Novel and efficient synthesis of 4-substituted-1,2,4-triazolidine-3,5- diones from anilines

Article abstract of DOI:10.1080/00397910701316862

A simple and efficient three-step synthetic procedure for the preparation of 4-substituted phenyl derivatives of 1,2,4-triazolidindiones (urazoles), starting from anilines, has been developed. In this method, aniline derivatives were reacted with 4-nitrophenyl chloroformate to provide corresponding carbamate derivatives. In the second step, semicarbazide derivatives were prepared from these carbamates by reaction with ethyl carbazate. The cyclization reaction of corresponding semicarbazides furnished 1,2,4-triazolidindiones in high yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701316862

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Novel and Efficient Synthesis of
4‐Substituted‐1,2,4‐triazolidine‐3,5‐diones
from Anilines
Shadpour Mallakpour a & Zahra Rafiee a
a Organic Polymer Chemistry Research Laboratory, College of Chemistry,
Isfahan University of Technology, Isfahan, Iran
Published online: 30 Jun 2007.
To cite this article: Shadpour Mallakpour & Zahra Rafiee (2007) Novel and Efficient Synthesis
of 4‐Substituted‐1,2,4‐triazolidine‐3,5‐diones from Anilines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:11, 1927-1934, DOI:
10.1080/00397910701316862
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Synthetic Communicationsw, 37: 1927–1934, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701316862
Novel and Efficient Synthesis of
4-Substituted-1,2,4-triazolidine-3,5-diones
from Anilines
Shadpour Mallakpour and Zahra Rafiee
Organic Polymer Chemistry Research Laboratory, College of Chemistry,
Isfahan University of Technology, Isfahan, Iran
Abstract: A simple and efficient three-step synthetic procedure for the preparation of
4-substituted phenyl derivatives of 1,2,4-triazolidindiones (urazoles), starting from
anilines, has been developed. In this method, aniline derivatives were reacted with
4-nitrophenyl chloroformate to provide corresponding carbamate derivatives. In the
second step, semicarbazide derivatives were prepared from these carbamates by
reaction with ethyl carbazate. The cyclization reaction of corresponding semicarba-
zides furnished 1,2,4-triazolidindiones in high yields.
Keywords: anilines, blocking agent, heterocyclic compounds, isocyanates,
p-nitrophenyl chloroformate, urazole derivatives
INTRODUCTION
Urazole derivatives are very interesting five-membered heterocyclic
compounds that contain three nitrogen atoms and two carbonyl groups. At
position 4, one can have a wide variety of aliphatic as well as aromatic sub-
stituents. These heterocyclic compounds have two N-H protons. These
protons are rather acidic with pKa of 4.71, almost the same as that of acetic
acid,[1] and can be replaced by different functional groups.
Much efforts has been directed toward development of methods for the
synthesis of numerous urazoles.[2–4] In general, substituted urazoles are
Received in the U.K. July 17, 2006
Address correspondence to Shadpour Mallakpour, Organic Polymer Chemistry
Research Laboratory, College of Chemistry, Isfahan University of Technology,
Isfahan 84156-83111, Iran. E-mail: mallak@cc.iut.ac.ir
1927

1928
S. Mallakpour and Z. Rafiee
prepared starting from isocyanates, amines, anilines, and carboxylic acids.
They are prepared in five steps from corresponding carboxylic acids[5,6] and
in two steps from corresponding isocyanates. In the case of anilines, 2-ethoxy-
carbonylhydrazinecarbonyl chloride has been used, which was prepared from
reaction of highly toxic and noxious phosgene gas with ethylcarbazate.[2]
Some urazole derivatives were found to be potent cytotoxic agents in
murrain and human cancer cell lines and also to reduce DNA synthesis signifi-
cantly, with moderate reduction in RNA synthesis. Kinetic studies suggest that
the inhibition of rate-limiting enzymes is responsible for its cytotoxicity.
Other pharmaceutical properties of urazole derivatives are hypolipidemic
activity via lowering both serum cholesterol and triglyceride levels[7] and
use as herbicides,[8] pesticides,[9] and insecticides.[10a–c] Preparation of
polymeric materials[11a–f] and manufacture of heat-resistant coatings,[12] tire
rubbers with high gripability,[13] and melamine resins[14] are among the
uses in the field of polymerization of urazole derivatives. Urazoles could
also be oxidized to the corresponding triazolinedione derivatives,[15a–e]
which are very active species toward cycloaddition and ene reactions[16a–d]
and as novel, reusable reagents for the oxidation of pyrazolines.[17]
RESULTS AND DISCUSSION
The purpose of this study was to develop a new and simple procedure for the
preparation of the 4-substituted phenylurazoles starting from anilines and
primary amines, which are relatively less toxic, more available, and less
expensive than corresponding diisocyanates. The aniline and its derivatives
were allowed to react with p-nitrophenyl chloroformate in the presence of
Et3N to afford carbamate 1. Subsequent reaction of 1 with ethyl carbazate
gave the corresponding 4-aryl-ethoxycarbonylsemicarbazide 3. Under these
conditions, two pathways are possible: (1) the direct addition of the ethyl
carbazate to the carbamate 1 to obtain product 3 or (2) the conversion of 1
to isocyanate 2 by elimination of the 4-nitrophenol moiety with subsequent
addition of another equivalent ethyl carbazate to give product
(Scheme 1).[18]
3
Compound 1 can be considered a blocked isocyanate. At high tempera-
tures, elimination of the blocking agent leads to the formation of free isocyanate
2, which then reacts with ethyl carbazate to form the corresponding semicarba-
zide 3. The IR absorption of compound 2 shows a characteristic strong peak
for isocyanate group at 2258 cm21. The cyclization reaction of the
4-aryl-ethoxycarbonylsemicarbazide 3 was performed in the usual manner
using sodium ethoxide as a base to furnish urazole derivatives 4a–4h in high
yields. The results are shown in Table 1. The MS spectra of 4d, 4e, and 4g
showed their molecular ion peaks that are consistent with the structure of
1
these compounds. The H NMR of compounds 4d, 4e, and 4g also confirmed
their structures.

4-Substituted-1,2,4-triazolidine-3,5-diones
1929
Scheme 1. Synthesis of 4-substituted-1,2,4-triazolidine-3,5-diones. Reagents and
conditions: (a) 4-NO2PhOCOCl, NEt3, THF/dichloromethane (DCM) (1:1 v/v), 08C
to 258C, 2 h; (b) NEt3, toluene, reflux, 8 h; (c) NH2NHCOOEt, THF, 258C (1 h) to
reflux (8 h); (d) NH2NHCOOEt, toluene, 08C to 258C, 8 h; (e) EtO2Naþ, reflux, 5 h.
It is interesting that for all urazoles prepared in this work, the yields of the
first and third step are rather high and the yield of second step is moderate to high.
In summary, we have developed a very simple and efficient route for the
synthesis of urazole derivatives starting from anilines and primary amine. In
Table 1. Conversion of anilines to 4-substituted-1,2,4-triazolidine-3,5-dione 4a–4h
Urazole yield
(%)
Compound
Ar
M.S. m/e
Mp (8C)
4a
C6H5-
90
—
204–206 (Lit.[19]
209–210)
:
4b
4c
p-Cl-C6H4-
p-NO2-C6H4-
95
98
—
—
233 (Lit.[20]: 236)
265–266 (Lit.[21]
:
264)
246–247
—
4d
4e
4f
o-NO2-C6H4-
m-NO2-C6H4-
Benzyl-
93
96
89
93
92
222
(Mþ)
222
214–216
—
184 (Lit.[22]: 189–
(Mþ)
—
190)
238–240
—
244–246 (Lit.[23]
243–244)
4g
4h
2-Cl-4-NO2-C6H3-
p-Me-C6H4-
257
(Mþ)
—
:

1930
S. Mallakpour and Z. Rafiee
this method, isocyanate is not used, and the reaction could be generated in situ
from isocyanate or even without isocyanate. This method is safe and can be
used for a wide variety of urazole synthesis. Furthermore, aniline derivatives
are more available and less expensive than corresponding isocyanates, which
will provide more choices for the synthesis of a wide variety of known and
novel urazoles. 2-Nitrophenyl urazole cannot be prepared from its carboxylic
acid derivative, but it was prepared simply by this method from its aniline
derivative in high yield.
EXPERIMENTAL
Materials
All reagents were purchased from Merck Chemical and Riedel-deHaen AG
(Seelze, Germany). Tetrahydrofuran (THF) was distilled from sodium-benzo-
phenone immediately before use. Petroleum ether is the fraction with 40–
1
558C. Proton nuclear magnetic resonance H NMR (500-MHz) spectra were
recorded in dimethyl sulfoxide (DMSO-d6) on a Bruker (Germany), Avance
500 instrument. IR spectra were recorded on a Shimadzu (Kyoto, Japan) 435
IR spectrophotometer. Spectra of solids were carried out using KBr pellets.
Vibrational transition frequencies are reported in wavenumber (cm21). All
melting points were taken with a Gallenham melting-point apparatus.
Typical Experimental Procedures and Data for Representative
Examples
Preparation of the 4-Nitrophenyl Carbamate (1)
2-Nitroaniline (0.1 g, 7.24 ꢀ 1024 mol) was dissolved in 10 mL of dry THF/
DCM (1:1 v/v), then cooled to 08C, and NEt3 (0.10 mL, 7.24 ꢀ 1024 mol)
was added. The reaction mixture was stirred for 10 min, and then a solution
of 4-nitrophenylchloroformate (0.146 g, 7.24 ꢀ 1024 mol) in dry THF/
DCM (1:1 v/v) (5 mL) was added dropwise in a period of 10 min. The
reaction mixture was stirred for 1 h at the same temperature and 1 h at
room temperature. Finally it was filtered off, washed with distilled water,
and dried under vacuum at 808C to give compound 1d. Mp: 118–1198C. IR
(KBr): 3350 (s, N-H), 1745 (s, C55O), 1485 (s, NO2), 1380 (s, NO2), 1290
(s, C-O) cm21. Yield: 0.200 g (91%).
Preparation of the Isocyanate (2)
4-Nitrophenyl carbamate (0.2 g, 6.59 ꢀ 1024 mol) was dissolved in dry
toluene (10 mL), and NEt3 (0.09 mL, 6.63 ꢀ 1024 mol) was added. The

4-Substituted-1,2,4-triazolidine-3,5-diones
1931
reaction mixture was refluxed for 8 h, and the progress of the reaction was
monitored by IR and thin-layer chromatography (TLC), then it was cooled
and filtered off to remove a small amount of undissolved solid. The isocyanate
was not isolated and was used directly for the next step of the reaction.
Preparation of the Semicarbazide (3) from Isocyanate (2)
Clear pale-yellow solution was cooled in an ice bath, and a solution of ethyl
carbazate (0.069 g, 6.59 ꢀ 1024 mol) in dry toluene (3 mL) was added
dropwise in a period of 10 min. The solution was allowed to reach to room temp-
erature and stirred for 8 h. After cooling in a water bath, the white crystals were
collected and dried under vacuum to give compound 3d. Mp: 178–1798C. IR
(KBr): 3250 (s, N-H), 2988 (m, C-H), 1759 (s, C55O), 1668 (s, C55O), 1490
(s, NO2), 1385 (s, NO2), 1240 (s, C-O) cm21. Yield: 0.145 g (82%).
Preparation of the Semicarbazide (3) from 4-Nitrophenyl Carbamate (1)
4-Nitrophenyl carbamate (0.2 g, 6.59 ꢀ 1024 mol) was dissolved in dry THF
(10 mL). After cooling to 08C, ethyl carbazate solution (0.069 g, 6.59 ꢀ 1024
mol) in dry THF (5 mL) was added dropwise. The slurry mixture was allowed
to reach to room temperature and was kept at this temperature for 1 h, then
refluxed for 8 h. The resulting white solid was washed with diethyl ether
several times. The white solid was collected by filtration and dried under
vacuum to give compound 3d. Yield: 0.139 g (79%).
Preparation of the Urazole (4d)
Sodium metal (0.017 g, 7.46 ꢀ 1024 mol) was dissolved in absolute ethanol
(25 mL). Nitrogen gas bubbled through the solution, and 1-ethoxycarbonyl-
4-(2-nitrophenyl) semicarbazide (0.2 g, 7.46 ꢀ 1024 mol) was added at
once. The solution was refluxed under nitrogen atmosphere for 5 h, and
then it was cooled in an ice bath. The solution was neutralized with conc.
HCl to reach to a pH of 2. The product was isolated and dried to give
1
compound 4d (Table 1). H NMR (500 MHz, DMSO-d6, d, ppm): d 7.86–
7.88 (m, 2H, Ar-H), 8.32–8.34 (m, 2H, Ar-H), 10.72 (s, 2H, N-H). IR
(KBr): 3200 (s, N-H), 1780 (m, C55O), 1700 (s, C55O), 1500 (s, NO2),
1350 (s, NO2) cm21. MS: m/z ¼ 222 (Mþ), Yield: 0.154 g (93%).
Data
4-Phenyl-1,2,4-triazolidine-3,5-dione (4a)
Yields: First step: 88%; second step: 41%; third step: 90%. IR (KBr): 3100
(s, N-H), 1780 (m, sh, C55O), 1680 (s, C55O) cm21
.

1932
S. Mallakpour and Z. Rafiee
4-(4-Chlorophenyl)-1,2,4-triazolidine-3,5-dione (4b)
Yields: First step: 91%; second step: 72%; third step: 95%. IR (KBr): 3200
(s, N-H), 1770 (s, sh, C55O), 1690 (s, C55O), 780 (s, C-Cl) cm21
.
4-(4-Nitrophenyl)-1,2,4-triazolidine-3,5-dione (4c)
Yields: First step: 93%; second step: 91%; third step: 98%. IR (KBr): 3200
(s, N-H), 1770 (m, C55O), 1720–1650 (s, br, C55O), 1510 (s, NO2), 1340
(s, NO2) cm21
.
4-(3-Nitrophenyl)-1,2,4-triazolidine-3,5-dione (4e)
1
Yields: First step: 92%; second step: 87%; third step: 96%. H NMR (500
MHz, DMSO-d6, d, ppm): d 7.68–7.72 (m, 2H, Ar-H), 7.86–7.90
(m, 1H, Ar-H), 8.13–8.15 (dd, 1H, Ar-H, J1 ¼ 8.08 Hz, J2 ¼ 1.18 Hz),
10.83 (s, 2H, N-H). IR (KBr): 3200 (s, N-H), 1770 (m, C55O),
1679 (s, C55O), 1500 (s, NO2), 1350 (s, NO2) cm21. MS: m/z ¼
222 (Mþ).
4-Benzyl-1,2,4-triazolidine-3,5-dione (4f)
Yields: First step: 85%; second step: 63%; third step: 89%. IR (KBr): 3240
(s, N-H), 2900 (m, C-H), 1780 (m, C55O), 1710 (s, C55O) cm21
.
4-(2-Chloro-4-nitrophenyl)-1,2,4-triazolidine-3,5-dione (4g)
Yields: First step: 87%; second step: 76%; third step: 93%.1H NMR
(500 MHz, DMSO-d6, d, ppm): d 7.95–7.98 (m, 1H, Ar-H), 8.18–8.21
(m, 1H, Ar-H), 8.29–8.30 (m, 1H, Ar-H), 10.84 (s, 2H, N-H). IR (KBr):
3230 (s, N-H), 1780 (m, C55O), 1690 (s, C55O), 1500 (s, NO2), 1340
(s, NO2), 780 (s, C-Cl) cm21. MS: m/z ¼ 257 (Mþ).
4-(4-Methylphenyl)-1,2,4-triazolidine-3,5-dione (4h)
Yields: First step: 94%; second step: 71%; third step: 92%. IR (KBr):
3200 (s, N-H), 1770 (m, C55O), 1710 (s, C55O) cm21
.
ACKNOWLEDGMENTS
We express our gratitude to the Research Affairs Division, Isfahan University
of Technology (IUT), Isfahan, for partial financial support. Further financial
support from Center of Excellency in Chemistry Research (IUT) is gratefully
acknowledged.

4-Substituted-1,2,4-triazolidine-3,5-diones
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