A one-pot synthesis of 4,5-disubstituted-1,2,4-triazole-3-thiones on solid support under microwave irradiation

Article abstract of DOI:10.1080/10426500500542992

4,5-Di-substituted-1,2,4-triazole-3-thiones (4a-f) have been prepared in one stage from the reaction of acid hydrazide 1 with alkyl or aryl isothiocyanate 2 in the presence of a KOH (10%) solution on the surface of silica gel as well as on the surface of montmorillonite K10 under microwave irradiation. These triazoles have also been prepared from the reaction of 4-substituted-1-aroyl thiosemicarbazides 3a-e, with a KOH (10%) solution on the surface of silica gel under microwave irradiation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500542992

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Phosphorus, Sulfur, and Silicon
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A One-Pot Synthesis of 4,5-
Disubstituted-1,2,4-triazole-3-
thiones on Solid Support under
Microwave Irradiation
a
a
Shahnaz Rostamizadeh , Kambiz Mollahoseini
&
a
Samar Moghadasi
a
Department of Chemistry, K.N. Toosi University of
Technology, Tehran, Iran
Available online: 01 Feb 2007
To cite this article: Shahnaz Rostamizadeh, Kambiz Mollahoseini & Samar Moghadasi
(2006): A One-Pot Synthesis of 4,5-Disubstituted-1,2,4-triazole-3-thiones on Solid
Support under Microwave Irradiation, Phosphorus, Sulfur, and Silicon and the Related
Elements, 181:8, 1839-1845
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Phosphorus, Sulfur, and Silicon, 181:1839–1845, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500542992
A One-Pot Synthesis of 4,5-Disubstituted-1,2,4-triazole-
3
-thiones on Solid Support under Microwave Irradiation
Shahnaz Rostamizadeh
Kambiz Mollahoseini
Samar Moghadasi
Department of Chemistry, K.N. Toosi University of Technology,
Tehran, Iran
4,5-Di-substituted-1,2,4-triazole-3-thiones (4a–f ) have been prepared in one stage
from the reaction of acid hydrazide 1 with alkyl or aryl isothiocyanate 2 in the
presence of a KOH (10%) solution on the surface of silica gel as well as on the
surface of montmorillonite K10 under microwave irradiation. These triazoles have
also been prepared from the reaction of 4-substituted-1-aroyl thiosemicarbazides
3a–e, with a KOH (10%) solution on the surface of silica gel under microwave
irradiation.
Keywords Acid hydrazide; isothiocyanate; microwave irradiation; solid support
INTRODUCTION
In recent years, there has been much attention in the use of surfaces of
inorganic oxides, such as silica, alumina, etc., as a nonconventional re-
1
,2
action medium for the preparation of organic compounds. Moreover,
advantages of using microwave energy for conducting synthetic trans-
formations, at highly accelerated rates, has become popular among or-
ganic chemists.3 A combination of microwave heating together with
using solid supports is now a very useful technique for conducting or-
ganic reactions.
,4
Many compounds bearing five-membered heterocyclic rings in their
structure have an extensive spectrum of pharmacological activi-
ties. Among them,1,2,4-triazole derivatives have attracted consid-
5
,6
7,18
erable interest and can be used as antifungal,
antibacterial,
Received January 4, 2005; accepted November 1, 2005.
Address correspondence to Shahnaz Rostamizadeh, K.N. Toosi University of Technol-
ogy, Department of Chemistry, P.O. Box 15875-4416, Tehran, Iran. E-mail: rostamizadeh@
hotmail.com
1839

1
840
S. Rostamizadeh et al.
TABLE I The Condesation of Acid
Hydrazides 1 and Corresponding
Aryl or Alkyl Isothiocyanates 2
Product
R1
R2
a
b
c
d
e
f
C6H5
4-Cl-C6H4
C6H5
4-Cl-C6H4
4-NO2-C6H4
CH3
C6H5
C6H5
CH3
CH3
C6H5
C6H5
8
9
10
antiinflammatory, antiasthmatic, antidepressant, tuberculothera-
1
1
12
13
peutic, hypoglycemic, and diuretic activities.
RESULTS AND DISCUSSION
In the twenty-first century, for which time is an important aspect to all
of us, finding methods that make longer reactions easy is very impor-
tant. In this research, we take advantage of microwave heating together
with using mineral solid supports, such as silica gel, alumina, etc., to
prevent the formation of byproducts, bring about a simple work-up, and
therefore shorten the reaction time.
1
,2,4-Triazole-3-thiones have been prepared from the reaction of
thiosemicarbazide with acyl halides and a subsequent cyclization of
1
4−17,10
the intermediate acylthiosemicarbazides in basic media.
They
also have been prepared from the reaction of acid hydrazides and
isothiocyanates.5
,18−22
A formation of these compounds from the reac-
tion of acid hydrazides with carbon disulfide and hydrazine hydrate was
also reported in the literature.8c The reaction of aroyl isothiocyanates
with hydrazine derivatives has also led to the formation of these types of
2
3,24,10
compounds.
thetic route to these compounds.
A continuation of our work on the synthesis of 1,2,4-triazoles,
A thionation of 1,2,4-triazole-3-ones is another syn-
25
2
6
and also the considerable biological activities of these useful triazoles,
prompted us to synthesize them via a very simple method.
In the present work, 3H-1,2,4-triazole-3-thiones-2,4-dihydro-4-
phenyl(methyl)-5-(4-substituted phenyl or methyl) have been prepared
by two methods (Scheme 1, Table 1). In the first one (Method A), we
first prepared 4-substituted-1-aroyl thiosemicarbazides 3a–f from the
reaction of acidhydrazides 1 and phenyl isothiocyanates 2 on the sur-
face of silica gel under microwave irradiation (Table II). A subsequent

4
,5-Disubstituted-1,2,4-Triazole-3-Thiones
1841
TABLE II The Preparation of Intermediates 3a–f
Product
Time (min)
Power (W)
Yield (%)
3a
3b
3c
3d
3e
3f
10
8
8
8
8
750
750
750
750
750
750
60
66
70
70
67
68
8
cyclization of these intermediates with a 10% KOH solution on the sur-
face of silica gel under microwave irradiation resulted in the forma-
tion of the triazoles 4a–f (Table III). In this method, only the inter-
mediate 1-benzoyl-4-phenyl-thiosemicarbazide 3a was identified, and
for the rest, 3b–f, only the final products 1,2,4-triazole-3-thiones 4a–
f were characterized by a comparison of their spectral and physi-
cal data with those of known samples. In Method B, it was then
decided to repeat the reaction by mixing all the starting materials
in one stage as a one-pot procedure. In this method for the prepa-
ration of 1,2,4-triazole-3-thiones 4a–f, an optimization of the reac-
tion conditions was carried out for the preparation of compound 4a.
(
a) The mixture of benzhydrazide 1a, phenylisothiocyanate 2a, and
◦
KOH 10% was first heated at 130 C under reflux condition. After re-
fluxing the mixture for 9 h, the product 4a obtained in a low yield.
(
b) The same reaction was also carried out in the presence of silica gel.
In this case, the reaction had gone to completion after 3 h without any
significant change in the yield of product 4a. (c) It was then decided to
do the same experiment on the surface of silica gel under microwave
irradiation. In this experiment, the product 4a obtained in an 82% yield
after 8 min. (d) When we used montmorillonit K10 instead of silica gel,
the same product was obtained in an 86% yield after 6 min without
TABLE III The Yield and Physical Characteristics of
4,5-Substituted-1,2,4-triazole-3-thiones on the Surface of Silica
Gel (Method A)
◦
◦
Product Time (min) Power (W) Yield (%) M.P. ( C) Lit. M.P. ( C) Ref.
4
4
4
4
4
4
a
b
c
d
e
f
8
6
6
6
6
8
750
750
750
750
750
750
82
80
70
75
85
70
280–282
271–272
166
209–210
268–269
214–215
277–278
272–273
164–166
210–212
270–271
215
13
27
10
10
17
28

1
842
S. Rostamizadeh et al.
SCHEME 1
any significant change in the chemical yield. Repetition of this exper-
iment on the surface of clayfen, neutral, and basic alumina, resulted
in the formation of more than one product. It should be noted that dif-
ferent irradiation power was also studied in which 750 W was the best
condition.
Therefore, the triazoles-3-thiones 4a–f were prepared from the re-
action of acidhydrazide 1, phenyl isothiocyanates 2, and 10% KOH
solution, on the surface of silica gel as well as on the surface of mont-
morillonit K10, under microwave irradiation (Scheme 1, Table IV).
TABLE IV The Yield and Physical Characteristics of
4
,5-Substituted-1,2,4-triazole-3-thiones on the Surface of Silica
Gel and Montmorillonite at 750 W (Method B)
Time (min) Yield (%)
◦
◦
Product
SiO2
K10
SiO2
K10
M.P. ( C)
Lit. M.P. ( C)
Ref.
4
4
4
4
4
4
a
b
c
d
e
f
8
8
10
10
6
6
4
6
6
4
8
85
88
78
75
90
77
86
87
81
78
88
72
280–282
271–272
166
209–210
268–269
214–215
277–278
272–273
164–166
210–212
270–271
215
13
27
10
10
17
28
8

4
,5-Disubstituted-1,2,4-Triazole-3-Thiones
1843
Thus, it seems that Method B, the one-pot procedure, provided an
easy route to these types of triazoles without isolating the intermediates
3
a–f, in comparison to Method A. Also, by performing the reaction on
the surface of montmorillonit K10, the reaction time was shortened
without any significant change in chemical yields. A moderate yield,
short reaction time, and easy work-up are advantages of this method
in comparison to the procedures in the literature.
EXPERIMENTAL
All products are known compounds and were identified by comparison
of their spectral and physical data with those of known samples. Melt-
ing points were taken on an Electrothermal 9100 aparatus. IR spec-
tra were recorded with Shimadzu IR-480 spectrometer (KBr). The 1H
NMR spectra were determined in CDCl3 on a Bruker DRX-500 Avance
(
500 MHz). Microwave irradiation was carried out using a domestic
microwave oven (Moulinex 2735A). Acid hydrazides were obtained ac-
cording to the literature29 by treating the corresponding esters with
hydrazine in ethanol under microwave irradiation.
The General Procedure for the Synthesis of
1-Aroyl-4-substituted Thiosemicarbazide (3a–e)
A mixture of methyl or phenyl isothiocyanates (1.5 mmol), acid hy-
drazides (1 mmol), and SiO2 (2 g) was well ground in a mortar and
then subjected to microwave irradiation in an open Pyrex beaker at
an appropriate power and time (Table II). The progress of the reaction
was monitored by TLC. After the completion of the reaction, the mix-
ture was extracted with ethyl acetate (250 mL). The extracts were then
combined, washed with water, and dried over MgSO4. An evaporation of
the solvent under vacuo gave the corresponding 1-aroyl-4-substituted
thiosemicarbazides.
The General Procedure for the Synthesis of 3H-1,2,4-Triazole-
3
-thiones-2,4-dihydro-4-phenyl(methyl)-5-(4-substituted
Phenyl or Methyl) (Method A)
A mixture of 1-aroyl-4-substituted thiosemicarbazides (2 mmol), KOH
(
10%) (2–3 mL), and SiO2 (2 gr), was well ground in a mortar and
then subjected to microwave irradiation in an open Pyrex beaker at
an appropriate power and time (Table III). The progress of the reaction
was monitored by TLC. After the completion of the reaction, the mix-
ture was extracted with ethyl acetate (250 mL); the extracts were then

1
844
S. Rostamizadeh et al.
combined, washed with water, and dried over MgSO4. An evaporation
of the solvent under vacuo gave the corresponding 4,5-di-substituted-
1,2,4-triazole-3-thiones. The products were further purified by recrys-
tallization from ethaol.
The General Procedure for the Synthesis of 3H-1,2,4-Triazole-
3
-thiones-2,4-dihydro-4-phenyl(methyl)-5-(4-substituted
Phenyl or Methyl (Method B)
A mixture of methyl or phenyl isothiocyanates (1.5 mmol), acid hy-
drazides (1 mmol), KOH (10%) (2–3 mL), montmorillonit K10, or silica
gel (2 g) was well ground in a mortar and then subjected to microwave
irradiation in an open Pyrex beaker at an appropriate power and time
(
Table IV). The progress of the reaction was monitored by TLC. After
the completion of the reaction, the mixture was extracted with ethyl
acetate (250 mL); the extracts were then combined, washed with wa-
ter, and dried over MgSO4. An evaporation of the solvent under vacuo
gave the corresponding 4,5-di-substituted-1,2,4-triazole-3-thiones. The
products were further purified by recrystallization from ethanol.
In conclusion, we have developed the one-pot synthesis of 4,5-di-
substituted-1,2,4-triazole-3-thiones to demonstrate once more that a
great simplification can be achieved by carrying out organic reactions
both on solid support and by exposing them to microwave irradiations.
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