Phase transfer catalyzed synthesis and biological activity of thiourea derivatives containing 1,2,3-thiadiazole moiety

Article abstract of DOI:10.14233/ajchem.2014.17152

A series of N-(substituted-phenyl)-N′-(4-methyl-1,2,3-thiadiazole-5-yl)-thiourea (7a-7e) were synthesized and characterized. The chemical structures of all the compounds were confirmed by ¹H NMR, MS and elemental analysis. All the compounds were investigated for fungicidal activity and plant growth regulatory activity. The bioassay results indicated that some of these compound exhibit moderate fungicidal activities.

Full text of DOI:10.14233/ajchem.2014.17152

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7413-7415
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17152
Phase Transfer Catalyzed Synthesis and Biological Activity of
Thiourea Derivatives Containing 1,2,3-Thiadiazole Moiety
1
2
2
2
2
2
2,*
LI-JING MIN , MING-YAN YANG , ZHAO-HUI SUN , CHENG-XIA TAN , JIAN-QUAN WENG , HONG-KE WU and XING-HAI LIU
1
2
College of Life Sciences, Huzhou Teachers College, Huzhou 313000, Zhejiang, P.R. China
College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, P.R. China
Corresponding author: E-mail: xhliu@zjut.edu.cn
Received: 31 January 2014; Accepted: 18 February 2014;
*
Published online: 30 September 2014;
AJC-16150
A series of N-(substituted-phenyl)-N'-(4-methyl-1,2,3-thiadiazole-5-yl)-thiourea (7a-7e) were synthesized and characterized. The chemical
1
structures of all the compounds were confirmed by H NMR, MS and elemental analysis. All the compounds were investigated for
fungicidal activity and plant growth regulatory activity. The bioassay results indicated that some of these compound exhibit moderate
fungicidal activities.
Keywords: 1,2,3-Thiadiazole, Thiourea, Synthesis, Fungicidal activity, Plant growth regulatory activity.
Phase transfer catalysis (PTC) is a powerful technique
accomplishing a variety of reactions under mild conditions
and efficient way. This technique has been widely recognized
INTRODUCTION
Heterocyclic compounds, especially nitro containing
heterocycles, received considerable attention due to their
13,14
as an efficient synthetic tool and attracted much attention
.
1-4
pharmacological and pesticidal importance . 1,2,3-Thiadiazole
exhibited diversity activities, some derivatives had been deve-
5
loped commercial pesticide, such as plant inducer thiadinal ,
6
BTH , (Fig. 1). So 1,2,3-thiadiazoles pesticide may become
In view of these facts, herein we report the synthesis of
N-(substituted-phenyl)-N'-(4-methyl-1,2,3-thiadiazole-5-yl)-
thiourea under the condition of solid-liquid phase transfer
catalysis using polyethylene glycol-600 (PEG-600) as the
catalyst (Fig. 2) and their biological activities were investigated.
one of the focuses in the research and development of agro-
7
chemicals .
On the other hand, thiourea and its derivatives, especially
8
acyl-thiourea compounds, had many functions in agriculture ,
EXPERIMENTAL
9
10
11
medicine , analytical chemistry and inorganic synthesis . For
example, N,N-disubstituted thiourea exhibited a remarkable
biological activities. Some thiourea was synthesized containing
Melting points were determined using a X-4 melting appa-
1
ratus and were uncorrected. H NMR spectra were measured
on a BrukerAC-P300 instrument (300 MHz) using tetramethyl-
1,2,3-thiadiazole, which exhibit some plant growth regulate
activities (Fig. 1) .
6
silane as an internal standard and DMSO-d as solvent. Mass
12
spectra were recorded on a Thermo Finnigan LCQAdvantage
LC/mass detector instrument. Elemental analyses were
performed on a Yanaco MT-3CHN elemental analyzer.
General procedure: The title compounds were synthesized
according to the route shown in Fig. 2 and the yields were not
optimized.
N
S
N
H
N
N
N
Cl
S
O
MeS
O
4
-Methyl-1,2,3-thiadiazole-5-carbonyl chloride: 4-
thiadinal
BTH
Methyl-1,2,3-thiadiazole-5-carboxylic acid was obtained
through ethyl 3-oxobutanoate and ethyl hydrazinecarboxylate
according the Hurd-Mori reaction. Then the SOCl was added
O
S
R
2
N
N
N
H
N
dropwise into 4-methyl-1,2,3-thiadiazole-5-carboxylic acid
and refluxed about 2 h, the acyl chloride was obtained after
R1
S
Fig. 1. Commercial pesticide containing 1,2,3-thiadiazole
2
evaporate the residue SOCl . The ethyl 4-methyl-1,2,3-

7
414 Min et al.
Asian J. Chem.
O
O
O
O
O
O
NH NH H O
2 2 2
O
NH
NH2
O
O
O
N
H
N
O
O
1
2
N
N
N
N
SOCl2
SOCl2
CH Cl
HCl
OH
N
Cl
N
O
S
S
S
2
2
O
O
O
3
4
5
N
PEG-600/CH Cl
2
N
H
N
H
N
2
N
N
NCS
S
NH NCS
4
R
S
O
S
O
6
7
Fig. 2. Synthetic route of title compounds
thiadiazole-5-carboxylate were stirred in the solution of HCl
at room temperature. Then 4-methyl-1,2,3-thiadiazole-5-
carbonxylic acid was reacted with SOCl to give 4-methyl-
8.48Hz, 1H, Ph), 8.02 (d, J = 7.72 Hz, 1H, Ph), 7.71 (t, J =
8.09 Hz, 1H, Ph), 2.82 (s, 3H, CH ); ESI-MS: 322 (M-1);Anal.
calcd. for C11 : C 40.86, H 2.81, N 21.66; found: C
40.89, H 3.01, N 21.66.
3
2
9 5 3 2
H N O S
1
,2,3-thiadiazole-5-carbonyl chloride.
N-(Substituted-phenyl)-N'-(4-methyl-1,2,3-thiadiazole-
-yl)-thiourea: Powdered ammonium thiocyanate (1.14 g, 15
N-5-(4-Methylphenyl)-N'-(4-methyl-1,2,3-thiadiazole-
5-yl)-thiourea (7d): Yellow solid, yield 88.9 %, m.p. 137-
1
138 °C; H NMR: 12.10 (s, 1H, NH), 11.96 (s, 1H, NH), 7.53
5
mmol), 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride
1.62 g, 10 mmol), PEG-600 (0.18 g, 3 % with respect to ammo-
(
(d, J = 8.30 Hz, 2H, Ph), 7.22 (d, J = 8.30 Hz, 2H, Ph), 2.80 (s,
nium thiocyanate) and methylene dichloride (25 mL) were
placed in a dried round-bottomed flask containing a magnetic
stirrer bar and stirred at room temperature for 1 h. Then substi-
tuted aniline (4.5 mmol) in methylene dichloride (10 mL) was
added dropwise over 0.5 h and the mixture was stirred for 1 h.
The corresponding N-(substituted-phenyl)-N'-(4-methyl-1,2,3-
thiadiazole-5-yl)-thiourea (7a-e) precipitated immediately. The
product was filtered, washed with water to remove inorganic
3H, CH
for C1
H 4.56, N 19.44.
3
), 2.31 (s, 3H, CH
3
); ESI-MS: 291 (M-1);Anal. calcd.
2
H
12
N
4
OS : C 49.29, H 4.14, N 19.16; found: C 49.10,
2
N-5-(4-nitrophenyl)-N'-(4-methyl-1,2,3-thiadiazole-5-
yl)-thiourea (7e): Yellow solid, yield 87.6 %, m.p. 175-177
1
°C; H NMR: 12.31 (bs, 2H, NH), 8.28 (d, J = 9.10 Hz, 2H,
Ph), 8.04 (d, J = 9.10 Hz, 2H, Ph), 2.81 (s, 3H, CH
322 (M-1); Anal. calcd. for C11 : C 40.86, H 2.81, N
21.66; found: C 40.77, H 2.78, N 21.54.
3
); ESI-MS:
9 5 3 2
H N O S
2
salts, dried and recrystallized from DMF-EtOH-H O to give
the title compounds 7a-e.
N-5-(2,5-Dichlorophenyl)-N'-(4-methyl-1,2,3-thiadiazole-
Bioassay of fungicidal activities: The method for testing
the primary biological activities was performed in an isolated
culture. Under a sterile condition, 1 mL of sample was added
to the culture plates, followed by the addition of 9 mL of culture
medium. The final mass concentration was 50 µg/mL. The
blank assay was performed with 1 mL of sterile water. Circle
mycelium with a diameter of 4 mm was cut using a drill. The
culture plates were cultivated at (24 ± 1) °C. The extended
diameters of the circle mycelium were measured after 72 h.
The relative inhibition rate of the circle mycelium compared
to blank assay was calculated via the following equation:
5
-yl)-thiourea (7a):Yellow solid, yield 85.9 %, m.p. 181-183
1
C; H NMR: 8.35 (s, 1H, NH), 8.14 (s, 1H, NH), 7.39-7.44
°
(
m, 1H, Ph), 7.18-7.30 (m, 1H, Ph), 7.13-7.17 (m, 1H, Ph),
.81 (s, 3H, CH ); ESI-MS: 346 (M-1); Anal. calcd. for
OS Cl : C 38.05, H 2.32, N 16.13; found: C 37.88, H
.21, N 16.32.
N-5-(4-Flurophenyl)-N'-(4-methyl-1,2,3-thiadiazole-5-
yl)-thiourea (7b): Yellow solid, yield 83.8 %, m.p. 166-168
2
3
C
11
H
N
8 4
2
2
2
1
°
C; H NMR: 11.96 (s, 1H, NH), 10 (s, 1H, NH), 7.63-7.66
m, 1H, Ph), 7.26-7.29 (m, 2H, Ph), 2.80 (s, 3H, CH ); ESI-
F: C 44.58, H
(
3
′
9 4 2
MS: 295 (M-1); Anal. calcd. for C11H N OS
dex – dex
Relative inhibition rate ( % ) =
×100 %
3
.06, N 18.91; found: C 44.46, H 3.13, N 18.76.
N-5-(3-Nitrophenyl)-N'-(4-methyl-1,2,3-thiadiazole-5-
dex
where dex is the extended diameter of the circle mycelium
during the blank assay; and dex′, is the extended diameter of
the circle mycelium during testing.
yl)-thiourea (7c):Yellow solid, yield 85.8 %, m.p. 115-117 °C;
1
H NMR: 12.20 (s, 1H, NH), 8.71 (s, 1H, NH), 8.13 (m, J =

Vol. 26, No. 21 (2014)
Synthesis and Biological Activity of Thiourea Derivatives Containing 1,2,3-Thiadiazole Moiety 7415
TABLE-1
BIOLOGICAL ACTIVITY OF TESTED COMPOUNDS
Phytophthora
infestans (Mont.)
de Bary
Botryosphaeria berengeriana
f. sp. piricola (Nose) koganezawa
et Sakuma
Fusarium
oxysporum f.sp.
cucumerinum
Cercospora
arachidicola
Cotyledon root
of cucumber
No.
G. zeae Petch
7
7
a
13.0
1
35.3
1
22.7
22.7
18.2
18.2
26.3
21.5
23.8
27.7
33.8
28.3
8.6
17.4
8.6
1
13.2
46.2
13.2
116.9
98.1
b
7
c
21.7
13.0
18.8
1
7
d
11.7
21.4
7
e
7.1
Plant growth regulatory activity assay: After dipping
into distilled water for 1 h at 23 °C, the cucumber seeds (Jinke,
No. 4, commercial availably) were then sown into the soil with
and plant growth regulatory activity of title compounds were
determined. The results were shown in Table-1. As shown in
Table-1, the title compound exhibit weak activity against G.
zeae Petch., Phytophthora infestans (Mont.) de Bary, Botryo-
sphaeria berengeriana f. sp. piricola (Nose) koganezawa et
Sakuma, Fusarium oxysporum f. sp. cucumerinum and
Cercospora arachidicola. Only compound 7a and 7d showed
fair fungicidal activity (35.3 and 33.8 %) against Botryo-
sphaeria berengeriana f. sp. piricola (Nose) koganezawa et
Sakuma and Fusarium oxysporum f.sp. cucumerinum,
respectively.
0
.7 % agar on a covered porcelain enamel plate and incubated
at 26 °C in a darkroom for 3 days. The same sized cotyledons
were carefully selected for the subsequent biological assay.
The analyte (3 mg) was resolved in N,N-dimethyl formamide
(3 mL) and this solution was then diluted to 10 % concentration
with distilled water. A sample solution (0.3 mL) was sprayed
over a 6 cm diametered filter paper and solvent was volatilized
to dryness on air. The filter paper thus prepared was placed
into a 6 cm diameter incubation vessel and soaked with 10 cm
distilled water. Finally, 10 pieces of cotyledon of the same
size were added into the incubation vessel. These cotyledons
were incubated at 26 °C in a darkroom for 5 days. Then the
rhizogenesis numbers of every 10 pieces of hypocotyls were
measured. Each sample was repeated twice. In contrast, the
distilled water was used as a blank experiment. The relative
ratios of cucumber cotyledon rhizogenesis were calculated
according to the following formula:
The cotyledon root of cucumber activity of title compounds
was determined. Surprisingly, as listed in Table-1, all the testing
compounds showed low activity on the roots cotyledon of
cucumber. The compound 7d and 7e showed excellent activity
(116.9 and 98.1).
ACKNOWLEDGEMENTS
This work was funded by National Natural Science
Foundation of China (No. 21002090), The Key Innovation
Team of Science and Technology in Zhejiang Province
(2010R50018-06) and the National Key Technologies R&D
Program (2011BAE06B03-01).
(
N – N )
S C
Relative ratio (%) =
× 100 %
NC
where N
S
and N are the numbers of cucumber cotyledon
C
rhizogenesis of tested compound and control experiment,
respectively.
REFERENCES
1
.
S. Nanjunda Swamy, Basappa, G. Sarala, B.S. Priya, S.L. Gaonkar, J.
Shashidhara Prasad and K.S. Rangappa, Bioorg. Med. Chem. Lett., 16,
RESULTS AND DISCUSSION
9
99 (2006).
F.Q. He, X.H. Liu, B.L. Wang and Z.M. Li, Heteroatom Chem., 19, 21
2008).
X.D. Yang, Heterocycl. Commun., 13, 387 (2007).
2
3
.
.
4
-Methyl-1,2,3-thiadiazole-5-carboxylic acid was
synthesized according the Hurd-Mori method. The hydrazone
must be added dropwise into the SOCl . PEG-600 was used as
(
4. S. Yang, Z. Li, L. Jin, B. Song, G. Liu, J. Chen, Z. Chen, D. Hu, W. Xue
2
and R. Xu, Bioorg. Med. Chem. Lett., 17, 2193 (2007).
solid-liquid phase transfer catalyst, this is a facile and conve-
nient method to afford the title compounds N-(substituted-
phenyl)-N'-(4-methyl-1,2,3-thiadiazole-5-yl)- thiourea. PEG-
5
6
.
.
K. Tsubata, O. Sanpei, K. Takagi, K. Umetani, T. Uchikurohane and S.
Tajima, WO 9923084 (1999); Chem. Abstr., 130, 311799 (1999).
W. Kunz, R. Schurter and T. Maetzke, Pestic. Sci., 50, 275 (1997).
6
6
00 can easily react with NH
+
4
SCN to form complex [PEG-
-
7. C.B. Ziegler Jr., W.V. Curran, N.A. Kuck, S.M. Harris and Y. Lin, J.
Heterocycl. Chem., 26, 1141 (1989).
-
4
00-NH ]SCN , which makes it possible for SCN to readily
8
.
X.Q. He, W.M. Tang, B.A. Song, D.Y. Hu, L.L. Pang, W.J. Sang, S.
Yang and L.H. Jin, Chin. J. Org. Chem., 24, 1284 (2004).
S.A.F. Rostom, Bioorg. Med. Chem., 14, 6475 (2006).
react with 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride and
leads to the formation of intermediate 6.Also the catalyst PEG-
9
.
6
00 is inexpensive, relatively nontoxic, highly stable and easily
available.
Biological activities: Fungicidal activities of the title com-
10. A. Lukomska and J. Sobkowski, J. Electroanal. Chem., 592, 68 (2006).
1
1. G. Binzet, H. Arslan, U. Flörke, N. Külcü and N. Duran, J. Coord.
Chem., 59, 1395 (2006).
1
1
2. Y.H. Dong and Z.X. Si, Chin. J. Appl. Chem., 12, 62 (1995).
3. P. Sharma,A. Kumar and P. Pandey, Indian J. Chem., 45B, 2077 (2006).
pounds against G. zeae Petch, Phytophthora infestans (Mont.)
de Bary, Botryosphaeria berengeriana f. sp. piricola (Nose)
koganezawa et Sakuma, Fusarium oxysporum f. sp. cucume-
rinum and Cercospora arachidicola. The fungicidal activities
14. T.B. Wei, H. Wang, Q. Lin and Y.M. Zhang, Chin. J. Org. Chem., 25,
565 (2005).
1