Domino synthesis of novel series of 4-substituted 5-thioxo-1,2,4- triazolidin-3-one derivatives

Article abstract of DOI:10.2478/s11696-012-0228-1

The efficient synthesis of 4-substituted 5-thioxo-1,2,4-triazolidin-3-one derivatives (4-substituted thiourazoles) via domino combination of thiophosgene, aliphatic or aromatic amines, and ethyl carbazate is presented.

Full text of DOI:10.2478/s11696-012-0228-1

Chemical Papers 66 (11) 1078–1081 (2012)
DOI: 10.2478/s11696-012-0228-1
SHORT COMMUNICATION
Domino synthesis of novel series of 4-substituted
5-thioxo-1,2,4-triazolidin-3-one derivatives
Arash Ghorbani-Choghamarani*, Sara Sardari
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
Received 18 February 2012; Revised 9 May 2012; Accepted 17 May 2012
The efficient synthesis of 4-substituted 5-thioxo-1,2,4-triazolidin-3-one derivatives (4-substituted
thiourazoles) via domino combination of thiophosgene, aliphatic or aromatic amines, and ethyl
carbazate is presented.
c
ꢀ 2012 Institute of Chemistry, Slovak Academy of Sciences
Keywords: thiourazole, thiophosgene, amine, ethyl carbazate, isothiocyanate
Heterocycles are essential moieties in a wide range
of biologically active molecules; it is hardly sur-
prising, therefore, that considerable effort has been
channelled towards the development of combinato-
rial synthetic methodologies for the preparation of
heterocyclic libraries (Phoon & Sim, 2002). Ura-
zole derivatives (1,2,4-triazolidine-3,5-diones) are use-
ful five-membered heterocyclic compounds which can
provide a wide variety of aliphatic as well as aro-
matic constituents at position 4 (Mallakpour & Rafiee,
2007). Urazoles were reported as possessing herbici-
dal and biological properties (Simlot et al., 1994). A
thiourazole compound also exhibited herbicidal activ-
ity (Shimizu et al., 1995).
As part of our ongoing programmes towards the
synthesis and modification of heterocyclic compounds
(Ghorbani-Choghamarani et al., 2008, 2009a, 2009b,
2010, 2011), we present an efficient route for the syn-
thesis of 4-substituted thiourazole derivatives.
Starting amines were purchased from Merck
(Darmstadt, Germany) and Acros Organics (Geel,
Belgium). Thiophosgene and ethyl carbazate were ob-
tained from Acros Organics (Geel, Belgium).
400Q spectrometer. EI mass spectra were measured
using Agilent Technologies (HP) mass spectrometer
at ionisation energy of 70 eV.
General procedure for the synthesis of
4-substituted 5-thioxo-1,2,4-triazolidin-3-ones
(IVa–IVj)
Thiophosgene (1 mmol) was added in portions over
2–3 min to a mixture of the corresponding amine
(RNH2, Ia–Ij) (1 mmol) and triethylamine (2 mmol)
in anhydrous THF (10 mL), and the mixture was
stirred at ambient temperature for 1 h. Ethyl car-
bazate (1.2 mmol) was then added and the reaction
mixture was heated under reflux for 2 h followed by
evaporation of the solvent to give the corresponding
ethyl 2-(R-carbamothioyl)hydrazinecarboxylate (IIIa–
IIIj). To this, an aqueous solution of KOH (5 M,
20 mL) was added and the mixure was heated under
reflux for 5 h, cooled in an ice bath and concentrated
HCl was added (to pH 1). The white crystalline prod-
uct was collected and dried to afford the correspond-
ing 4-substituted thiourazole (for substituent R, see
Table 1).
Melting points were determined with an Elec-
trothermal IA 9100 apparatus and are uncorrected.
IR spectra (in nujol) were recorded on a Bomem IR
spectrometer. 1H NMR (400 MHz) and 13C NMR
(100.6 MHz) spectra (in DMSO-d6 using TMS as an
internal standard) were recorded using Bruker FX
Starting from 4-bromoaniline (Ia) and thiophos-
gene in the presence of triethylamine in THF as
a solvent, 4-bromophenyl isothiocyanate (IIa) was
obtained within 1 h. In the next step, IIa and
ethyl carbazate in THF were heated under re-
*Corresponding author, e-mail: arashghch58@yahoo.com, a.ghorbani@mail.ilam.ac.ir

A. Ghorbani-Choghamarani, S. Sardari/Chemical Papers 66 (11) 1078–1081 (2012)
1079
Fig. 1. Synthesis of 4-substituted 5-thioxo-1,2,4-triazolidin-3-ones (IVa–IVj). Reaction conditions: i) thiophosgene, triethylamine,
THF, 25◦C, 1 h; ii) ethyl carbazate, THF, reflux, 2 h; iii) 5 M KOH, reflux, 5 h.
Table 1. Characterisation data of newly prepared 4-substituted 5-thioxo-1,2,4-triazolidin-3-ones (IVa–IVj)
Compound
Ra
Formula
Mr
Yieldb/%
M.p./◦C
IVa
IVb
C8H6N3BrOS
C9H9N3OS
272.12
207.25
65
75
232–235
213–216
IVc
C11H13N3OS
235.31
55
189–191
IVd
IVe
C10H11N3OS
C8H13N3OS
221.28
199.27
72
70
195–198
181–183
IIIf
C10H17N3OS
227.33
80
228–230
IIIg
IIIh
C8H7N3OS
C9H9N3OS
193.23
207.25
70
78
190–192c
214–216d
IVi
IIIj
C12H9N3OS
243.28
435.54
52
98
251–254
185–189
C27H21N3OS
a) See Fig. 1; b) isolated yield after recrystallisation; c) 193.5–195.5◦C (reported by Bradsher et al. (1958)); d) 216.5–217.5◦C
(reported by Bradsher et al. (1958)).
flux for 2 h to afford 1-(4-bromophenyl)-2-thiobiurea
(IIIa) (quantitatively) which was dissolved in a 5 M
aqueous solution of KOH and heated under reflux
to give 4-(4-bromophenyl)-5-thioxo-1,2,4-triazolidin-
3-one (IVa). Subsequently, transformation of Ia to IVa
was performed via a cascade domino reaction (with-
out isolation of intermediates), affording IVa in 65 %
yield.
Analogously, a series of new 4-substituted thioura-
zoles was prepared by cascade domino reaction using
different types of starting amines (Fig. 1). The char-
acterisation and spectral data of the compounds pre-
pared are given in Tables 1 and 2, respectively.
In the synthesis of thiourazoles as intermediates
for the preparation of inhibitors of the c-Jun N-
terminal kinase, De et al. (2009) assigned structure

1080
A. Ghorbani-Choghamarani, S. Sardari/Chemical Papers 66 (11) 1078–1081 (2012)
Table 2. Spectral data of prepared compounds
Compound
Spectral data
IIIa
IVa
1H NMR (DMSO-d6), δ: 9.82 (s, 1H), 9.66 (s, 1H), 9.38 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H),
4.08 (q, J = 6.8 Hz, 2H), 1.22 (t, J = 6.8 Hz, 3H)
13C NMR (DMSO-d6), δ: 181.3, 156.4, 139.1, 131.2, 128.1, 126.1, 61.4, 15.0
MS, m/z (Ir/%): 319 (26) (M+ + 2), 317 (21) (M+), 273 (5), 215 (87), 213 (76), 104 (100), 57 (18), 41 (13)
IR, ν˜/cm−1: 3134, 2932, 1699, 1515, 1456, 1377, 1301, 1201, 1184, 921, 896, 800
1H NMR (DMSO-d6), δ: 12.53 (br, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 6.4 Hz, 2H)
13C NMR (DMSO-d6), δ: 167.4, 152.8, 136.9, 132.3, 130.5, 122.2
MS, m/z (Ir/%): 274 (2.5) (M+ + 2), 272 (2.3) (M+), 260 (17), 167 (17), 151 (100), 149 (42), 83 (29), 64 (60), 57
(47), 41 (36)
IVb
IVc
IR, ν˜/cm−1: 3137, 2928, 1699, 1646, 1511, 1459, 1372, 1315, 1302, 1245, 1180, 1105, 770
1H NMR (DMSO-d6), δ: 13.15–12.35 (br, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8 Hz, 2H), 2.35 (s, 3H)
13C NMR (DMSO-d6), δ: 167.4, 152.8, 138.6, 130.7, 129.7, 128.5, 21.2
MS, m/z (Ir/%): 207 (82) (M+), 178 (2), 149 (100), 133 (21), 107 (18), 91 (24), 57 (34), 43 (24)
IR, ν˜/cm−1: 3285, 2956, 2924, 1714, 1687, 1527, 1462, 1377, 1315, 1248, 1032, 721
1H NMR (DMSO-d6), δ: 12.71 (br, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 2.95 (sep, J = 6.8 Hz,
1H), 1.23 (d, J = 6.8 Hz, 6H)
13C NMR (DMSO-d6), δ: 167.2, 152.8, 149.2, 130.9, 128.6, 127.1, 33.7, 24.3
MS, m/z (Ir/%): 235 (100) (M+), 220 (69), 207 (3), 193 (53), 167 (31), 149 (80), 91 (16), 57 (26), 43 (25)
IVd
IVe
IR, ν˜/cm−1: 3417, 1720, 1651, 1512, 1415, 1258, 1047, 722
1H NMR (DMSO-d6), δ: 12.50 (br, 2H), 7.34–7.05 (m, 4H), 2.65 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H)
13C NMR (DMSO-d6), δ: 167.3, 153.1, 144.8, 130.7, 128.6, 128.4, 28.3, 15.9
MS, m/z (Ir/%): 221 (100) (M+), 206 (18), 192 (4), 163 (13), 148 (11), 132 (28), 120 (7), 91 (6), 77 (13), 43 (3)
IR, ν˜/cm−1: 3308, 3128, 1668, 1564, 1460, 1370, 1308, 1261, 1228, 986, 891, 721
1H NMR (DMSO-d6), δ: 12.81–12.11 (br, 2H), 4.32 (m, 1H), 2.21–2.11 (m, 2H), 1.79–1.76 (m, 2H), 1.59–1.56 (m,
3H), 1.29–1.08 (m, 3H)
13C NMR (DMSO-d6), δ: 167.1, 153.1, 53.6, 28.6, 25.8, 25.3
MS, m/z (Ir/%): 199 (26) (M+), 167 (23), 149 (62), 118 (100), 117 (46), 98 (10), 91 (2), 83 (16), 67 (17), 55 (48),
41 (39)
IVf
IR, ν˜/cm−1: 3369, 3165, 1665, 1556, 1456, 1372, 1310, 1080, 754, 716
1H NMR (DMSO-d6), δ: 12.43 (br, 2H), 4.55 (m, 1H), 2.21 (m, 3H), 1.74–1.47 (m, 11H)
13C NMR (DMSO-d6), δ: 166.2, 153.3, 54.3, 30.8, 26.4, 25.9, 25.0
MS, m/z (Ir/%): 227 (25) (M+), 216 (3), 177 (1), 149 (4), 118 (100), 117 (33), 111 (11), 95 (10), 91 (2), 81 (18), 69
(57), 67 (20), 55 (33), 41 (33)
IVg
IR, ν˜/cm−1: 3395, 3150, 1703, 1456, 1372, 1251, 1084, 1042, 716
1H NMR (DMSO-d6), δ: 12.66 (br, 2H), 7.51–7.35 (m, 5H)
13C NMR (DMSO-d6), δ: 164.3, 153.7, 132.8, 129.4, 129.1, 128.2
MS, m/z (Ir/%): 193 (74) (M+), 178 (23), 167 (35), 161 (12), 150 (16), 149 (100), 136 (8), 117 (15), 104 (13), 91
(11), 77 (28), 71 (27), 57 (45), 43 (36), 41 (32)
IVh
IVi
1H NMR (DMSO-d6), δ: 12.58 (br, 2H), 7.30–7.26 (m, 5H), 4.81 (s, 2H)
13C NMR (DMSO-d6), δ: 167.8, 158.2, 141.5, 133.6, 132.8, 132.7
MS, m/z (Ir/%): 207 (21) (M+), 191 (4), 174 (7), 167 (1), 149 (6), 106 (30), 91 (100), 86 (3), 77 (8), 65 (15), 57 (2),
43 (3), 41 (4)
IR, ν˜/cm−1: 3328, 1720, 1650, 1462, 1415
1H NMR (DMSO-d6), δ: 12.78 (br, 2H), 8.10–8.04 (m, 2H), 7.57–7.51 (m, 5H)
13C NMR (DMSO-d6), δ: 168.1, 153.2, 134.3, 130.4, 130.2, 129.8, 128.8, 128.5, 127.6, 127.0, 126.0, 122.8
MS, m/z (Ir/%): 243 (12) (M+), 193 (3), 178 (5), 149 (100), 113 (12), 104 (8), 83 (12), 71 (25), 57 (42), 55 (24), 43
(30), 41 (28)
IVj
IR, ν˜/cm−1: 3371, 2929, 1711, 1678, 1462, 1377, 1083, 1048, 721
1H NMR (DMSO-d6), δ: 12.62 (br, 2H), 7.26–7.08 (m, 19H)
13C NMR (DMSO-d6), δ: 169.8.1, 153.7, 147.4, 146.5, 131.4, 130.9, 128.3, 128.0, 127.3, 126.6
MS, m/z (Ir/%): 435 (18) (M+), 358 (46), 335 (49), 258 (100), 243 (21), 221 (27), 207 (48), 180 (26), 165 (46), 133
(15), 118 (12), 104 (12), 86 (81), 58 (22), 41 (20)
B to thiourazole tautomer (Fig. 1). By contrast, the
1H and 13C spectral data of 4-substituted thioura-
zoles IVa–IVj indicate tautomeric structure A, simi-
larly to 13C NMR data observed by Phoon and Sim
(2002) for 1,2,4-trisubstituted thiourazoles, which can-
not assume the B tautomer structure. In this case,
the two most deshielded 13C resonances for 1,2,4-
trisubstituted thiourazoles occur at δ approximately
of 153 and 170 (in CDCl3). 13C NMR spectra of 4-
substituted thiourazoles IVa–IVj (in DMSO-d6 be-
cause they are insoluble in CDCl3) showed the most
deshielded resonances at δ approximately of 153 and
167, almost identical chemical shifts to those reported
by Phoon and Sim (2002).

A. Ghorbani-Choghamarani, S. Sardari/Chemical Papers 66 (11) 1078–1081 (2012)
1081
In summary, an efficient method for the synthesis
of 4-substituted-5-thioxo-1,2,4-triazolidin-3-ones via a
cascade tandem reaction of various amines with thio-
phosgene and ethyl carbazate was developed. Good to
excellent yields of the products can be achieved with
aliphatic as well as aromatic amines.
Ghorbani-Choghamarani, A., Hajjami, M., Goudarziafshar, H.,
Nikoorazm, M., Mallakpour, S., Sadeghizadeh, F., & Azadi,
G. (2009b). Catalytic oxidation of urazoles and bis-urazoles
to their corresponding triazolinediones using aluminium ni-
trate and a catalytic amount of silica sulfuric acid. Monat-
shefte fu¨r Chemie, 140, 607–610. DOI: 10.1007/s00706-008-
0100-8.
Ghorbani-Choghamarani, A., Zolfigol, M. A., Hajjami, M.,
Rastgoo, S., & Mallakpour, S. (2010). Metal-free oxidation of
urazole and 1,4-dihydropyridine derivatives under mild and
heterogeneous conditions by nitro urea, derived from urea ni-
trate, and silica sulfuric acid. Letters in Organic Chemistry,
7, 249–254.
Ghorbani-Choghamarani, A., Zolfigol, M. A., Hajjami, M.,
Goudarziafshar, H., Nikoorazm, M., Yousefi, S., & Tahmasbi,
B. (2011). Nano aluminium nitride as a solid source of ammo-
nia for the preparation of Hantzsch 1,4-dihydropyridines and
bis-(1,4-dihydropyridines) in water via one pot multicompo-
nent reaction. Journal of the Brazilian Chemical Society, 22,
525–531.
Mallakpour, S., & Rafiee, Z. (2007). A novel one-pot synthesis
of 4-substituted 1,2,4-triazolidine-3,5-diones. Synlett, 2007,
1255–1256. DOI: 10.1055/s-2007-977413.
Phoon, C. W., & Sim, M. M. (2002). Solid-phase synthe-
ses of 1,2,4-trisubstituted urazole and thiourazole deriva-
tives. Journal of Combinatorial Chemistry, 4, 491–495. DOI:
10.1021/cc0200134.
Shimizu, T., Hashimoto, N., Nakayama, I., Nakao, T., Mizu-
tani, H., Unai, T., Yamaguchi, M., & Abe, H. (1995). A
novel isourazole herbicide, fluthiacet-methyl, is a potent in-
hibitor of protoporphyrinogen oxidase after isomerization by
glutathione S-transferase. Plant & Cell Physiology, 36, 625–
632.
Acknowledgements. The authors express their gratitude to
the research facilities of Ilam University, Ilam, Iran for finan-
cial support for this research.
References
Bradsher, C. K., Brown, F. C., & Webster, S. T. (1958). Some 4-
substituted thiourazoles. The Journal of Organic Chemistry,
23, 618–619. DOI: 10.1021/jo01098a607.
De, S. K., Stebbins, J. L., Chen, L. H., Riel-Mehan, M., Mach-
leidt, T., Dahl, R., Yuan, H., Emdadi, A., Barile, E., Chen,
V., Murphy, R., & Pellecchia, M. (2009). Design, synthesis,
and structure-activity relationship of substrate competitive,
selective, and in vivo active triazole and thiadiazole inhibitors
of the c-Jun N-terminal kinase. Journal of Medicinal Chem-
istry, 52, 1943–1952. DOI: 10.1021/jm801503n.
Ghorbani-Choghamarani, A., Zolfigol, M. A., Salehi, P., Ghae-
mi, E., Madrakian, E., Nasr-Isfahani, H., & Shahamirian, M.
(2008). An efficient procedure for the synthesis of Hantzsch
1,4-dihydropyridines under mild conditions. Acta Chimica
Slovenica, 55, 644–647.
Ghorbani-Choghamarani, A., Chenani, Z., & Mallakpour, S.
(2009a). Supported nitric acid on silica gel and polyvinyl
pyrrolidone (PVP) as an efficient oxidizing agent for the ox-
idation of urazoles and bis-urazoles. Synthetic Communica-
tions, 39, 4264–4270. DOI: 10.1080/00397910902898619.
Simlot, R., Izydore, R. A., Wong, O. T.,
& Hall, I. H.
(1994). Hypolipidemic activity of 4-substituted 1,2-diacyl-
1,2,4-triazolidine-3,5-diones in rodents. Journal of Pharma-
ceutical Sciences, 83, 367–371. DOI: 10.1002/jps.2600830320.