Rapid synthesis of 2,5-disubtituted 1,3,4-thiadiazoles under microwave irradiation

Article abstract of DOI:10.1002/jhet.5570420538

The one pot, three-components condensation of aromatic aldehydes, hydrazine and sulfur in ethanol under microwave irradiation provided symmetrically 3,5-disubstituted 1,3,4-thiadiazoles in high yields and good purity. This reaction must be conducted under pressure of hydrogen sulfide produced in-situ. The structure of the compounds was confirmed by ¹H, ¹³C NMR, MS and elemental analysis.

Full text of DOI:10.1002/jhet.5570420538

Jul-Aug 2005
991
Rapid Synthesis of 2,5-Disubtituted 1,3,4-Thiadiazoles under
Microwave Irradiation
a
a,b
a,
Mounim Lebrini , Fouad Bentiss and Michel Lagrenée *
a
Laboratoire de Cristallochimie et Physicochimie du Solide, CNRS UMR 8012
ENSCL, B.P. 90108, F-59652 Villeneuve d’Ascq Cedex, France
Laboratoire de Chimie de Coordination et d'Analytique, Université Chouaib Doukkali,
Faculté des Sciences, B.P. 20, El Jadida, Morocco
b
Received December 6, 2004
The one pot, three-components condensation of aromatic aldehydes, hydrazine and sulfur in ethanol under
microwave irradiation provided symmetrically 3,5-disubstituted 1,3,4-thiadiazoles in high yields and good
purity. This reaction must be conducted under pressure of hydrogen sulfide produced in-situ. The structure of
1
13
the compounds was confirmed by H, C NMR, MS and elemental analysis.
J. Heterocyclic Chem., 42, 991 (2005).
Introduction
must be conducted under pressure of hydrogen sulfide. For
this purpose we have used a microwave equipment
designed for extraction, digestion, dissolution, hydrolysis
or drying material. The primary purpose of this equipment
is the rapid preparation of samples for a variety of analysis
procedures, but we report here that it can be very efficient
for organic syntheses, which must be carried out under a
moderate controlled pressure. In each synthesis of thiadia-
zoles, the initial product is the yellow colored benzalazine,
which can be isolated after 15 mn of reaction. After 1 h of
microwave heating under pressure of hydrogen sulfide, the
thiadiazoles can be obtained in excellent yields and good
purity. Under classical heating, a good completion of this
reaction required much longer times (12 h) and if the reac-
tion is stopped after 1 hour of reaction as in microwave
experiments, the thiadiazoles can be detected in very low
quantities, the major products of the reaction being the cor-
responding azines. 2-Chlorobenzaldehyde yields 3H-1,2-
benzodithiole-3-thione under the same experimental con-
ditions, as it was reported by G. Mazzone et al. [8]. The
elemental analysis (Table 2) and mass spectra are in accor-
dance with the proposed structures. The melting points of
the already known thiadiazoles agree will those reported in
As a part of a program directed to obtain heterocyclic
molecules which can be used as corrosion inhibitors [1-4]
and which can exhibit antimicotic and antibacterial activi-
ties [5,6], a number of symmetrically 2,5-disubstituted-
1,3,4-thiadiazoles are quickly prepared by the reaction of
aromatic aldehyde on hydrazine hydrate in presence of sul-
phur under microwave irradiation. Several publication and
patents describe the synthesis of these heterocyclic com-
pounds by treatment of mono or 1,2-dibenzoylhydrazine
with phosphorous pentasulfide [7] and by treatment of aro-
matic aldehydes with sulphur and hydrazine hydrate in a
steel autoclave at 150 °C for 12 hours [8]. Microwave
assisted organic reaction constitute an emerging technol-
ogy that make experimentally and industrially important
organic syntheses more effective and more eco-friendly
than conventional reactions [9,10]. This technique has
been applied with success to a number of synthesis of het-
erocylic compounds proceeding with or without solvent
such as 1,2,4-triazoles [11,12], 1,3,4-oxadiazoles [13] and
1,3,4-thiadiazoles [14].
Results and Discussion
1
13
The reaction of aromatic aldehydes with hydrazine
hydrate and sulfur takes place in good yields and rapidly
under microwave irradiation (Scheme and Table 1) and
the literature (Table 2). The H and C nmr data are given
in Table 3 and 4. A typical reaction procedure is as follows
for the preparation compounds 2a-p.
Scheme 1
1, 2a Ar = 2-HOC H
1, 2i
Ar = 4-(CH ) NC H
3 2 6 4
6
4
b
c
d
e
f
Ar = 3-HOC H
j
k
l
m
n
o
p
Ar = 4-CH C H
Ar = 4-ClC H
6 4
6
4
3 6 4
Ar = 4-HOC H
6
4
Ar = 3,4-HOC H
Ar = 2-pyridyl
Ar =3-pyridyl
Ar = 4-pyridyl
Ar = 2-thienyl
Ar = 3-thienyl
6
4
Ar = C H
6
5
Ar = 2-CH OC H
3
6
4
4
4
g
h
Ar = 3-CH OC H
3 6
Ar = 4-CH OC H
3
6

992
M. Lebrini , F. Bentiss and M. Lagrenée
Vol. 42
Table 1
2,5-Diaryl-1,3,4-thiadiazoles 2a-p
Compound
No.
Ar
Yield
(%)
Mp
(°C)
Lit Mp
(°C)
m/z
(M +1)
References
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2-HOC H
83.7
97
97.4
94
89
87
94
92
76
94.2
94
230-231
273-274
308-309
318 dec.
143-144
305 dec
90-91
171.5-172
289-290
163-164
224-225
218-219
222-223
239-240
158-159
170.5-171
231-232
307-308
143-144
271
271
271
303
239
299
299
299
325
267
308
241
241
241
251
251
[8]
[8]
[8]
6
4
4
4
3-HOC H
6
4-HOC H
6
3,4-HOC H
6
4
C H
6
5
2-CH OC H
3
6
4
4
4
3-CH OC H
89-90
[8]
[8]
[8]
[8]
[8]
3
6
4-CH OC H
171-172
290-292
162-163
224-225
3
6
4-(CH ) NC H
3 2
6 4
4-CH C H
3
6 4
4-ClC H
6 4
2-pyridyl
3-pyridyl
4-pyridyl
2-thienyl
3-thienyl
80
83
82
75
78
Table 2
Elemental Analyses of 2a-p
Compound
No.
Molecular
Formula
Calcd.
Found
C
H
N
S
C
H
N
S
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
C
C
C
C
H
N O S
62.22
62.22
62.22
55.62
70.58
64.42
64.42
64.42
66.60
72.18
54.73
60.00
60.00
60.00
48.00
48.00
3.70
3.70
3.70
3.31
4.20
4.69
4.69
4.69
6.17
5.26
2.60
3.33
3.33
3.33
2.40
2.40
10.37
10.37
10.37
9.27
11.76
9.39
11.85
11.85
11.85
10.59
13.44
10.73
10.73
10.73
9.87
12.03
10.42
13.33
13.33
13.33
38.40
38.40
62.18
62.25
62.30
55.71
70.72
64.52
64.61
64.58
66.73
72.26
54.82
60.13
60.09
60.12
48.11
48.08
3.69
3.71
3.68
3.35
4.18
4.65
4.72
4.68
6.19
5.24
2.42
3.32
3.30
3.37
2.38
2.41
10.36
10.34
10.38
9.24
11.80
9.43
11.89
11.81
11.83
10.61
13.50
10.71
10.68
10.66
9.82
12.00
10.46
13.27
13.31
13.27
38.36
38.39
14 10
2 2
H
N O S
14 10
2 2
H
N O S
2 2
14 10
H
N O S
14 10
2 4
C
H
N S
14 10
2
C
C
C
H N O S
H
H
16 14 2 2
N O S
9.39
9.39
9.42
9.43
16 14
2 2
N O S
16 14
2 2
C
C
H
N S
17.28
10.52
9.12
23.33
23.33
23.33
11.20
11.20
17.21
10.485
9.31
23.41
23.45
23.38
11.16
11.17
18 20
4
H
N S
16 14
2
C H Cl N S
14 8 2 2
C
C
C
H N S
12
12
12
8 4
H N S
8 4
H N S
8
4
C
C
H N S
H N S
6 2
10
10
6 2
3
3
It is well known that the aldehydes react very rapidly
with hydrazine to give the corresponding azines.
Subsequent reaction with hydrogen sulfide, first produced
Scheme 2
Figure. Evolution of temperature and pressure during the reaction.

Jul-Aug 2005
Rapid Synthesis of 2,5-Disubtituted 1,3,4-Thiadiazoles under Microwave Irradiation
993
Table 3
1
H nmr data (d values, dimethyl-d sulfoxide) for 2,5-Diaryl-1,3,4-thiadiazoles 2a-p
6
Compound
No.
Aromatic signals
Substituent
2a
7.02 (t, J = 7.2 Hz, 2H); 7.09 (d, J = 8.06 Hz, 2H),
7.39 (t, J = 7.08 Hz, 2H); 8.25 (d, J = 7.33 Hz, 2H)
6.96-7.00 (m, 2H); 7.41-7.42 (m, 6H)
6.95 (d, J = 8.79 Hz, 4H); 7.81 (d, J = 8.54 Hz, 4H)
6.88 (d, J = 8.06 Hz, 2H); 7.25 (d, J = 8.06 Hz, 2H);
7.41 (s, 2H)
11.31 (s, 2H) OH
2b
2c
2d
9.97 (s, 2H) OH
10.41 (s, 2H) OH
9.60 (s, 4H) OH
2e
2f
7.58-7.61 (m, 6H); 8.00-8.05 (m, 4H)
—
6.91 (d, J = 7.32 Hz, 2H); 7.00 (t, J = 8.24 Hz, 2H);
7.16 (d, J = 7.33 Hz, 2H); 7.29 (t, J = 7.78 Hz, 2H)
7.16 (d, J = 7.63 Hz, 2H); 7.45-7.59 (m, 6H)
7.13 (d, J = 8.54 Hz, 4H); 7.94 (d, J = 8.54 Hz, 4H)
6.82 (d, J = 8.54 Hz, 4H); 7.76 (d, J = 8.54 Hz, 4H)
7.32 (d, J = 7.94 Hz, 4H); 7.84 (d, J = 7.94 Hz, 4H)
7.69 (d, J = 7.82 Hz, 4H); 8.05 (d, J = 7.82 Hz, 4H);
7.62 (d, J = 6.1 Hz, 2H); 8.07 (d, J = 7.78 Hz, 2H)
8.34 (t, J = 7.92 Hz, 2H); 8.76 (t, J = 3.96 Hz, 2H)
7.65 (t, J = 4.85 Hz, 2H); 8.44 (d, J = 7.82 Hz, 2H);
8.79 (d, J = 7.82 Hz, 2H); 9.22 (s, 2H)
3.78 (s, 6H) OCH
3
2g
2h
2i
2j
2k
2l
3.85 (s, 6H) OCH
3.85 (s, 6H) OCH
3.01 (s, 12H) CH
3
3
3
2.37 (s, 6H) CH
3
—
—
2m
—
2n
2o
8.02 (d, J = 6.4 Hz, 4H); 8.84 (d, J = 6.4 Hz, 4H)
7.27 (t, J = 4.42 Hz, 2H); 7.81 (d, J = 3.67 Hz, 2H);
7.88 (d, J = 4.88 Hz, 2H)
—
—
2p
7.68 (d, J = 5.19 Hz, 2H); 7.80 (d, J = 5.19 Hz, 2H);
8.33 (s, 2H)
—
Table 4
13
C nmr data (d values, dimethyl-d sulfoxide) for 2,5-Diary-1,3,4-thiadiazoles 2a-p
6
(Numerotation of C is given is Scheme 1)
Compound
No.
C
C
C
C
C
C
C
7
Substituent
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
163.12
167.64
166.55
166.58
167.72
169.56
167.63
166.58
168.52
161.12
166.91
171.14
171.12
170.23
160.89
161.76
116.49
130.67
120.63
119.79
131.45
124.91
130.64
122.15
127.54
130.96
129.59
148.17
126.20
137.27
131.10
128.62
154.74
118.67
129.20
114.10
127.64
156.95
130.73
129.16
126.09
128.69
128.20
—
116.80
157.99
116.18
148.64
129.46
111.12
159.73
114.85
114.15
130.69
129.35
150.30
—
131.87
113.72
160.28
145.83
129.51
130.79
117.35
161.56
151.85
140.5
136.15
126.22
150.29
—
128.67
127.95
119.66
130.56
116.18
116.19
129.46
120.03
112.28
114.85
114.15
130.69
129.35
138.02
120.54
152.22
130.94
126.21
127.65
118.56
129.20
120.95
127.64
128.96
120.15
129.16
126.09
128.69
128.20
120.56
137.99
122.76
—
—
—
—
—
—
55.43
55.40
55.46
39.68
21.25
—
—
—
—
—
148.16
122.76
—
152.22
130.69
—
130.75
—
—
by the reaction of hydrazine with sulfur, leads to the for-
mation of the tertrahydrothiadiazole ring, which is rapidly
dehydrogenated by the sulfur (Scheme 2).
stabilization of the pressure (15 min), the yield in thiadi-
azoles is very poor and the azine can be isolated in good
quantity.
The first step, the azine formation, is expected to be
faster than the second one, the addition of hydrogen sul-
fide, which must be present in excess as it can be seen on
the figure. When the reaction is stopped just after the
Several new 1,3,4-thiadiazoles have been tested as cor-
rosion inhibitors for steel in acidic media. These studies
have shown that the thiadiazole derivatives are very effi-
-4
cient even at low concentration (10 M) [3,15].

994
M. Lebrini , F. Bentiss and M. Lagrenée
Vol. 42
320-436-814; E-mail address: michel.lagrenee@ensc-lille.fr (Michel
Lagrenée).
EXPERIMENTAL
[1] F. Bentiss, M. Traisnel and M. Lagrenée, J. Appl.
Electrochem., 31, 41 (2001).
[2] M. Lagrenée, B. Mernari, M. Bouanis, M. Traisnel and F.
Bentiss, Corros. Sci., 44, 573 (2002).
[3] M. El Azhar, B. Mernari, M. Traisnel, F. Bentiss and M.
Lagrenée, Corros. Sci., 43, 2229 (2001).
[4] F. Bentiss, M. Lebrini, H. Vezin and M. Lagrenée, Mater.
Chem. Pphys., 87, 18 (2004).
[5] G. .Mazzone, F. Bonina, G. Puglisi, R. Arrigo-Reina, C.
Cosentino and G. Blandino, Il Farmaco Ed Sci., 37, 685 (1982).
[6] P. R. Naik, S. N. Pandeya and P. N. Singh, Pharmakeutike,
4, 44 (1991).
[7] A. E. Siegrist, E. Maeder, M. Duennenberger and P.
Liechti, Swiss Patent, 426, 848, (1967); Chem. Abstr., 68, 69002
(1968).
[8] G. Mazzone, G. Puglisi, F. Bonina and A. Corsaro, J.
Heterocyclic Chem., 20, 1399 (1983).
[9] C. O. Kappe, Angew. Chem. Int. Ed., 43, 6250, 2004.
[10] A. Loupy, Microwaves in Organic Synthesis, Wiley-VCH,
Germany, 2002.
A mixture of aromatic aldehyde 1a-r (0.02 moles), sulfur (0.03
g-atom) and hydrazine hydrate (0.08 moles) in ethanol (20 ml)
was introduced into a fluoropolymere cylindrical flask placed in a
MARS5 XP-1500 PLUS CEM multimode microwave reactor and
irradiated for 1 h (300 W) at 150 °C under pressure (Figure). After
cooling, the solvent was evaporated under reduced pressure.
2,5-Diaryl-1,3,4-thiadiazoles 2a-d.
The residue was treated with ethanol and filtered to remove the
sulfur. The ethanolic solution was evaporated under reduced pres-
sure and the residue was treated with 50 ml of an aqueous solution
of sodium hydroxide (20 %) and filtered. Treatment of the filtrate
with an aqueous hydrochloric acid solution (37 %) gives a yellow-
ish precipitate, which is collected by filtration and washed with
water and dried. Products were crystallized from ethanol.
2,5-Diaryl-1,3,4-thiadiazoles 2e-p.
The residue was dissolved in chloroform. The chloroform
solution was shaken with a concentrated sodium sulfide solution
(to remove most of the sulfur), with water, dried (magnesium sul-
fate), filtered and then evaporated by rotary evaporation. The
resulting residue was crystallized from ethanol.
[11] F. Bentiss, M. Lagrenée and D. Barbry, Tetrahedron Lett.,
41, 1539 (2000).
[12] S. Rostamizadch, H. Tajik and S. Yazdanfarahi, Synth.
Commun., 33 (1), 113 (2003).
1
13
Products 2a-p was identified by H and C nmr and MS: data
[13] F. Bentiss, M. Lagrenée and D. Barbry, Synth. Commun.,
31 (6), 935 (2001).
are in accordance with the proposed structures.
[14] H.-M. Huang, H.-T. Yu, P.-L. Chen, J. Han and J.-B.
Meng, Youji Huaxue, 24 (5), 502 (2004).
REFERENCES AND NOTES
[15] M. Lebrini, M. Lagrenée, H. Vezin, L. Gengembre and F.
Bentiss, Corros. Sci,. 47 (2) (2005) 485.
*
Corresponding author: Tel.: +33-320-337-746; fax: +33-