Synthesis and biological activities of 3-(2-chloro-3,3,3-trifluoroprop-1- enyl)-2,2-dimethyl-N-substituted phenylcyclopropanecarboxamide

Article abstract of DOI:10.14233/ajchem.2013.14425

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

Full text of DOI:10.14233/ajchem.2013.14425

Asian Journal of Chemistry; Vol. 25, No. 12 (2013), 6697-6699
http://dx.doi.org/10.14233/ajchem.2013.14425
Synthesis and Biological Activities of 3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-
2,2-dimethyl-N-Substituted Phenylcyclopropanecarboxamide
*
MIN-JUN WANG, NA-BO SUN , JIAN-ZHONG JIN, JIAN-FEN ZHANG and HUI-YING XU
College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, P.R. China
*Corresponding author: E-mail: nabosun@gmail.com
(
Received: 9 August 2012;
Accepted: 27 May 2013)
AJC-13552
1
Some amide compounds containing pyrethroids are synthesized. Their structures were confirmed by H NMR, MS and elemental analysis.
The bioassay results indicated that they showed moderate fungicidal activity.
Key Words: Cyclopropanecarboxamide, Synthesis, Fungicidal activity.
General procedure: λ-Cyhalthrin acid was synthesized
in our laboratory according to literature. Thionyl chloride
INTRODUCTION
Cyclopropane derivatives, as a kind of highly bioactive
1
compounds, have been studied broadly for many years . In
(
100 mL) was added into lambda cyhalthrin acid (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. Dropwised the acid
1
940s, cyclopropane compounds, especially pyrethroids were
marketed as low toxic insecticides. From then, a large variety
of pyrethroids derivatives have been synthesized and lots of
them, such as deltamethrin, cypermethrin, bifenthrin,
3
chloride to substituted aniline (10 mmol) and Et N (12 mmol),
then vigorously stirred at ambient temperature. TLC was
employed to trace the process. Stop the reaction and cool the
resultant mixture under room temperature. The corresponding
amide precipitated immediately. The product was filtered,
washed with diluted acetic acid, dried and purified by silica-
gel column eluted with ethyl acetate/petroleum ether to give
the title compounds 4.
2
fenvalerate, tefluthrin, etc. are commercially available . So it
is a research hotspot in agriculture, many biologically active
and structurally stable cyclopropane compounds had been
3
synthesized .
Amide group is widely used in medicinal chemistry and
agricultural chemistry, because of their excellent biological
4
activities . It displayed broad biological activities, such as her-
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-phenylcyclopropanecarboxamide (4a): White crystal;
bicidal, fungicidal and insecticidal activities, etc. Due to their
variety bioactivities and in line with our continuous efforts to
synthesize bioactive compounds for crop protection, 3-(2-
chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-N-substituted
phenylcyclopropanecarboxamide were designed some amide
compounds and their biological activity tested.
1
yield, 82.3 %; m.p. 143-146 ºC; H NMR (CDCl
H, CH ), 1.38 (s, 3H, CH ), 1.82 (d, J = 8.4 Hz, 1H, cyclo-
propane H), 2.19(t, J = 8.8 Hz, 1H, cyclopropane H), 7.09-
.13 (m, 1H, Ph), 7.17 (d, J = 9.2 Hz, 1H, C=CH), 7.30-7.36
m, 2H, Ph), 7.46-7.48 (m, 2H, Ph), 7.80 (s, 1H, NH); Ms m/
3
) δ: 1.33 (s,
3
3
3
7
(
+
z (relative intensity/%): 317 (M , 42), 282(63), 224 (62), 198
55), 141 (17), 120 (90), 93 (20), 77 (11). Anal. calcd. (%) for
: C 56.70, H 4.76, N 4.41, found (%): C 56.82,
H 4.80, N 4.50.
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(4-chlorophenyl)cyclopropanecarboxamide (4b): White
EXPERIMENTAL
(
Melting points were determined by an X-4 apparatus and
1
uncorrected. H NMR spectra were measured on a Bruker
15 3
C H15NOClF
Avance 400 DMX instrument using TMS as an internal
3
standard and CDCl as the solvent. Mass spectra were recorded
1
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.
crystal; yield, 78.2 %; m.p. 143-145 ºC; H NMR (CDCl
3
) δ:
1.33 (s, 3H, CH ), 1.37 (s, 3H, CH ), 1.80 (d, J = 8.0 Hz, 1H,
3
3
cyclopropane H), 2.20 (t, J = 8.8 Hz, 1H, cyclopropane H),
7.13 (d, J = 9.6 Hz, 1H, C=CH), 7.26-7.33 (m, 2H, Ph), 7.42-

6
698 Wang et al.
Asian J. Chem.
7
.44 (m, 2H, Ph), 7.81 (s, 1H, NH); Ms m/z (relative intensity/
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(4-nitrophenyl)cyclopropanecarboxamide (4h): Yellow
+
%
): 352 (M , 27), 316 (19), 258 (25), 225 (19), 198 (43), 163
30), 154 (100), 141 (42), 126 (78), 99 (19), 91 (13), 75 (17);
Anal. calcd. (%) for C15 : C 51.16, H 4.01, N 3.98,
found (%): C 51.22, H 4.05, N 3.86.
-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(2-chlorophenyl)cyclopropanecarboxamide (4c): White
1
crystal; yield 72.6 %; m.p. 137-140 ºC; H NMR (CDCl
(
3
) δ:
H14NOCl F
2 3
3 3
1.36 (s, 3H, CH ), 1.38 (s, 3H, CH ), 1.86 (d, J = 8.0 Hz, 1H,
cyclopropane H), 2.27(t, J = 8.8 Hz, 1H, cyclopropane H),
7.09 (d, J = 9.2 Hz, 1H, C=CH), 7.67-7.69 (m, 2H, Ph), 7.78(s,
1H, NH), 8.20-8.22 (m, 2H, Ph); Ms m/z (relative intensity/
3
1
+
crystal; yield, 80.7 %; m.p. 128-131 ºC; H NMR (CDCl
.36 (s, 3H, CH ), 1.38 (s, 3H, CH ), 1.90 (d, J = 8.0 Hz, 1H,
cyclopropane H), 2.23(t, J = 8.8 Hz, 1H, cyclopropane H),
3
) δ:
%): 363 (M , 70), 327 (20), 269 (23), 225 (32), 198 (74), 165
(100), 141 (90), 127 (19), 91 (29), 77 (15); anal. calcd. (%)
1
3
3
14 2 3 3
for C15H N O ClF : C 49.67, H 3.89, N 7.72, found (%): C
7
7
.02-7.06 (m, 1H, Ph), 7.12 (d, J = 9.2 Hz, 1H, C=CH), 7.24-
.28 (m, 2H, Ph), 7.36-7.38 (m, 1H, Ph), 7.77(s, 1H, NH); Ms
49.83, H 3.87, N 7.75.
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(3-trifluoromethylphenyl)cyclopropanecarboxamide
+
m/z (relative intensity/%): 352 (M , 57), 316(23), 258(24),
1
(4i): White crystal; yield 87.1 %; m.p. 149-151 ºC; H NMR
225 (19), 198 (41), 163 (22), 154 (100), 141 (37), 126 (72),
99(19), 91(13), 75(10); anal. calcd. (%) for C15 : C
51.16, H 4.01, N 3.98, found (%): C 51.25, H 4.04, N 3.93.
-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(3-phenyl)cyclopropanecarboxamide (4d): White crystal;
H14NOCl F
2 3
3 3 3
(CDCl ) δ: 1.34(s, 3H, CH ), 1.38 (s, 3H, CH ), 1.82 (d, J =
8.4 Hz, 1H, cyclopropane H), 2.22(t, J = 8.8 Hz, 1H, cyclo-
propane H), 7.13 (d, J = 9.2 Hz, 1H, C=CH), 7.34-7.68(m,
4H, Ph), 7.73(s, 1H, NH); Ms m/z (relative intensity/%): 386
3
1
+
yield, 76.8 %; m.p. 129-131 ºC; H NMR (CDCl
3
) δ: 1.33 (s,
(M , 62), 350 (19), 292 (31), 225 (20), 198 (59), 188 (100),
3
H, CH ), 1.37 (s, 3H, CH ), 1.79 (d, J = 8.0 Hz, 1H, cyclo-
3
3
160 (49), 141 (45), 91 (13), 77 (12); anal. calcd. (%) for
propane H), 2.19 (t, J = 8.8 Hz, 1H, cyclopropane H), 7.08 (d,
J = 7.2 Hz, 1H, C=CH), 7.11-7.34 (m, 4H, Ph), 7.60 (s, 1H,
+
NH); Ms m/z (relative intensity/%): 352 (M , 55), 316 (30),
C
16
H
14NOClF
6
: C 49.82, H 3.66, N 3.63, found (%): C 49.89,
H 3.69, N 3.66.
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
2
1
58 (28), 225 (25), 198 (59), 163 (38), 154 (100), 141 (49),
26 (73), 111 (46), 91 (16), 75 (19); anal. calcd. (%) for
N-(3,4-dichlorophenyl)cyclopropanecarboxamide (4j):
1
White crystal; yield, 89.6 %; m.p. 133-134 ºC; H NMR
C
15
H
14NOCl
2
F
3
: C 51.16, H 4.01, N 3.98, found (%): C 51.27,
H 3.97, N 4.05.
-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(4-methylphenyl)cyclopropanecarboxamide (4e): White
3 3 3
(CDCl ) δ: 1.32 (s, 3H, CH ), 1.36 (s, 3H, CH ), 1.79 (d, J =
8.0 Hz, 1H, cyclopropane H), 2.21 (t, J = 8.8 Hz, 1H, cyclo-
propane H), 7.10 (d, J = 9.2 Hz, 1H, C=CH), 7.23-7.25 (m,
1H, Ph), 7.32-7.35 (m, 1H, Ph), 7.45 (s, 1H, Ph), 7.70 (s, 1H,
3
1
+
crystal; yield, 83.1 %; m.p. 129-130 ºC; H NMR (CDCl
.32 (s, 3H, CH ), 1.36 (s, 3H, CH ), 1.80 (d, J = 8.0 Hz, 1H,
cyclopropane H), 2.16(t, J = 8.8 Hz, 1H, cyclopropane H),
.30 (s, 3H, CH ), 7.11 (d, J = 8.0 Hz, 1H, C=CH), 7.16-7.18
m, 2H, Ph), 7.32-7.34 (m, 2H, Ph), 7.62 (s, 1H, NH); Ms m/
3
) δ:
NH); Ms m/z (relative intensity/%): 385 ([M-1] , 24), 350 (26),
292 (37), 225 (32), 198 (65), 188 (100), 163 (31), 141 (24),
1
3
3
3 3
91 (8), 77 (6). Anal. calcd. (%) for C15H13NOCl F : C 46.60,
2
3
H 3.39, N 3.62, found (%): C 46.81, H 3.42, N 3.65.
(
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(2,4-dichlorophenyl)cyclopropanecarboxamide (4k):
+
z (relative intensity/%): 332 (M , 31), 296 (23), 238 (19), 225
1
White crystal; yield 87.5 %, m.p. 130-133 ºC; H NMR (CDCl
(
7), 198 (10), 134 (74), 106 (100), 91 (26), 77 (23); anal. calcd.
: C 57.92, H 5.16, N 4.22, found (%): C
8.03, H 5.12, N 4.16.
-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(2-methylphenyl)cyclopropanecarboxamide (4f): White
3
)
(
%) for C16
H
17NOClF
3
3 3
δ: 1.30 (s, 3H, CH ), 1.37 (s, 3H, CH ), 1.81 (d, J = 8.0 Hz,
5
1H, cyclopropane H), 2.23 (t, J = 8.8 Hz, 1H, cyclopropane
H), 7.15 (d, J = 9.2 Hz, 1H, C=CH), 7.25-7.28 (m, 2H, Ph),
7.39-7.42 (m, 1H, Ph), 7.82 (s, 1H, NH); Ms m/z (relative
3
1
+
crystal; yield, 81.3 %; m.p. 140-143 ºC; H NMR (CDCl
.35 (s, 3H, CH ), 1.38 (s, 3H, CH ), 1.87 (d, J = 8.0 Hz, 1H,
cyclopropane H), 2.20(t, J = 8.8 Hz, 1H, cyclopropane H),
.26 (s, 3H, CH ), 7.09 (d, J = 7.2 Hz, 1H, C=CH), 7.15-7.25
m, 4H, Ph), 7.70 (s, 1H, NH); Ms m/z (relative intensity/%):
3
) δ:
intensity/%): 385 ([M-1] , 40), 350 (13), 292 (39), 225 (41),
198 (73), 188 (100), 163 (29), 141 (24), 91 (9), 77 (12); anal.
1
3
3
calcd. (%) for C15
3 3
H13NOCl F : C 46.60, H 3.39, N 3.62, found
2
3
(%): C 46.76, H 3.33, N 3.68.
(
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(2,4-difluorophenylcyclopropanecarboxamide (4l):
+
3
32 (M , 44), 296(26), 238(11), 225(12), 198(14), 134 (100),
06(79), 91(50), 77(23). C16 ; anal. calcd. (%) for
17NOClF : C 58.92, H 5.16, N 4.22, found (%): C 60.06,
H 5.12, N 4.13.
1
White crystal; yield 84.2 %; m.p. 148-149 ºC; H NMR (CDCl
1
H
17NOClF
3
3
)
C
16
H
3
3 3
δ: 1.35 (s, 3H, CH ), 1.37 (s, 3H, CH ), 1.86 (d, J = 8.8 Hz,
1H, cyclopropane H), 2.22 (t, J = 8.8 Hz, 1H, cyclopropane
H), 6.85-6.89 (m, 2H, Ph), 7.12 (d, J = 9.6 Hz, 1H, C=CH),
7.38 (s, 1H, NH), 8.17-8.21(m, 1H, Ph); Ms m/z (relative in-
3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-
N-(3-methylphenyl)cyclopropanecarboxamide (4g): White
1
crystal; yield, 86.8 %; m.p. 137-139 ºC; H NMR (CDCl
+
3
) δ:
tensity/%): 353 (M , 15), 318(16), 260(19), 225(10), 198(36),
1
.33 (s, 3H, CH
cyclopropane H), 2.18(t, J = 8.8 Hz, 1H, cyclopropane H),
.33 (s, 3H, CH ), 7.12 (d, J = 7.2 Hz, 1H, C=CH), 7.15-7.25
m, 4H, Ph), 7.34 (s, 1H, NH); Ms m/z (relative intensity/%):
3
), 1.37(s, 3H, CH
3
), 1.79 (d, J = 8.0 Hz, 1H,
163(48), 156(100), 141(29), 128(60), 91(10), 77(6); anal.
5
calcd. (%) for C15H13NOClF : C 50.93, H 3.70, N 3.96, found
2
3
(%): C 51.05, H 3.74, N 3.90.
(
Biological activities
+
3
32 (M , 51), 296 (31), 238 (29), 225 (10), 198 (21), 134 (100),
06 (83), 91 (55), 77 (22); anal. calcd. (%) for C16
1
C 57.92, H 5.16, N 4.22, found (%): C 58.09, H 5.11, N 4.15.
H
17NOClF
3
:
Bioassay of fungicidal activities: The method for testing
the primary biological activities was performed in an isolated

Vol. 25, No. 12 (2013)
Synthesis and Biological Activities of N-Substituted Phenylcyclopropanecarboxamide 6699
culture. Under a sterile condition, 1 mL DMSO of title compound
was added to the culture plates, followed by the addition of
NMR, mass spectra and elemental analysis data of the
compounds are in agreement with the proposed structures. In
1
the H NMR spectra, the N-H protons of the amide derivatives
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 inhibition rate of the
circle mycelium compared to blank assay was calculated via
the following equation:
were observed as singlets at 7.38-7.82 ppm. All other aromatic
protons were observed in the expected regions. All the title
compounds of mass spectra are molecular ion peak.
Bioassay
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 Pseudo-
peronospora cubensis. Surprisingly, compound 4k exhibited
good activity against Rhizoctonia solani (63.8 %). As shown
in Table-1, compound displayed good activity against Botrytis
cinerea.Among them, compounds 4a, 4c, 4j and 4k have good
fungicidal activity (50-70 %) against Botrytis cinerea at the

(CK − PT)
Relative inhibition rate (%) =
×100 %



CK

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
-1
concentration of 200 µg mL . For the Sphaerotheca fuliginea,
it was found that most of them had low activity.
TABLE-1
FUNGICIDAL ACTIVITIES OF 4 (INHIBITION %)
Compound S. fuliginea P. cubensis B. cinerea
R. solani
4
a
26.3
18.6
16.3
14.2
8.8
7.6
7.2
0
0
0
54.2
20.3
50.7
29.6
38.9
10.6
9.8
0
18.9
0
4
were tested as control under the same conditions.
The insecticidal activities of compounds 4 were evaluated
4b
4
c
0
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
armyworm larvae were put into each dish. Per cent mortalities
were evaluated 2 days after treatment. Each treatment was
replicated for three times.
4d
0
0
4
e
5.6
0
15.7
0
4
f
4g
0
0
4h
0
6.8
0
4i
0
0
20.8
71.8
57.8
8.8
0
4j
30.5
0
0
4k
38.9
16.9
3.8
63.8
10.2
4
l
0
RESULTS AND DISCUSSION
The synthetic routes of title compounds were illustrated
as outlined in Scheme-I. The starting material λ-cyhalthrin
ACKNOWLEDGEMENTS
The project was supported by the Program of National
Natural Science Foundation of China (B020706).
2
acid (1) was treated with SOCl 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.
Then it reacted with substituted aniline at room temperature
as shown in Scheme-I.
REFERENCES
1. (a) X.H. Liu, J.Q. Weng, C.X. Tan and H.J. Liu, Acta Cryst., E67,
o1940 (2011); (b) X.H. Liu, J.Q. Weng, C.X. Tan, L. Pan, B.L. Wang
and Z.M. Li, Asian J. Chem., 23, 4031 (2011); (c) H.J. Liu, J.Q. Weng,
C.X. Tan and X.H. Liu, Acta Cryst., E67, o1940 (2011).
Cl
C
Cl
C
COCl
COOH
SOCl
2
2. 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).
F
3
C
C
H
F
3
C
C
H
H C CH
3
H C
CH
3
3. (a) 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);
3
3
1
2
(
b) X.H. Liu, L. Pan, J.Q. Weng, C.X. Tan, Y.H. Li, B.L. Wang and
O
C
R
H
N
Z.M. Li, Mol. Divers., 16, 251 (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).
Cl
C
2
H N
F
3
C
C
H
4
.
(a) X.H. Liu, C.X. Tan and J.Q. Weng, Phosphorus Sulfur Silicon Rel.
Elem., 186, 552 (2011); (b) P.Q. Chen, C.X. Tan, J.Q. Weng and X.H.
Liu, Asian J. Chem., 24, 2808 (2012); (c) Y.L. Xue, Y.G. Zhang and
X.H. Liu, Asian J. Chem., 24, 3016 (2012); (d) Y.L. Xue, Y.G. Zhang
and X.H. Liu, Asian J. Chem., 24, 1571 (2012); (e) X.H. Liu, C.X. Tan
and J.Q. Weng, Phosphorus Sulfur Silicon Rel. Elem., 186, 558 (2011);
H
3
C
CH
3
3
4
4
a, R=H; 5b, R=4-Cl; 5c, R=2-Cl; 5d, R=3-Cl; 5e, R=4-Me; 5f, R=2-Me;
g, R=3-Me; 5h, R=4-NO ; 5i, R=3-CF ; 5j, R=3,4-Cl ; 5k, R=2,4-Cl ; 5l,R=2,4-F
2
5
2
3
2
2
Scheme-I: Synthetic route of title compounds
(f) X.F. Liu and X.H. Liu, Acta Cryst., E67, o202 (2011).
The chemical structures of the title compounds were
1
1
confirmed by H NMR, mass and elemental analysis. The H