Synthesis and biological activities of 3-1-(3-(2-chloro-3,3,3-trifluoro- prop-1-enyl- 2,2-dimethylcyclopropanecarbonyl)-3-substituted phenyl thiourea

Article abstract of DOI:10.14233/ajchem.2013.14097

Some thiourea compounds containing pyrethroids are synthesized. Their structures were confirmed by ¹H NMR, MS and elemental analysis. The bioassay results indicated that they showed moderate insecticidal and fungicidal activity.

Full text of DOI:10.14233/ajchem.2013.14097

Asian Journal of Chemistry; Vol. 25, No. 7 (2013), 4064-4066
http://dx.doi.org/10.14233/ajchem.2013.14097
Synthesis and Biological Activities of 3-1-(3-(2-Chloro-3,3,3-trifluoro-prop-1-enyl-
2,2-dimethylcyclopropanecarbonyl)-3-Substituted Phenyl Thiourea
*
NA-BO SUN , JIAN-ZHONG JIN, HUI-YING XU and WEI KE
College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, P.R. China
*Corresponding author: E-mail: nabosun@gmail.com
(Received: 23 May 2012;
Accepted: 25 January 2013)
AJC-12756
1
Some thiourea compounds containing pyrethroids are synthesized. Their structures were confirmed by H NMR, MS and elemental
analysis. The bioassay results indicated that they showed moderate insecticidal and fungicidal activity.
Key Words: Pyrethroid, Synthesis, Insecticidal activity, Fungicidal Activity.
Avance 400 DMX instrument using TMS as an internal
standard and CDCl3 as the solvent. Mass spectra were recorded
on a HP 5989B mass detector instrument. Elemental analyses
were performed on a Carlo erba EA1110 elemental analyzer.
All the reagents are of analytical grade or freshly prepared
before use.
INTRODUCTION
Cyclopropane derivatives, as a kind of highly bioactive
compounds, have been studied1. In 1940s, cyclopropane
compounds, especially pyrethroids were marketed as low toxic
insecticides. From then, a large variety of pyrethroids deriva-
tives have been synthesized, such as deltamethrin, cypermethrin,
bifenthrin, fenvalerate, tefluthrin etc., are commercially avail-
able2. So it is a research hotspot in agriculture, many biologi-
cally active and structurally stable cyclopropane compounds
had been synthesized3.
Cycloprothrine was synthesized in our laboratory accor-
ding to literature. Thionyl chloride (100 mL) was added into
cycloprothrine (2.75 g, 10 mmol) and the mixture was refluxed
for 8 h. Next, the excessive thionyl chloride was distilled off
under reduced pressure. The desired acid chloride was not
purification.
In the bioactive compounds research area, thiourea is a
novel type molecule, which is also extensively used in medi-
cinal chemistry and agricultural chemistry, because of their
excellent biological activities. Thiourea and its derivatives,
especially acyl-thiourea compounds, exhibit a variety of
herbicidal, fungicidal and insecticidal activities due to they
contain amide group and thioamide group4. Because of their
superior features, we believe that the rational combination of
pyrethroids and thiourea should be promising in the develop-
ment of novel bioactive compounds.
KNCS (1.46 g, 15 mmol), acid chloride, CH3CN (20 mL)
were charged into a dry round-bottomed flask equipped with
a magnetic stirrer bar and stirred at reflux temperature for 1 h.
Subsequently remove the precipitate KCl using pumping
filtration and the filtrate can be directly used without purifica-
tion.Add substituted aniline (8.8 mmol) to the filtrate followed
by reflux for 3-4 h at 80 ºC. TLC was employed to trace the
process. Stop the reaction and cool the resultant mixture under
room temperature. Finally pumping filtration gives yellow
powder washed with petroleum. Then the products was recrysta-
llized from DMF-EtOH-H2O. Finally, the acyl thiourea were
obtained as a solid.
In line with our continuous efforts to synthesize bioactive
lead compounds for crop protection, the title compounds were
designed some thiourea compounds and their biologicial
activity tested. The preliminary biological test showed that
the synthesized compound has moderate fungicidal and
insecticidal activities.
1-(2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropane-
carbonyl)-3-phenylthiourea(5a).Yellow crystal; yield, 75.3
%; m.p., 132-135 ºC; 1H NMR (CDCl3) δ: 1.44 (t, J = 6.8 Hz,
3H, CH3), 2.08(d, J = 7.2 Hz, 1H, cyclopropane H), 2.81 (d, J
= 7.2 Hz, 1H, cyclopropane H), 4.04-4.10 (m, 2H, CH2), 7.01-
7.05 (m, 2H, Ph), 7.24-7.45 (m, 5H, Ph), 7.61-7.63 (m, 2H,
Ph), 8.77 (s, 1H, NH), 12.08 (s, 1H, NH); Ms m/z (relative
EXPERIMENTAL
Melting points were determined by an X-4 apparatus and
1
uncorrected. H NMR spectra were measured on a Bruker

Vol. 25, No. 7 (2013)
Synthesis and Biological Activities of Substituted Phenyl Thiourea 4065
KSCN
SOCl2
C2H5O
C COCl
C2H5O
C COOH
Cl
Cl
Cl
Cl
2
1
R2
R1
R1
R2
R3
S
O
C
O
H
N
H2N
N C S
HN
C
R3
C2H5O
C2H5O
C
Cl
Cl
Cl
Cl
4
3
5
5a, R1=R2=R3=R4=H; 5b, R1=R2=H, R3=CH3; 5c, R1=R3=H, R2=CH3; 5d, R2=R3=H, R1=CH3;
Scheme-I: Synthetic route of title compounds
intensity/%): 409 (M+, 39), 258 (100), 223 (46), 187 (16), 159
(31), 151 (15), 119 (8), 114 (41), 92 (19), 77 (14); Anal. calcd
for C19H18N2O2SCl2 (%): C 55.75, H 4.43, N 6.84, found:
C 55.81, H 4.46, N 6.79.
of 9 mL of culture medium. The final mass concentration of
the title compound 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) ºC. The extended diameters of the
circle mycelium were measured after 72 h. The relative inhibi-
tion rate of the circle mycelium compared to blank assay was
calculated via the following equation:
1-(2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropane-
carbonyl)-3-(4-methylphenyl)thiourea(5b). White crystal;
yield, 45.2 %; m.p., 147-150 ºC; 1H NMR (CDCl3) δ: 1.44 (t,
J = 6.8 Hz, 3H, CH3CH2O), 1.96 (d, J = 7.2 Hz, 1H, cyclopropane
H), 2.28 (s, 3H, CH3), 2.86 (d, J = 7.2 Hz, 1H, cyclopropane
H), 4.04-4.08 (m, 2H, CH2), 6.97-7.08 (m, 4H, Ph), 7.25-7.27
(m, 2H, Ph), 7.43-7.45 (m, 2H, Ph), 8.90 (s, 1H, NH), 12.25
(s, 1H, NH); Ms m/z (relative intensity/%): 423 (M+, 36), 258
(100), 223 (32), 187 (10), 159 (48), 133 (39), 114 (16), 106
(9), 91 (14), 77 (18); Anal. calcd. for C20H20N2O2SCl2 (%): C
56.74, H 4.76, N 6.62, found: C 56.80, H 4.79, N 6.57.
1-(2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropane-
carbonyl)-3-(3-methylphenyl)thiourea(5c). White crystal;
yield, 43.8 %; m.p., 149-152 ºC; 1H NMR (CDCl3) δ: 1.43 (t,
J = 6.8 Hz, 3H, CH3CH2O), 2.01 (d, J = 7.2 Hz, 1H, cyclopropane
H), 2.32 (s, 3H, CH3), 2.87 (d, J = 7.2 Hz, 1H, cyclopropane
H), 4.00-4.04 (m, 2H, CH2), 7.01-7.10 (m, 4H, Ph), 7.36-7.39
(m, 2H, Ph), 7.51-7.53 (m, 2H, Ph), 9.11 (s, 1H, NH), 12.20
(s, 1H, NH); Ms m/z (relative intensity/%): 423 (M+, 41), 258
(100), 223 (16), 187 (8), 159 (58), 133 (20), 114 (32), 106
(18), 91 (7), 77 (13); Anal. calcd. for C20H20N2O2SCl2 (%): C
56.74, H 4.76, N 6.62, found: C 56.83, H 4.75, N 6.60.
1-(2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropane-
carbonyl)-3-(2-methylphenyl)thiourea(5d). White crystal;
yield, 49.8 %; m.p., 151-153 º; 1H NMR (CDCl3) δ: 1.43 (t,
J = 6.8 Hz, 3H, CH3CH2O), 1.96 (d, J = 7.2 Hz, 1H, cyclopropane
H), 2.26 (s, 3H, CH3), 2.79 (d, J = 7.2 Hz, 1H, cyclopropane
H), 4.04-4.07 (m, 2H, CH2), 7.04-7.09 (m, 3H, Ph), 7.26-7.30
(m, 3H, Ph), 7.59-7.61 (m, 2H, Ph), 8.92 (s, 1H, NH), 12.02
(s, 1H, NH); Ms m/z (relative intensity/%): 423 (M+, 38), 258
(100), 223 (22), 187 (26), 159 (36), 133 (51), 114 (26), 106
(19), 91 (9), 77 (13); Anal. calcd for C20H20N2O2SCl2 (%): C
56.74, H 4.76, N 6.62, found: C 56.84, H 4.73, N 6.65.
Biological activities
Relative inhibition rate (%) = [(CK-PT)/CK] × 100 %
where, CK is the extended diameter of the circle mycelium
during the blank assay; and PT, is the extended diameter of
the circle mycelium during testing.
Bioassay of insecticidal activities: Insecticidal activities
against Nilaparvata legen, Mythimna separate, Tetranychus
cinnabarnus and Aphis medicagini were performed in the
greenhouse. The bioassay was operated at 25 1 ºC according
to statistical requirements. Assessments were made on a dead/
alive basis and mortality rates were corrected according to
Abbott's formula. Per cent mortality was evaluated. Error of
the experiments was 5 %. For comparative purpose, compound
5 were tested as control under the same conditions.
The insecticidal activities of compounds 5 were evaluated
according FAO procedure. The insecticidal activity against
oriental armyworm was tested by foliar application, individual
corn leaves were placed on moistened pieces of filter paper in
Petri dishes. The leaves were then sprayed with the test solution
and allowed to dry. Then every 10 fourth-instar oriental army-
worm larvae were put into each dish. Percent mortalities were
evaluated 2 days after treatment. Each treatment was replicated
for three times.
RESULTS AND DISCUSSION
The synthetic routes of title compounds were illustrated
as outlined in Scheme-I. The starting material cycloprothrine
1 was treated with SOCl2 as chlorination reagent to generate
acid chloride 2. The excess thionyl chloride was removed by
reduced pressure distillation. For the next step the acyl chloride
was used without additional purification. After solubilization
in dry acetonitrile, acid chloride was treated with a solution of
potassium rhodanate in acetonitrile to afford acyl isothio-
cyanate. The resulting acyl isothiocyanate was not isolated
from the mixture and was converted into the corresponding
Bioassay of fungicidal activities: The method for testing
the primary biological activities was performed in an isolated
culture. Under a sterile condition, 1 mL DMSO of title comp-
ound was added to the culture plates, followed by the addition

4066 Sun et al.
Asian J. Chem.
thioureas (5a-d) by adding various substituted anilines and
refluxing for an hour in dry acetonitrile.
TABLE-2
INSECTICIDAL ACTIVITIES OF 5 (MORTALITY/%)
Nilaparvata Mythimna Tetranychus
Aphis
cinnabarnus medicagini
The chemical structures of the newly synthesized
compounds were elucidated by 1H NMR, mass and elemental
analysis. The 1H NMR, mass spectra and elemental analysis
data of the compounds are in agreement with the proposed
Compd.
legen
15.6
11.3
7.6
separate
43.2
5a
5b
5c
5d
36.8
13.5
10.4
11.2
0
0
0
0
35.6
26.9
1
structures. In the H NMR spectra, the N-H protons of the
8.9
26.4
thiourea (5a-d) derivatives were observed as singlets at 8.77-
9.11 ppm and 12.02-12.25 ppm, respectively. All other
aromatic protons were observed in the expected regions.
Fungicidal activity: The in vivo fungicidal results of all
of the compounds against Rhizoctonia solani, Pseudoperonospora
cubensis, Sphaerotheca fuliginea and Botrytis cinerea were
listed in Table-1. As shown in Table-1, all these compounds
did not display obvious fungicidal activities against Rhizoctonia
solani, Pseudoperonospora cubensis, Sphaerotheca fuliginea.
Among them, compounds 5a have fair to moderate fungicidal
activity against Botrytis cinerea and Rhizoctonia solani at the
concentration of 200 µg mL-1.
REFERENCES
1. a) X.H. Liu, C.X. Tan, J.Q. Weng and H.J. Liu, Acta Cryst., E68,
o493(2012); b) X.H. Liu, P.Q. Chen, B.L. Wang, Y.H. Li and Z.M. Li,
Bioorg. Med. Chem. Lett., 17, 3784 (2007); c) X.H. Liu, P.Q. Chen,
F.Q. He,Y.H. Li, S.H. Wang and Z.M. Li, Struct. Chem., 5, 563 (2007);
d) X.H. Liu, C.Y. Zhang, W.C. Guo, Y.H. Li, P.Q. Chen, T. Wang, W.L.
Dong, B.L. Wang, H.W. Sun and Z.M. Li, J. Enzym. Inhib. Med. Chem.,
24, 545 (2009); e) X.H. Liu, Y.X. Shi, Y. Ma, G.R. He, W.L. Dong,
C.Y. Zhang, B.L. Wang, S.H. Wang, B.J. Li and Z.M. Li, Chem. Biol.
Drug Des., 73, 320 (2009); f) X.H. Liu, Y.X. Shi, Y. Ma, C.Y. Zhang,
W.L. Dong, P. Li, B.L. Wang, B.J. Li and Z.M. Li, Eur. J. Med. Chem.,
44, 2782 (2009); g) X.H. Liu, J.Q. Weng, C.X. Tan, L. Pan, B.L. Wang
and Z.M. Li, Asian J. Chem., 23, 4031 (2011); h) H.J. Liu, J.Q. Weng,
C.X. Tan and X.H. Liu, Acta Cryst., E67, o1940 (2011).
TABLE-1
FUNGICIDAL ACTIVITIES OF 5 (INHIBITION/%)
2. a) X.H. Liu, L. Pan, J.Q. Weng, C.X. Tan,Y.H. Li, B.L. Wang and Z.M.
Li, Mol. Divers., 16, 251 (2012); b) C.X. Tan, Y.X. Shi, J.Q. Weng,
X.H. Liu, B.J. Li and W.G. Zhao, Lett. Drug Des. Discov., 9, 431 (2012);
c) X.H. Liu, L. Pan, C.X. Tan, J.Q. Weng, B.L. Wang and Z.M. Li,
Pestic. Biochem. Physiol., 101, 143 (2011); d) C.X. Tan, Y.X. Shi, J.Q.
Weng, X.H. Liu, B.J. Li and W.G. Zhao, J. Heterocycl. Chem.,
DOI:10.1002/jhet.1656; e) X.H. Liu, W.G. Zhao, B.L. Wang and Z.M.
Li, Res. Chem. Intermed., 38, 1999 (2012).
Sphaerotheca Pseudoperonospora Botrytis Rhizoctonia
Compd.
fuliginea
18.3
11.4
9.7
cubensis
15.8
7.2
cinerea
31.8
solani
38.6
12.3
9.8
5a
5b
5c
5d
21.3
4.1
16.8
7.8
3.2
15.9
7.4
3. K. Matsuda, K. Iharada, K.H. Suzuki, M. Yamashita, H. Okimoto, K.
Nishimura, K.T. Ueno and K. Komai, J. Pestic. Sci., 20, 487 (1995).
4. a) X.H. Liu, C.X. Tan and J.Q. Weng, Phosphorus Sulfur Silicon Rel.
Elem., 186, 552 (2011); b) X.H. Liu, C.X. Tan and J.Q. Weng, Phosphorus
Sulfur Silicon Rel. Elem., 186, 558 (2011); c) X.H. Liu, L. Pan, Y. Ma,
J.Q. Weng, C.X. Tan, Y.H. Li,Y.X. Shi, B.J. Li, Z.M. Li andY.G. Zhang,
Chem. Biol. Drug Des., 78, 689 (2011); d) P.Q. Chen, C.X. Tan, J.Q.
Weng and X.H. Liu, Asian J. Chem., 24, 2808 (2012); e) J.Q. Weng,
C.X. Tan, L. Wang and X.H. Liu, J. Chem. Soc. Pak., 34, 1248 (2012);
f)Y.L. Xue,Y.G. Zhang and X.H. Liu, Asian J. Chem., 24, 3016 (2012);
g)Y.L. Xue,Y.G. Zhang and X.H. Liu, Asian J. Chem., 24, 1571 (2012);
h) X.F. Liu and X.H. Liu, Acta Cryst., E67, o202 (2011).
Insecticidal activity: The insecticidal activity of comp-
ounds 5 against Nilaparvata legen, Mythimna separate,
Tetranychus cinnabarnus and Aphis medicagini was summa-
rized in Table-2. In general, all the title compounds exhibited
no insecticidal activity against Aphis medicagini. Also, title
compounds showed low insecticidal activities against
Nilaparvata legen, Mythimna separate, Tetranychus cinnabarnus.
Surprisingly, only compounds 5a displayed moderate insecti-
cidal activity against Mythimna separate.
ACKNOWLEDGEMENTS
The project was supported by the Program of National
Natural Science Foundation of China (21102131).