The microwave-assisted dehydrative cyclization of thiosemicarbazides forming substituted 1,2,4-triazoles

Article abstract of DOI:10.1080/10426500500543859

Different types of 4,5-disubstituted 1,2,4-triazole-3-thiones were prepared by microwave irradiation as well as by a classical method. The beneficial effect of microwave irradiation on the dehydrative cyclization of thiosemicarbazides in different reactio

Full text of DOI:10.1080/10426500500543859

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Phosphorus, Sulfur, and Silicon
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The Microwave-Assisted
Dehydrative Cyclization of
Thiosemicarbazides Forming
Substituted 1,2,4-Triazoles
Khosrow Zamani a & Shirindokht Bagheri a
a Department of Chemistry , Arak University , Arak,
Iran
Published online: 01 Feb 2007.
To cite this article: Khosrow Zamani & Shirindokht Bagheri (2006) The Microwave-
Assisted Dehydrative Cyclization of Thiosemicarbazides Forming Substituted 1,2,4-
Triazoles, Phosphorus, Sulfur, and Silicon and the Related Elements, 181:8, 1913-1918,
DOI: 10.1080/10426500500543859
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Phosphorus, Sulfur, and Silicon, 181:1913–1918, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500543859
The Microwave-Assisted Dehydrative Cyclization of
Thiosemicarbazides Forming Substituted 1,2,4-Triazoles
Khosrow Zamani
Shirindokht Bagheri
Department of Chemistry, Arak University, Arak, Iran
Different types of 4,5-disubstituted 1,2,4-triazole-3-thiones were prepared by mi-
crowave irradiation as well as by a classical method. The beneficial effect of mi-
crowave irradiation on the dehydrative cyclization of thiosemicarbazides in dif-
ferent reaction media is described. Our results show that the effect of microwave
irradiation on the reaction studied was the shortening of reaction times (from 2–9 h
to 2–4 min) and a minor decrease (1–4%) in yields. The structure of the new com-
1
pounds was established by FTIR, MS, and H NMR spectral data.
Keywords Cyclization; microwave; thiosemicarbazides
INTRODUCTION
Substituted 1,2,4-triazoles are of interest because of their indus-
try application1 and biological activity, such as bactericidal,2 and
antiinflammatory,3 and antiviruse activity.4 The 1,2,4-triazole ring is
obtained either by the synthesis from acyclic compounds or by the trans-
formation of other cyclic systems. A number of methods for the synthesis
of substituted 1,2,4-triazole are present in the literature.5,6 The forma-
tion of this heterocycle can be the main reaction with semicarbazides
or thiosemicarbazides, which are used extensively in the preparation
of the triazolinones and triazolinethiones in an alkaline medium. How-
ever, the majority of these methods requires a long time for a comple-
tion of the reaction. The development of simple and efficient methods
of synthesis of new analogues of 1,2,4-triazole compounds from readily
synthesized starting material has become an important problem in our
laboratory in these years. Recently, we have described the preparation
of some new substituted 1,2,4-triazoles in good to moderate yields by
Received January 24, 2005; accepted October 20, 2005.
Address correspondence to Khosrow Zamani, Arak University, Department of
Chemistry, Arak, 38156 Iran. E-mail: k-zamani@araku.ac.ir
1913

1914
K. Zamani and S. Bagheri
a classical method of dehydrative cyclization of the thiosemicarbazides
in an alkaline madium.7
In the last few years, there has been an interest in the use of mi-
crowave heating in organic synthesis.8−10 The use of such unconven-
tional reaction conditions reveals several features, like a short reac-
tion time compared to conventional heating, an ease of work-up after
the reaction, a reduction in the usual thermal degradation, and better
selectivity.11 A reaction under “dry conditions” (i.e., the absence of a sol-
vent, on a solid support with or without catalyst) was originally devel-
oped in the late 1980s.12 Synthesis without solvents under microwave
irradiation offers several advantages13 because solvent are often expen-
sive, toxic, difficult to remove, and are environmental polluting agents.
The absence of a solvent reduces the risk of explosions when the reac-
tion takes place in a closed vessel in an oven.
Now we describe here the synthesis of some 4,5-disubstituted 1,2,4-
triazoles by the reaction of thiosemicarbazide in a few drops of ethanol
in the presence of sodium hydroxide using microwave irradiation. For
comparison of the reaction rate and the yield of the reaction, these
reactions were carried out with alumina or silica gel instead of sodium
hydroxide as base (Scheme 1).
SCHEME 1
RESULTS AND DISCUSSION
The aim of this article is to show that under microwave irradiation
the intramolecular dehydrative cyclization of substituted thiosemicar-
bazides can be successfully applied to the synthesis of a number of sub-
stituted 1,2,4-triazoles. It is reported as a very simple, rapid, and gen-
eral procedure in the presence of a base under solvent-free conditions.
The time required favorably is less than those for traditional heating.
The reaction is usually completed within 2–4 min and gives good to
moderate yields. No product was obtained when we did not use any
basic support. In the absence of ethanol, the yield of the reaction was
low (Table I). The microwave-assisted synthesis of 4,5-disubstituted

Thiosemicarbazides
1915
TABLE I Physical Data for Compounds 4,5(a–c) Prepared by a
Microwave Irradiation in a Different Base
Compounds
Base
Temp. Time (min) Power (W) M.P. (◦C) Yield %
3a
3b
3c
4a
4b
4c
3a
3b
3c
4a
4b
4c
3a
3b
3c
4a
4b
4c
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Alumina
Alumina
Alumina
Alumina
Alumina
Alumina
NaOH
250
250
250
250
250
180
250
250
250
250
250
180
250
250
250
250
250
180
5
5
5
5
5
5
5
5
5
5
5
5
2
3
3
3
4
4
900
450
900
150
900
900
900
450
900
450
900
900
450
450
450
300
300
300
182–184
173–175
209
219
234–236
279
32
23
25
25
25
29
32.5
26
31
32
31
25
85
75
75
72
95
86
185
172–174
209–211
218–220
235
270.5
182–184
176
210
219–220
231
NaOH
NaOH
NaOH
NaOH
NaOH
273
1,2,4-triazoles in the presence of sodium hydroxide instead of silica gel
or alumina and a few drops of ethanol (10 drops) improved the yields
of the products 2–3 times. Moreover, the work-up procedure was sim-
ply reduced to the acidification of the product in an appropriate solvent
and filtration. The results from the experiments are shown in Tables I
and II. In Table III, yields of the cyclization under different conditions
TABLE II Physical Data of Compounds 3,4(a–c) Preparation by a
Classical Condition
Reflux (h)
Time
Reported
Compounds
R
Rꢀ
M.P. (◦C) M.P. (◦C) Yield, %
3a
3b
3c
4a
4b
4c
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Pyridyl 2-Methylphenyl
3-Pyridyl 2-Methylphenyl
4-Pyridyl 2-Methylphenyl
Benzyl
Benzyl
Benzyl
2
9
8
4
9
7
187–188
175
212
219
231.5
273–274
184.514
175.514
212.514
—
—
—
84
76
98
83
76.4
89

1916
K. Zamani and S. Bagheri
TABLE III The Yields of 4,5-Disubstituted 1,2,4-Triazoles
3–4(a–c)
Compounds Reaction Condition
3a 4a
3b
4b
3c
4c
Traditional method
Microwave/NaOH
Microwave/Silica gel
Microwave/Alumina
Microwave/Silica gel/2–5 drops of ethanol
Microwave/Alumina/2–5 drops of ethanol
84
85
32
33
32
33
81
77
25
32
25
32
76
75
23
26
23
26
76
72
25
31
25
31
98
95
25
81
25
81
89
86
29
25
29
25
are compared. It is revealed from the table that the best conditions for
cyclization under microwave irradiation were obtained when sodium
hydroxide was used as a base and the reaction was carried out in pres-
ence of ethanol. All of the synthesized compounds were characterized
by their melting points and FTIR, 1H NMR, and mass spectroscopy.
EXPERIMENTAL
Melting points were determined using an electerothermal melting point
apparatus. Fourier transformer infrared spectra were recorded on a
Galaxy series FTIR 5000 spectrophotometer (KBr). 1H NMR spec-
tra were recorded on a Bruker 500 MHz instrument. The EIMS was
recorded on a MAT-112-s-machine.
General Procedure
Method 1. Thiosemicarbazides 1–2(a–c) (0.01 mol) were added to 80–
180 mL of 4 N sodium hydroxide solution. The reaction mixture was
refluxed and was allowed to cool to r.t. It was filtered, and the filtrate
was acidified with 4 N hydrochloric acid. The solid was removed by
filtration, washed with water, and recrystallized (ethanol/water 70:30).
Method 2. Thiosemicarbazides 1–2a–c (1.6 × 10−4 mol) was mixed
with an inorganic solid support (sodium hydroxide, silica gel, or alu-
mina) (0.1 g). The mixture was homogenized and then was placed into
a quartz tube and irradiated in a microwave oven (Samsung microwave
oven CE 375 BF) for the time mentioned in Table I. After the mixture
was cooled to r.t. water was added, and the mixture was filtered. The
filtrate was acidified with 2 N hydrochloric acid. The precipitate was re-
moved by filtration, washed with cool water, dried, and recrystallaized
(ethanol:water 70:30). The physical data and yields of the products are
tabulated in Table I.

Thiosemicarbazides
1917
Method 3. Thiosemicarbazides 1–2a–c (1.6 × 10−4 mol) was mixed
with inorganic solid support (sodium hydroxide, silica gel, or alumina)
(0.1 g). Ethanol (2–5 drops) was added, and the mixture was homog-
enized and placed into a quartz tube. The previously discussed proce-
dures were then followed.
3a: IR (KBr): υmax 3078–3028 (Ar-H), 2927 (C H), 2768 (N CH),
1
2588 (SH), 1585, 1276 (C C, C N) cm−1; H NMR (500 MHz, DMSO-
d6) 4.71 (s, 2H, CH2), 4.72 (s, 0.6H, SH), 7.21 (s, 1H, Ar-H), 7.28–7.31 (d,
3H, Ar-H), 7.62–7.65 (t, 1H, Ar-H), 8.00–8.03 (t, 1H, Ar-H), 8.05–8.07
(d, 1H, Ar-H), 8.59 (s, 1H, Ar-H), 8.69 (s, 1H, Ar-H), 10.6 (s, 0.4H,
NH).
3b: IR(KBr): υmax 3125–3016 (Ar-H), 2885 (C H), 2727 (N CH),
1
2584 (SH), 1609, 1276 (C C, C N) cm−1; H NMR (500 MHz, DMSO-
d6) 4.2–4.3 (d, 2H, CH2), 5.1 (s, 0.6H, SH), 7.10–7.11 (d, 2H, Ar-H),
7.12–7.16 (d, 1H, Ar-H), 7.18–7.20 (d, 1H, Ar-H), 7.21(s, 1H, Ar-H), 7.24–
7.25 (d, 1H, Ar-H), 7.27–7.29 (d, 1H, Ar-H), 7.30–7.33 (d, 1H, Ar-H),
7.34–7.36 (d, 1H, Ar-H), 12.8 (s, 0.4H, NH).
3c: IR(KBr): υmax 3254–3011 (Ar-H), 2866 (N CH), 2651 (SH), 1651,
1388 (C C, C N) cm−1 1H NMR (500 MHz, DMSO-d6), 5.4 (s, 2H,
;
CH2), 7.03–7.05 (d, 2H, Ar-H), 7.24–7.27 (t, 3H, Ar-H), 7.55–7.56 (d,
2H, Ar-H), 8.6–8.67 (d, 2H, Ar-H), 14.39 (s, 1H, NH); mass spectrum
(70 ev): m/z (%) 268 (100), 267 (50), 235 (60), 169 (2), 149 (20), 131 (4),
105 (20), 91 (28), 78 (22).
4a: IR(KBr): υmax 3051–3028 (Ar-H), 2964 (C H), 2859 (N CH),
1
2565 (SH), 1604–1396 (C C, C N) cm−1; H NMR (500 MHz, DMSO-
d6) 1.9–2.2 (t, 3H, CH3), 5.4 (s, 0.7 H, SH), 7.03–7.04 (d, 2H, Ar-H),
7.22–7.24 (d, 2H, Ar-H), 7.23–7.26 (d, 1H, Ar-H), 7.55–7.56 (d, 2H,
Ar-H), 8.66–8.67 (d, 1H, Ar-H), 14.39 (s, 1H, NH).
4b: IR(KBr): υmax 3274–3058 (Ar-H), 2920 (C H), 2859 (N CH),
1
2499 (SH), 1654, 1354 (C C, C N) cm−1; H NMR (500 MHz, DMSO-
d6) 2.5 (s, 3H, CH3), 5.8 (s, 0.65H, SH), 7.13–7.18 (q, 2H, Ar-H),
7.2–7.23 (t, 2H, Ar-H), 7.4–7.52 (q, 1H, Ar-H), 7.93–7.94 (d, 2H, Ar-
H), 8.65–8.66 (d, 1H, Ar-H), 14.2 (s, 0.35H, NH). 13C NMR (500 MHz,
DMSO-d6) 150, 149, 148, 143, 141, 139, 138, 132, 131, 128, 126, 123,
121, 16.
4c: IR(KBr): υmax 3174–3120 (Ar-H), 2920 (C H), 2788 (N CH), 2482
1
(SH), 1585, 1242 (C C, C N) cm−1; H NMR (500 MHz, DMSO-d6)
2.3 (s, 3H, CH3), 5.7 (s, 0.8H, SH), 6.55 (s, 2H, Ar-H), 7.14–7.15 (d,
2H, Ar-H), 7.41 (s, 2H, Ar-H), 8.46–8.48 (d, 2H, Ar-H), 9.45 (s, 0.2H,
NH); mass spectrum (70 ev): m/z (%) 268 (100), 267 (90), 235 (100),
209 (10), 169 (40), 149 (10), 131 (65), 105 (10), 109 (40), 91 (22), 77
(22).

1918
K. Zamani and S. Bagheri
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