One-pot and novel route for the synthesis of 4-substituted-1,2,4- triazolidine-3,5-diones

Article abstract of DOI:10.1016/j.cclet.2013.11.020

The efficient and one-pot synthesis of 4-substituted-1,2,4-triazolidin-3,5- dione derivatives (4-substituted urazoles) via combination of triphosgene, substituted anilines, and ethyl carbazate in the presence of cesium carbonate is presented.

Full text of DOI:10.1016/j.cclet.2013.11.020

Chinese Chemical Letters 25 (2014) 451–454
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
One-pot and novel route for the synthesis of 4-substituted-1,2,4-
triazolidine-3,5-diones
*
Arash Ghorbani-Choghamarani , Mohsen Nikoorazm, Gouhar Azadi
Department of Chemistry, Faculty of Science, Ilam University, Ilam 69315516, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
The efficient and one-pot synthesis of 4-substituted-1,2,4-triazolidin-3,5-dione derivatives (4-
substituted urazoles) via combination of triphosgene, substituted anilines, and ethyl carbazate in the
presence of cesium carbonate is presented.
Received 5 September 2013
Received in revised form 21 October 2013
Accepted 4 November 2013
Available online 21 November 2013
ß 2013 Arash Ghorbani-Choghamarani. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Keywords:
Urazole
Triphosgene
Aniline
Ethyl carbazate
Cesium carbonate
1. Introduction
2. Experimental
Heterocyclic compounds are important and valuable parts of
biologically active molecules and natural products; therefore, the
design of new strategies to synthesize them is currently an
important area of research. An interesting class of these
compounds is 1,2,4-triazolidine-3,5-diones, which are five-mem-
bered heterocyclic compounds including three azo atoms with a
wide variety of aliphatic as well as aromatic constituents at
position 4 [1]. 1,2,4-Triazolidine-3,5-diones are of interest because
of their role as reagents in laboratory and industry; for instance,
application in preparing of automobile air bags, as a blowing agent
in plastic compounds, in the production of herbicides, as an
anticonvulsant, in antifungal compounds, and in polymeric
materials [2–6]. These compounds are also used for the prepara-
tion of organometallic compounds [7]. There are few reports for the
synthesis of these heterocyclic compounds [1,8,9]. Many of these
reported methods suffer from one or more drawbacks, such as low
yields, hazardous reaction conditions, and multistep processes.
Therefore, the search for a more suitable preparation of 1,2,4-
triazolidine-3,5-diones continues today.
Typical procedure for the synthesis of 4-substituted-urazoles: p-
toluidine (3 mmol) and cesium carbonate (3.5 mmol) were dis-
solved in anhydrous 1,4-dioxane (10 mL). Triphosgene (1 mmol)
was added in portions over 2, 3 min, and this mixture was stirred at
room temperature. After 1.5 h, ethyl carbazate (3.2 mmol) was
added, and the reaction mixture was stirred overnight. Following
evaporation to dryness, the reaction mixture was refluxed in
aqueous 5 mol/L KOH for 5 h then cooled down in an ice bath.
The solution was neutralized with concentrated HCl to reach pH 1, 2.
The white crystalline product was collected and dried to give 4-(4-
methylphenyl)-1,2,4-triazolidine-3,5-dione with 84% yield.
4-(4-Isopropylphenyl)-1,2,4-triazolidine-3,5-dione (4a): White
crystalline solid, 0.162 g (74%); mp: 231–234 8C; 1H NMR
(400 MHz, DMSO-d6):
1H, J = 6.8 Hz), 1.21 (d, 6H, J = 6.8 Hz); 13C NMR (100.6 MHz,
DMSO-d6): 154.1, 148.5, 130.0, 127.1, 126.6, 33.7, 24.3. Anal.
d 10.45 (s, 2H), 7.36 (br, 4H), 2.94 (septet,
d
Calcd. for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C, 61.13;
H, 5.68; N, 18.89.
4-(4-Bromophenyl)-1,2,4-triazolidine-3,5-dione (4c): White
crystalline solid, 0.159 g (62%); mp: 210–212 8C; 1H NMR
(400 MHz, DMSO-d6):
d
10.60 (s, 2H), 7.70 (d, 2H, J = 8.8 Hz),
153.4,
7.47 (d, J = 8.8 Hz, 2H); 13C NMR (100.6 MHz, DMSO-d6):
d
132.2, 131.8, 128.2, 120.7. Anal. Calcd. for C8H6BrN3O2: C, 37.53; H,
2.36; N, 16.41. Found: C, 37.88; H, 2.68; N, 15.87.
4-(4-Ethylphenyl)-1,2,4-triazolidine-3,5-dione (4d): White
crystalline solid, 0.201 g (98%); mp: 246–248 8C; 1H NMR
*
Corresponding author.
E-mail addresses: arashghch58@yahoo.com, a.ghorbani@mail.ilam.ac.ir
(A. Ghorbani-Choghamarani).
1001-8417/$ – see front matter ß 2013 Arash Ghorbani-Choghamarani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.11.020

452
A. Ghorbani-Choghamarani et al. / Chinese Chemical Letters 25 (2014) 451–454
O
O
Cs CO
2
3
NH
NCO
+
Cl CO
OCCl
3
+
2
NH
3
2
EtO
N
H
Dioxane, r.t.
1.5 h
2a
1a
OEt
O
O
NH
NH
NH
NH
KOH (5 mol/L)
Reflux, 5 h
Dioxane
N
NH
r.t., overnight
O
O
4a
Scheme 1. Synthesis of 4-(4-isopropylphenyl)-1,2,4-triazolidine-3,5-dione.
HN NH
N
(400 MHz, DMSO-d6):
d 10.46 (s, 2H), 7.33–7.36 (m, 4H), 2.65 (q,
1) Triphosgene, Cs2CO3, dioxane, r.t., 1.5 h
2H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz); 13C NMR (100.6 MHz, DMSO-
R
NH2
O
O
2) Ethyl carbazate, dioxane, r.t., overnight
3) KOH (5 mol/L), reflux, 5 h
d6):
d 154.0, 143.9, 129.9, 128.6, 126.6, 28.3, 16.1. Anal. Calcd. for
C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.34; H, 5.11; N,
20.21.
R
1
4
4-(2,4-Dimethoxyphenyl)-1,2,4-triazolidine-3,5-dione
White crystalline solid, 0.130 g (55%); mp: 245–246 8C; 1H NMR
(400 MHz, DMSO-d6): 10.20 (s, 2H), 7.16 (d, 1H, J = 8.4 Hz), 6.71
(s, 1H), 6.60 (d, 1H, J = 8.4 Hz), 3.82 (s, 3H), 3.76 (s, 3H); 13C NMR
(100.6 MHz, DMSO-d6): 161.6, 156.9, 154.8, 131.4, 113,2, 105.4,
(4e):
Scheme 2. Synthesis of 4-substituted-1,2,4-triazolidin-3,5-diones.
d
3. Results and discussion
d
99.7, 56.3, 56.0. Anal. Calcd. for C10H11N3O4: C, 50.63; H, 4.67; N,
17.71. Found: C, 49.28; H, 3.13; N, 17.78.
In light of the aforementioned biologic, laboratorial, and
industrial activities and as part of our ongoing program towards
the synthesis of heterocyclic compounds [10–15], we delineated
an efficient route for the synthesis of urazole derivatives.
4-(4-Tritylphenyl)-1,2,4-triazolidine-3,5-dione (4f): White
crystalline solid, 0.411 g (98%); mp: 300 8C (dec.); 1H NMR
(400 MHz, DMSO-d6):
d
10.58 (s, 2H), 7.02–7.41 (m, 19H); 13C
Initially, we performed the reaction between 4-isopropylaniline
1a and triphosgene in the presence of different bases (such as
triethylamine, potassium hydroxide, sodium carbonate, and
cesium carbonate) and solvents (such as dichloromethane,
acetone, 1,4-dioxane, ethyl acetate, and tetrahydro furane) to
achieve 4-isopropylisocyanate 2a. After consumption of 4-iso-
propylaniline, ethyl carbazate was added to the solution to afford
intermediate 3a. The best solvent and base for these two steps
were 1,4-dioxane and cesium carbonate, respectively. After
consumption of 4-isopropylisocyanate, the solvent was evaporated
and 5 mol/L KOH was added to the mixture and refluxed; this step
was found to be completed within 5 h, affording 4-(4-isopropyl-
phenyl)-1,2,4-triazolidine-3,5-dione 4a (Scheme 1).
NMR (100.6 MHz, DMSO-d6):
d
153.7, 146.7, 146.2, 131.2, 130.9,
130.1, 128.4, 126.6, 125.6, 64.8. Anal. Calcd. for C27H21N3O4: C,
77.31; H, 5.05; N, 10.02. Found: C, 76.89; H, 2.90; N, 9.52.
4-(4-Fluorophenyl)-1,2,4-triazolidine-3,5-dione (4h): White
crystalline solid, 0.150 g (77%); mp: 269–270 8C; 1H NMR
(400 MHz, DMSO-d6):
d
10.53 (s, 2H), 7.45-7.53 (m, 2H), 7.31–
161.4 (d, Jc–
7.36 (m, 2H); 13C NMR (100.6 MHz, DMSO-d6):
d
F = 243 Hz), 153.8, 128.7 (d, Jc–F = 9 Hz), 120.5 (d, Jc–F = 8 Hz), 116.1
(d, Jc–F = 23 Hz). Anal. Calcd. for C8H6FN3O4: C, 49.24; H, 3.10; N,
21.53. Found: C, 49.97; H, 2.56; N, 21.53.
The NMR spectra can be found in the Supporting information
file.
O
O
O
-
-Cl
Cs2CO3
-2HCl
Cl
Cl
+
R
Cl
NH2
Cl
R
N C O
Cl
Cl
NH2
R
Cl
O
2
O
O
Cl3CO
OCCl3
R
NH2
+
R
N
H
Cl3CO
OCCl3
OCCl3
NH2
R
1
O
O
O
-
-Cl
Cs2CO3
-2HCl
Cl
Cl
Cl + R NH2
Cl
NH2
R
R
N C O
Cl
Cl
Cl
O
2
R
R
N
H
OCCl3 +
Cs2CO3
R
N
C O
2
O
O
O
O
HN
HN
-EtOH
OEt
EtO
NHNH
N
R
H2N
HN
+ H2NHN
C O
OEt
N
N
R
O
RHN
O
3
4
O
Scheme 3. Mechanism of the urazole synthesis.

A. Ghorbani-Choghamarani et al. / Chinese Chemical Letters 25 (2014) 451–454
453
Table 1
Synthesis of 4-substituted-1,2,4-triazolidin-3,5-diones via one-pot combination of different types of anilines with triphosgene and ethyl carbazate in the presence of cesium
carbonate.
Entry
1
Amine
Urazole
Yielda (%)
74
Mp (8C)
Ref.
–
Observed
231–234
Reported
–
O
1a
NH
2
NH
NH
4a
N
O
2
3
84
62
243–244
210–212
245–246
[2]
O
1b
H3C
Br
NH2
NH2
NH
4b
N
H3C
NH
O
–
–
O
1c
NH
4c
Br
N
NH
O
4
98
246–248
–
–
O
1d
H3CH2C
MeO
NH2
NH
NH
4d
H3CH2C
N
O
5
6
55
98
245–246
–
–
–
–
O
NH2
1e
NH
MeO
N
4e
OMe
NH
OMe
O
300 (dec)
O
N
NH
NH
1f
C
NH2
4f
C
O
7
8
65
77
224–227
269–270
231–232
[2]
O
N
1g
Cl
NH2
NH
NH
4g
Cl
F
O
–
–
O
1h
F
NH2
NH
4h
N
O
NH
a
Isolated yield.
Based on these results, we investigate the scope and
limitations of this synthesis strategy by varying the structure
of amine. Therefore, a novel series of 4-substituted urazoles has
been synthesized by a one-pot multicomponent reaction using
different types of anilines, triphosgene, and ethyl carbazate
(Scheme 2).
The results of these syntheses are summarized in Table 1. A
plausible mechanism for the synthesis of 4-substituted urazoles,
has been outlined in Scheme 3, based on previously reported
papers [1,8,9,16]. The interesting point of this mechanism is the in
situ generation of three equivalent isocyanates (2) from the
reaction of one equivalent triphosgene and three equivalent
aniline. Subsequently, reaction of isocyanate with ethyl carbazate
was followed by cyclization of intermediate (3) to generate
corresponding 4-substituted-1,2,4-triazolidin-3,5-dione (4).
4. Conclusion
In summary, we have delineated an efficient synthesis of
structurally diverse 4-substituted urazoles via one-pot combina-
tion of a variety of anilines with triphosgene and ethyl carbazate in
the presence of cesium carbonate. Simple reaction conditions,
broad substrate scope, and no additional solvent extraction steps
are the advantages of this procedure. The greenness and simplicity
of this synthetic procedure makes it an interesting alternative to
other approaches.

454
A. Ghorbani-Choghamarani et al. / Chinese Chemical Letters 25 (2014) 451–454
[7] D.A. Gianolio, M. Lanfranchi, F. Lusardi, L. Marchio, M.A. Pellinghelli, Synthesis
Acknowledgment
and characterization of Co(II), Ni(II), Cu(II) and Zn(II) complexes of 4-amino-
1,2,4-triazolidine-3,5-dione (urazine), Inorg. Chim. Acta 309 (2000) 91–
102.
Financial support to this work by the Ilam University, Ilam, Iran
is gratefully acknowledged.
[8] S. Mallakpour, Z. Rafiee, Novel and efficient synthesis of 4-substituted-1,2,4-
triazolidine-3,5-diones from anilines, Synth. Commun. 37 (2007) 1927–
1934.
[9] K.H. Park, L.J. Cox, Solid-phase synthesis of 1,2,4-triazolidine-3,5-diones, Tetra-
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.cclet.
2013.11.020.
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