A novel one-pot synthesis of 4-substituted 1,2,4-triazolidine-3,5-diones

Article abstract of DOI:10.1055/s-2007-977413

A simple and one-pot pathway for the preparation of 4-substituted phenyl derivatives of triazolidindiones (urazoles), starting from aniline derivatives is reported. In these methods aniline derivatives were reacted with ethyl chloroformate, to give the corresponding carbamate derivatives. In the second step semicarbazide derivatives were prepared from these carbamates by reaction with ethyl carbazide. The cyclization reactions of the corresponding semicarbazides furnished triazolidindiones. All reactions were performed in one vessel without the isolation of reaction intermediates, such as carbamates and semicarbazides, and the final products were isolated in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977413

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LETTER
1255
A Novel One-Pot Synthesis of 4-Substituted 1,2,4-Triazolidine-3,5-diones
N
ovel One-Po
h
t
Synthesis
o
a
f
4-Substitu
d
ted 1,2,4-T
r
p
iazolidine-3,5
o
-
diones ur Mallakpour,* Zahra Rafiee
Organic Polymer Chemistry Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156-83111, Iran
Fax +98(311)3912350; E-mail: mallak@cc.iutac.ir
Received 25 November 2006
(high cost of starting materials and need for completely
Abstract: A simple and one-pot pathway for the preparation of 4-
anhydrous conditions) and safety problems of the reported
methods from amines (use of toxic phosgene).
substituted phenyl derivatives of triazolidindiones (urazoles),
starting from aniline derivatives is reported. In these methods
aniline derivatives were reacted with ethyl chloroformate, to give
Much effort has been directed towards methods develop-
the corresponding carbamate derivatives. In the second step
ment for the synthesis of numerous urazoles.10–12 In gen-
semicarbazide derivatives were prepared from these carbamates by
eral, substituted urazoles were prepared starting from
reaction with ethyl carbazide. The cyclization reactions of the
isocyanates, amines, anilines and carboxylic acids. Re-
corresponding semicarbazides furnished triazolidindiones. All reac-
cently we noticed that the 4-substituted phenyl derivatives
can be readily synthesized from anilines in three steps.13
Herein, we report a simple and straightforward method for
the one-pot preparation of 4-substituted phenyl urazoles
from anilines without isolation of reaction intermediates.
tions were performed in one vessel without the isolation of reaction
intermediates, such as carbamates and semicarbazides, and the final
products were isolated in good yields.
Key words: urazole derivatives, heterocyclic compounds, semi-
carbazide, carbamate, one-pot reaction
In this method 4-substituted phenyl urazoles were pre-
pared from readily available anilines in one-pot reaction
(Scheme 1). The reaction of ethyl chloroformate with
anilines in the presence of Et3N afforded the intermediate
1, which upon treatment with ethyl carbazate gave semi-
carbazide intermediate 2. The cyclization of 2 gave the
final products 3 in good yields and purity (Table 1).
Urazole derivatives (1,2,4-triazolidine-3,5-diones) are
very interesting five-membered heterocyclic compounds,
which at position 4 can provide a wide variety of aliphatic
as well as aromatic constituents. There are only few com-
mercially available urazoles. Urazoles are unusual be-
cause they possess two pyramidal nitrogen atoms (sp3)
and a planar nitrogen atom (sp2) in the same molecule.
They are also unusual since the two pyramidal nitrogen
atoms are bonded to one another. Since optically active
forms of urazole do not appear to exist, it has always been
assumed that nitrogen inversion takes place in urazole that
is similar to nitrogen inversions in other amines.1
O
i
ArNHCOEt
Ar NH2
O
1
ii
NH2NHCOEt
H
H
O
O
N
N
Urazole is also an important chemical reagent in the labo-
ratory and in industry. Industrially urazole is used in the
manufacture of automobile air bags, as a blowing agent in
plastics, in the production of herbicides,2 and antifungal
compounds and in polymeric materials.3 It is also used in
the production of antitumor drugs4,5 and as a stabilizer in
milk. Urazole is used as a laboratory reagent for the
synthesis of novel heterocyclic6–9 and organometallic
compounds. Urazole has also been used in studies of the
origin of life due to its chemical similarity to uracil.1
iii
ArNHCNHNHCOEt
O
O
N
Ar
3
2
Scheme 1 Reagents and conditions: (i) EtOCOCl, Et3N, (Me)2CO,
0 °C to 25 °C, 1 h; (ii) NH2NHCOOEt, reflux, (Me)2CO, 10 h; (iii)
cyclization.
It is important to note that the original Et3N which was
added acts as a base for the last step which is the cycliza-
tion reaction. This method is simple, safe, and efficient. It
is noteworthy that 2-nitrophenyl urazole cannot be pre-
pared from its carboxylic acid derivative,14 but it was
prepared simply by this method from its aniline derivative
in high yield.
As part of our efforts towards the preparation of poly-
meric materials from urazole derivatives, we disclose
here an efficient route for the preparation of urazole
derivatives and its synthetic strategy applicable to one-pot
approaches.
Our goals in undertaking this work for the preparation of
urazole derivatives were to overcome the limitations and
drawbacks of the reported methods from isocyanates
In summary, a series of 4-substituted urazoles have been
successfully synthesized by a one-pot path-way, via sim-
ple reactions. This procedure proved to be much more ef-
ficient than the three-step sequence that was deployed.13
The reaction proceeds rapidly under mild conditions.
The reported one-pot synthetic sequences are short and
allow the rapid preparation of urazoles in good yields. It
SYNLETT 2007, No. 8, pp 1255–1256
1
6.
0
5.
2
0
0
7
Advanced online publication: 03.04.2007
DOI: 10.1055/s-2007-977413; Art ID: D35906ST
© Georg Thieme Verlag Stuttgart · New York

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1256
S. Mallakpour, Z. Rafiee
LETTER
Table 1 Conversion of Anilines to 1,2,4-Triazolidine-3,5-diones 3a–h in One-Pot Reaction
Compd
Ar
Yield (%)
MS (m/z)
Melting point (°C)
Literature
Found
3a
Ph
38
52
84
92
71
61
59
28
–
202–204 °C
231–232 °C
258–260 °C
245 °C
209–210 °C15
3b
p-ClC6H4
p-NO2C6H4
o-NO2C6H4
m-NO2C6H4
Bn
–
236 °C16
3c
–
264 °C17
3d18
3e19
3f
222 [M+]
222 [M+]
–
–
210–212 °C
182–183 °C
238–239 °C
245–246 °C
–
189–190 °C20
–
3g19
3h
o-Cl-p-NO2C6H3
p-MeC6H4
257 [M+]
–
243–244 °C21
(11) Little, T.; Meara, J.; Ruan, F.; Nguyen, M.; Qabar, M. Synth.
Commun. 2002, 32, 1741.
is interesting to note that this procedure has the great
advantage of eliminating nontoxic ethanol. In addition, by
using the one-step reaction, the amount of organic sol-
vents used decreases significantly.
(12) Park, K. H.; Cox, L. J. Tetrahedron Lett. 2002, 43, 3899.
(13) Mallakpour, S.; Rafiee, Z. Synth. Commun. 2007, in press.
(14) Mallakpour, S.; Rafiee, Z., unpublished results.
(15) Cookson, R. C.; Gilani, S. S.; Stevens, I. D. R.; Watts, C. T.
Org. Synth. 1971, 51, 121.
Acknowledgment
(16) Pesson, M.; Dupin, S. Bull. Soc. Chim. Fr. 1962, 250.
(17) Cookson, R. C.; Gupte, S. S.; Stevens, I. D. R.; Watts, C. T.
Org. Synth., Coll. Vol. VI; Wiley: New York, 1988, 936.
(18) One-Pot Preparation of 4-(2-Nitrophenyl)-1,2,4-
triazolidine-3,5-dione (3d): 2-Nitrophenyl aniline (0.100 g,
0.0724 mmol) in acetone (5 mL) was cooled to 0 °C and
Et3N (0.07 mL, 0.0724 mmol) in acetone (1 mL) was added.
The reaction mixture was stirred for a further 1 h and then a
solution of ethyl chloroformate (0.078 g, 0.0724 mmol) in
acetone (2 mL) was added at 0 °C. The resulting reaction
mixture was stirred for 1 h at the same temperature and then
a solution ethyl carbazate (0.075 g, 0.0724 mmol) in acetone
(2 mL) was added dropwise. Finally the reaction mixture
was refluxed for 10 h. The solid was collected by filtration
and recrystallized from distilled H2O. IR (KBr): 3200 (s,
NH), 1780 (m, C=O), 1700 (s, C=O), 1500 (s, NO2), 1350 (s,
NO2) cm–1. MS: m/z = 222 [M+]. 1H NMR (500 MHz,
DMSO-d6): d = 7.86–7.88 (m, 2 H, ArH), 8.32–8.34 (m, 2 H,
ArH), 10.72 (s, 2 H, NH).
We wish to express our gratitude to the Research Affairs Division
of Isfahan University of Technology (IUT), Isfahan, for partial
financial support. Further financial support from the Center of Ex-
cellence in Chemistry Research (IUT) is gratefully acknowledged.
References and Notes
(1) Jensen, J. O. Spectrochim. Acta, Part A 2003, 59, 637.
(2) Jikihara, T.; Matsuya, K.; Ohta, H.; Suzuki, S.;
Wakabayashi, O. US Patent, US 4249934, 1981; Chem.
Abstr. 1981, 95, 62219y.
(3) (a) Mallakpour, S. E. J. Chem. Educ. 1992, 69, 238.
(b) Mallakpour, S.; Rafiee, Z. Polym. Bull. (Berlin) 2006, in
press. (c) Mallakpour, S.; Rafiee, Z. J. Appl. Polym. Sci.
2004, 91, 2103. (d) Mallakpour, S.; Rafiee, Z. J. Appl.
Polym. Sci. 2003, 90, 2861. (e) Mallakpour, S. E.;
Rostamizadeh, H. J. Appl. Polym. Sci. 2001, 80, 1335.
(f) Mallakpour, S. E.; Nasr-Isfahani, H. J. Appl. Polym. Sci.
2001, 82, 3177. (g) Mallakpour, S. E.; Sheikholeslami, B.
Polym. Int. 1999, 48, 41.
(4) Simlot, R.; Izydore, R. A.; Wong, O. T.; Hall, A. H.
J. Pharm. Sci. 1994, 83, 367.
(5) Hall, I. H.; Wong, O. T.; Simlot, R.; Miller, M. C.; Izydore,
R. Anticancer Res. 1992, 12, 1355.
(6) Boldi, A. M.; Johnson, C. E.; Eissa, H. O. Tetrahedron Lett.
1999, 40, 619.
(7) Barton, D. H. R.; Lusihchi, X.; Sandoval-Ramirez, J.
Tetrahedron Lett. 1983, 24, 2995.
(19) 4-(3-Nitrophenyl)-1,2,4-triazolidine-3,5-dione (3e): IR
(KBr): 3200 (s, NH), 1770 (m, C=O), 1679 (s, C=O), 1500
(s, NO2), 1350 (s, NO2) cm–1. MS: m/z = 222 [M+]. 1H NMR
(500 MHz, DMSO-d6): d = 7.68–7.72 (m, 2 H, ArH), 7.86–
7.90 (m, 1 H, ArH), 8.13–8.15 (dd, J1 = 8.08 Hz, J2 = 1.18
Hz, 1 H, ArH), 10.83 (s, 2 H, NH).
4-(2-Chloro-4-nitrophenyl)-1,2,4-triazolidine-3,5-dione
(3g): IR (KBr): 3230 (s, NH), 1780 (m, C=O), 1690 (s,
C=O), 1500 (s, NO2), 1340 (s, NO2), 780 (s, CCl) cm–1. MS:
m/z = 257 [M+]. 1H NMR (500 MHz, DMSO-d6): d = 7.95–
7.98 (m, 1 H, ArH), 8.18–8.21 (m, 1 H, ArH), 8.29–8.30 (m,
1 H, ArH), 10.84 (s, 2 H, NH).
(8) Paquette, L. A.; Kretschmer, G. J. Am. Chem. Soc. 1979,
101, 4655.
(9) Herweh, J. E.; Fantazier, R. M. Tetrahedron Lett. 1973, 14,
2101.
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Chem. Incl. Med. Chem. 1976, 14, 883.
(21) Tsuji, T. Pharm. Bull. 1954, 2, 403.
(10) Gilbertson, T. J.; Ryan, T. Synthesis 1982, 159.
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