; IR (KBr, νmax, cm-1): 3192, 1759, 1517, 1409,
1349, 1271, 1195, 1108; ESI HRMS exact mass calcd. for
(C12H14N2OS + Na)+ requires m/z 257.0719, found m/z
257.0732.
5-Benzyl-3-(4-methoxyphenyl)-2-thioxoimidazolidin-
1
4-one (3c): White solid; yield: 90 %; m.p. 216-218 °C; H
NMR (300 MHz, CDCl3): δ = 3.04-3.12 (m, 1H), 3.33-3.38
(m, 1H), 3.82 (s, 3H), 4.50-4.54 (m, 1H), 6.93-7.00 (m, 4H),
7.26-7.28 (m, 3H), 7.34-7.40 (m, 3H); 13C NMR (150 MHz,
CDCl3): δ = 37.7, 55.4, 60.8, 125.0, 127.8, 129.1, 129.3, 129.4,
134.3, 172.8, 184.1; IR (KBr, νmax, cm-1): 3182, 1754, 1516,
1408, 1350, 1252, 1172, 1110; ESI HRMS exact mass calcd.
for (C17H16N2O2S + Na)+ requires m/z 335.0825, found m/z
335.0826.
RESULTS AND DISCUSSION
The classical method for the synthesis of thiohydantoins
is the reaction of isothiocyanates with amino acids. Generally,
thiourea was firstly produced and then cyclized to thio-
hydantoins. For entirely cyclization, acidic or basic conditions
are usually required. However, this is not suitable for the
synthesis of thiohydantoins with a pH-sensitive group.As part
of our program to seek effective, economical and green
reactions21-23, we wish to synthesize thiohydantoins with amino
esters and isothiocyanates in the absence of acid and base.
Firstly, we took the reaction of methyl 2-amino-3-phenyl-
propanoate (1a) and phenyl isothiocyanate (2a) as a model
reaction to develop the optimum reaction conditions. When
the reaction went through two days in dichloromethane at
40 °C, the yield of 3a was only 16 %. The main product was
the thiourea. At the same reaction conditions, we tried other
solvents such as toluene, water (H2O) and N,N-dimethylformamide
(DMF). There was only trace product in toluene. The yield of
3a were higher in H2O and DMF. So we considered use of the
mixture of DMF and H2O as the solvent. To our surprise, the
yield of 3a enhanced to 92 % after two days when DMF/H2O
(3:1) was used. Considering the microwave technology has
been blossomed into a useful technique in synthetic chemistry
due to the fast reaction rate and high yields24-26, we used it to
increase the efficiency. Much to our surprise, the product yield
was enhanced to 98 % in DMF/H2O (3:1) at 40 °C after only
5 min with the power of 400 W. And then, the power of
microwave irradiation was studied. When the power was
300 W, the yield of product was decreased to 91 % (entry 7,
Table-1). Further enhancing the power to 600W has little effect
on the yield (entries 8-9, Table-1). We also investigated the
effects of temperature. The results showed that the effects of
temperature is the same as the power. Lower temperature dis-
advantaged the yield and higher temperature has little effect
on the yield (entries 10-12, Table-1).
5-Benzyl-2-thioxo-3-p-tolylimidazolidin-4-one (3d):
1
White solid; yield: 94 %; m.p. 214-215 °C; H NMR (300
MHz, CDCl3): δ = 2.37 (s, 3H), 3.07-3.11 (m, 1H), 3.31-3. 33
(m, 1H), 4.49-4.51 (m, 1H), 6.93 (d, J = 8.16 Hz, 2H), 7.24-
7.37 (m, 7H), 7.62 (brs, 1H); 13C NMR (150 MHz, CDCl3): δ =
21.3, 37.6, 60.8, 127.8, 127.9, 129.0, 129.4, 129.9, 134.2, 139.4,
172.7, 183.9; IR (KBr, νmax, cm-1): 3175, 1753, 1518, 1408,
1347, 1269, 1189, 1112; ESI HRMS exact mass calcd. for
(C17H16N2OS-H)+ requires m/z 295.3901, found m/z 295.0906.
5-Benzyl-3-methyl-2-thioxoimidazolidin-4-one (3e):
1
White solid; yield: 84 %; m.p. 130-132 °C; H NMR (300
MHz, CDCl3): δ = 2.27-2.86 (m, 1H), 3.20 (s, 3H), 3.31-3.37
(m, 1H), 4.28-4.33 (m, 1H), 7.10 (brs, 1H), 7.20 (d, J = 6.24
Hz, 2H), 7.31-7.38 (m, 3H); 13C NMR (150 MHz, CDCl3): δ =
27.5, 37.6, 60.7, 127.4, 129.0, 129.2, 134.9, 173.2, 184.1; IR
(KBr, νmax, cm-1): 3201, 1743, 1519, 1446, 1337, 1298, 1126,
1103; ESI MS (M + H)+ 221.1.
5-(4-Hydroxybenzyl)-3-methyl-2-thioxoimidazolidin-
1
4-one (3f): White solid; yield: 91 %; m.p. 178-179 °C; H
NMR (300 MHz, CDCl3): δ = 2.77-2.81 (m, 1H), 3.20 (s, 3H),
3.20-3.24 (m,1H), 4.08-4.26 (m, 1H), 5.30 (brs, 1H), 6.80 (d,
J = 8.46 Hz, 2H), 6.91 (brs, 1H), 7.07 (d, J = 8.40 Hz, 2H),;
13C NMR (150 MHz, CDCl3): δ = 27.5, 36.8, 60.8, 126.8,
130.3, 155.2, 173.2, 184.2; IR (KBr, νmax, cm-1): 3186, 1736,
1518, 1438, 1338, 1267, 1094; ESI HRMS exact mass calcd.
for (C11H12N2O2S + H)+ requires m/z 237.0692, found m/z
237.0703.
3-Methyl-5-phenyl-2-thioxoimidazolidin-4-one (3g):
1
White solid; yield: 88 %; m.p. 157-159 °C; H NMR (300
MHz, CDCl3): δ = 3.29 (s, 3H), 5.11 (s, 1H), 7.16 (brs, 1H),
7.31-7.33 (m, 2H), 7.40-7.43 (m, 3H); 13C NMR (150 MHz,
CDCl3): δ = 27.8, 62.8, 126.6, 129.3, 129.5, 133.0, 172.3,
184.7; IR (KBr): 3184, 1758, 1520, 1497, 1273, 1247, 1173,
1108; ESI HRMS exact mass calcd. for (C10H11N2O2S + H)+
requires m/z 207.0587, found m/z 207.0585.
Having established the optimal reaction conditions, we
next examined the generality of this microwave-assisted
protocol. Various amino esters and isothiocyanates were tested
under assistant of microwave irradiation (400 W) at 40 °C in
the absence of catalysts with DMF/ H2O (3:1) as the solvents.
As shown in Scheme-I, the methyl 2-amino-3-phenyl-
propanoate, methyl 2-amino-3-(4-hydroxy-phenyl)propanoate,
methyl 2-amino-2-phenylacetate and methyl 2-amino-3-
methylbutanoate all cyclized to thiohydantions with phenyl
isothiocyanate, 4-chloro-phenyl isothiocyanate,4-methoxy-
phenyl isothiocyanate, 4-methyl-phenyl isothiocyanate and
methyl isothiocyanate to afford the desired thiohydantoins in
excellent yields (84-98 %, Scheme-I).
3,5-Diphenyl-2-thioxoimidazolidin-4-one (3h): White
1
solid; yield: 96 %; m.p. 236-237 °C; H NMR (300 MHz,
CDCl3): δ = 5.30 (s, 1H), 7.32-7.52 (m, 10H); 13C NMR (150
MHz, CDCl3): δ = 63.1, 126.6, 128.3, 128.8, 129.2, 129.3,
129.5, 129.6, 130.9, 133.2, 171.5, 184.2; IR (KBr, νmax, cm-1):
3148, 1758, 1520, 1404, 1273, 1183, 1105; ESI HRMS exact
mass calcd. for (C15H12N2OS + Na)+ requires m/z 291.0563,
found m/z 291.0565.
5-Isopropyl-3-phenyl-2-thioxoimidazolidin-4-one (3i):
1
White solid; yield: 91 %; m.p. 211-212 °C; H NMR (300
In summary, we have developed a highly efficient catalyst-
free method for the synthesis of thiohydantions. With this
protocol, a set of thiohydantions can be synthesized with
MHz, CDCl3): δ = 1.05 (d, J = 6.80 Hz, 3H), 1.14 (d, J = 6.99

Vol. 26, No. 4 (2014)
Synthesis of Thiohydantoins with α-Amino Esters Under Microwave Irradiation 1173
TABLE-1
EFFECTS OF REACTION CONDITIONS ON THE SYNTHESIS OF THIOHYDANTOINa
H
N
NH2
NCS
+
S
COOMe
N
O
2a
1a
3a
Entry
1
Solvent
CH2Cl2
Temp. (°C)
Power (W)
Time
2d
Yield (%)b
40
40
40
40
40
40
40
40
40
20
60
80
-
16
Trace
35
2
Toluene
-
2d
3
H2O
-
2d
4
DMF
-
2d
21
5
DMF/H2O (1/3)
DMF/H2O (1/3)
DMF/H2O (1/3)
DMF/H2O (1/3)
DMF/H2O (1/3)
DMF/H2O (1/3)
DMF/H2O (1/3)
DMF/H2O (1/3)
-
2d
92
6
400
300
500
600
400
400
400
5 min
5 min
5 min
5 min
5 min
5 min
5 min
98
7
91
8
97
9
97
10
11
12
75
97
97
aUnless specified otherwise, the reaction was performed at 2 mmol scale in 8 mL solvent, bIsolated yield
3. A.A. El-Barbary, A.I. Khodair, E.B. Pedersen and C.J. Nielsen, Med.
Chem., 37, 73 (1994).
H
N
H
N
H
N
4. B. Mo, J. Li and S. Liang, Anal. Biochem., 249, 207 (1997).
5. E. Osz, L. Somsak, L. Szilagyi, L. Kovacs, T. Docsa, B. Toth and P.
Gergely, Bioorg. Med. Chem. Lett., 9, 1385 (1999).
6. R. Kuang, J.B. Epp, S. Ruan, H. Yu, P. Huang, S. He, J. Tu, N.M.
Schechter, J. Turbov, C.J. Froelich and W.C. Groutas, J. Am. Chem.
Soc., 121, 8128 (1999).
S
S
S
N
N
N
O
O
O
OMe
C l
7. Lee, Chen, Liu, JY. CW. S. T.-S. Lee, L.-C. Chen, Y. Liu, J. Wu, Y.-C.
Liang and W.-S. Lee, Naunyn Schmiedebergs Arch. Pharmacol., 382,
43 (2010).
3a: 98 % yield
3b: 89 % yield
3c: 90 % yield
H
N
H
N
H
N
8.
M.E. Jung, S. Ouk, D. Yoo, C.L. Sawyers, C. Chen, C. Tran and J.
Wongvipat, J. Med. Chem., 53, 2779 (2010).
S
S
N
O
S
N
O
9. M. Ono, S. Hayashi, K. Matsumura, H. Kimura, Y. Okamoto, M. Ihara,
R. Takahashi, H. Mori and H. Saji, ACS Chem. Neurosci, 2, 269 (2011).
10. J. Han, H. Dong, Z. Xu, J. Lei and M. Wang, Int. J. Mol. Sci., 14,
12484 (2013).
HO
N
O
3f: 91 % yield
Me
3e: 84 % yield
3d: 94 % yield
11. N. Hussain, A. Joshi, C. Sharma and G.L. Talesara, Asian J. Chem., 24,
5917 (2012).
H
N
12. D.S. Raghuvanshi and K.N. Singh, Phosphorus Sulfur Silicon Rel. Elem.,
185, 2243 (2010).
H
N
S
H
N
S
13. C.Yao,Y. Zhang, G. Zhang, W. Chen,Y. Yu and R.A. Houghten, Synth.
Commun., 40, 717 (2010).
N
O
N
S
O
N
O
14. M. Carboni, J.-M. Gomis, O. Loreau and F. Taran, Synthesis, 417 (2008).
15. S. Cao, L.J. Zhu, C.M. Zhao, X.H. Tang, H.J. Sun, X. Feng and X.H.
Qian, Monatsh. Chem., 139, 923 (2008).
3g: 88 % yield
3h: 91 % yield
3i: 96 % yield
16. G.S.M. Sundaram, C.Venkatesh, H. Ila and H. Junjappa, Synlett, 251 (2007).
17. Z.D. Wang, S.O. Sheikh and Y. Zhang, Molecules, 11, 739 (2006).
18. S. Reyes and K. Burgess, J. Org. Chem., 71, 2507 (2006).
19. S. Porwal, R. Kumar, P.R. Maulik and P.M.S. Chauhan, Tetrahedron
Lett., 47, 5863 (2006).
Scheme-I
excellent yields in absence of any additional catalyst under
microwave irradiation.
20. J.P. Li, C.M. Ma and G.R. Qu, Synth. Commun., 35, 1203 (2005).
21. J. Li, Z. Wang, Z. Jiang, S. Jiang and L. Xiong, Asian J. Chem., 23,
4101 (2011).
ACKNOWLEDGEMENTS
22. S. Jiang, Z. Wang, Z. Jiang, J. Li, S. Zhou and L. Pu, Lett. Org. Chem.,
9, 24 (2012).
The authors are grateful for the financial supports from
the National Natural Science Foundation of China (21102115),
the Open Fund of the Key Laboratory of Sichuan Province
(Szjj2011-005) and the National Undergraduate Innovation and
Entrepreneurship Training Programs of China (201210623009).
23. S R. S. Caddick and R. Fitzmaurice, Tetrahedron, 65, 3325 (2009).
24. H.M. Hugel, Molecules, 14, 4936 (2009).
25. E.D.. E. Guenin and D. Meziane, Curr. Org. Chem., 15, 3465 (2011).
26. G.K. Gupta, N. Rani andV. Kumar, Mini Rev. Org. Chem., 9, 270 (2012).
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