Synthesis and biological activities of 2,2-dichloro-1-(4-ethoxyphenyl)-n- substituted phenyl cyclopropanecarboxamide

Article abstract of DOI:10.14233/ajchem.2013.14097a

Some new amide-type compounds are synthesized from 1-(4-ethyoxyphenyl)-2,2- dichlorocyclopropane-1-carboxylic acid and substituted anilline. Their structures were confirmed by 1H NMR, MS and elemental analysis. The bioassay results indicated that they sho

Full text of DOI:10.14233/ajchem.2013.14097a

Asian Journal of Chemistry; Vol. 25, No. 7 (2013), 4071-4073
http://dx.doi.org/10.14233/ajchem.2013.14097A
Synthesis and Biological Activities of 2,2-Dichloro-1-(4-ethoxyphenyl)-
N-Substituted Phenyl Cyclopropanecarboxamide
*
NA-BO SUN , CHAO LEI, JIAN-ZHONG JIN 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: 28 January 2013)
AJC-12758
Some new amide-type compounds are synthesized from 1-(4-ethyoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid and substituted
1
anilline. Their structures were confirmed by H NMR, MS and elemental analysis. The bioassay results indicated that they showed
moderate fungicidal and insecticidal activities.
Key Words: Pyrethroid, Amide, Synthesis, Fungicidal activity, Insecticidal activity.
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 studied broadly for many years1. At
the end of 1940s, cyclopropane compounds, such as pyre-
throids, were marketed as low toxic insecticides. Since the
first pyrethroids insecticide-Allethrin was found, a large variety
of pyrethroids derivatives have been synthesized and lots of
them, such as deltamethrin, cypermethrin, bifenthrin, fenva-
lerate, tefluthrin and so on, are commercially available2. From
then on, many biologically active and structurally stable
cyclopropane compounds had been synthesized3.
1-(4-Ethyoxyphenyl)-2,2-dichlorocyclopropane-1-
carboxylic acid was synthesized in our laboratory according
to literature. Thionyl chloride (100 mL) was added into 1-(4-
ethyoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acid
(10 mmol) and the mixture was refluxed for 8 h. The excessive
thionyl chloride was distilled off under reduced pressure. The
desired acid chloride was not purified. Dropwised the acid
chloride to substituted substituted aniline (10 mmol) and Et3N
(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 corres-
ponding 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.
In recent years, synthesis of broader spectrum and highly
bioactive substituted cyclopropane compounds. Due to the
amide group exhibited the good biological activity, such as
herbicidal activity, fungicidal activity, insecticide activity, etc.4.
In line with our continuous efforts to synthesize bioactive lead
compounds for crop protection, the title compounds were
designed by introducing amide pharmacophore into the
cyclopropane scaffold and their biological activity tested. Then,
the single crystal of the title compound was determined. The
preliminary biological test showed that the synthesized comp-
ound has moderate fungicidal and insecticidal activities.
2,2-Dichloro-1-(4-ethoxyphenyl)-N-phenylcyclopropane
carboxamide(4a). White crystal;yield, 80.5 %; m.p., 148-151
ºC; 1H NMR (CDCl3) δ: 1.38 (t, J = 7.2 Hz, 3H, CH3), 2.22 (d,
J = 8.0 Hz, 1H, cyclopropane H), 2.72 (d, J = 8.4 Hz, 1H,
cyclopropane H), 4.00-4.04 (m, 2H, CH3CH2O), 6.93-6.95 (m,
2H, Ph), 7.21-7.25 (m, 3H, Ph), 7.56 (s, 1H, NH), 7.70-7.72
(m, 2H, Ph), 7.92-7.94 (m, 2H, Ph); Ms m/z (relative intensity/
%): 350 (M+, 36), 315 (21), 279 (14), 258 (100), 187 (39),
165 (74), 92 (17), 77 (9); Anal. calcd. for C18H17NO2Cl2 (%):
C 61.73, H 4.89, N 4.00, found: C 61.45, H 4.87, N 4.02.
2,2-Dichloro-1-(4-ethoxyphenyl)-N-(3-methylphenyl)-
cyclopropane carboxamide(4b). White crystal; yield, 78.4 %;
EXPERIMENTAL
Melting points were determined by an X-4 apparatus and
1
uncorrected. H NMR spectra were measured on a Bruker
Avance 400 DMX instrument using TMS as an internal stan-
dard and CDCl3 as the solvent. Mass spectra were recorded on
a HP 5989B mass detector instrument. Elemental analyses were

4072 Sun et al.
Asian J. Chem.
m.p., 128-131 ºC; 1H NMR (CDCl3) δ: 1.37 (t, J = 7.2 Hz, 3H,
CH3), 2.25 (d, J = 8.0 Hz, 1H, cyclopropane H), 2.38 (s, 3H,
CH3), 2.81 (d, J = 8.8 Hz, 1H, cyclopropane H), 3.98-4.02 (m,
2H, CH3CH2O), 6.96-6.98 (m, 2H, Ph), 7.31-7.35 (m, 3H, Ph),
7.56 (s, 1H, NH), 7.81-7.93 (m, 3H, Ph); Ms m/z (relative
intensity/%): 364 (M+, 29), 330 (49), 294 (20), 258 (100),
187(12), 165 (68), 92 (12), 77 (6). Anal. calcd. for
C19H19NO2Cl2(%): C 62.65, H 5.26, N 3.85, found: C 62.70, H
5.23, N 3.79.
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:
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. Percent 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 4 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
armyworm larvae were put into each dish. Percent mortalities
were evaluated 2 days after treatment. Each treatment was
replicated for three times.
2,2-Dichloro-1-(4-ethoxyphenyl)-N-(4-methylphenyl)-
cyclopropane carboxamide(4c). White crystal; yield, 77.8 %;
m.p., 120-123 ºC; 1H NMR (CDCl3) δ: 1.40 (t, J = 7.2 Hz, 3H,
CH3), 2.26 (d, J = 8.0 Hz, 1H, cyclopropane H), 2.39 (s, 3H,
CH3), 2.79 (d, J = 8.8 Hz, 1H, cyclopropane H), 3.99-4.03 (m,
2H, CH3CH2O), 6.99-7.01 (m, 2H, Ph), 7.28-7.30 (m, 2H, Ph),
7.66 (s, 1H, NH), 7.88-8.02 (m, 4H, Ph); Ms m/z (relative
intensity/%): 364 (M+, 36), 330 (20), 294 (39), 258 (100), 187
(40), 165 (56), 92 (18), 77 (11).Anal. calcd. for C19H19NO2Cl2
(%): C 62.65, H 5.26, N 3.85, found: C 62.77, H 5.24, N 3.81.
2,2-Dichloro-1-(4-ethoxyphenyl)-N-(2-methylphenyl)-
cyclopropane carboxamide(4d). White crystal; yield, 81.6 %;
m.p., 132-134 ºC; 1H NMR (CDCl3) δ: 1.38 (t, J = 7.2 Hz, 3H,
CH3), 2.26 (d, J = 8.4 Hz, 1H, cyclopropane H), 2.40 (s, 3H,
CH3), 2.88 (d, J = 8.8 Hz, 1H, cyclopropane H), 3.98-4.01 (m,
2H, CH3CH2O), 6.95-6.97 (m, 2H, Ph), 7.40-7.45 (m, 3H, Ph),
7.59 (s, 1H, NH), 7.82-7.95 (m, 3H, Ph); Ms m/z (relative
intensity/%): 364 (M+, 22), 330 (40), 294 (36), 258 (100), 187
(29), 165 (76), 92 (24), 77 (18). Calcd. for C19H19NO2Cl2 (%):
C 62.65, H 5.26, N 3.85, found: C 62.58, H 5.21, N 3.93.
2,2-Dichloro-1-(4-ethoxyphenyl)-N-(4-nitrophenyl)-
cyclopropane carboxamide(4e). White crystal; yield, 70.2 %;
m.p., 134-136 ºC; 1H NMR (CDCl3) δ: 1.41 (t, J = 7.2 Hz, 3H,
CH3), 2.26 (d, J = 8.0 Hz, 1H, cyclopropane H), 2.79 (d, J =
8.8 Hz, 1H, cyclopropane H), 3.98-4.03 (m, 2H, CH3CH2O),
6.91-6.93 (m, 2H, Ph), 7.29-7.31 (m, 2H, Ph), 7.78 (s, 1H,
NH), 8.01-8.12 (m, 3H, Ph); Ms m/z (relative intensity/%):
395 (M+, 41), 360 (22), 324 (36), 258 (100), 187 (11), 165
(44), 92 (19), 77 (28). Calcd. for C18H16N2O4Cl2 (%): C 54.70,
H 4.08, N 7.09, found: C 54.54, H 4.05, N 7.13.
RESULTS AND DISCUSSION
The synthetic routes of title compounds were illustrated
as outlined in Scheme-I. The starting material lambda
cyhalthrin acid 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.
Then it reacted with substituted aniline at room temperature
as shown in Scheme-I.
SOCl
2
C H O
C
COOH
Cl
C H
2
O
5
C
COCl
Cl
2
5
2,2-Dichloro-1-(4-ethoxyphenyl)-N-(2,4-difluoro-
phenyl)cyclopropane carboxamide(4f). White crystal; yield,
76.4 %; m.p., 126-129 ºC; 1H NMR (CDCl3) δ: 1.41 (t, J = 7.6
Hz, 3H, CH3), 2.31 (d, J = 8.0 Hz, 1H, cyclopropane H), 2.79
(d, J = 8.4 Hz, 1H, cyclopropane H), 4.00-4.04 (m, 2H,
CH3CH2O), 7.00-7.02 (m, 2H, Ph), 7.45-7.47 (m, 2H, Ph),
7.70 (s, 1H, NH), 7.82-7.90 (m, 3H, Ph); Ms m/z (relative
intensity/%): 386 (M+, 28), 350 (31), 315 (12), 258 (100), 187
(32), 165 (48), 92 (20), 77 (29); Calcd. for C18H15NO2Cl2F2
(%): C 55.98, H 3.91, N 3.63, found: C 56.08, H 3.86, N 3.69.
Cl
Cl
2
1
R
O
R
H
H2N
N
C H O
2 5
C
3
Cl
Cl
4
4a, R=H; 4b, R=3-Me; 4c, R=4-Me; 4d, R=2-M e; 4e, R=4-NO ; 4f, R=2,4-F
2
2
Scheme-I: Synthetic route of title compounds
The chemical structures of the title compounds were
confirmed by 1H NMR, mass and elemental analysis. The 1H
NMR, mass spectra and elemental analysis data of the comp-
ounds are in agreement with the proposed structures. In the
1H NMR spectra, the N-H protons of the amide derivatives
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.
Biological activities
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 compound
was added to the culture plates, followed by the addition 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
Fungicidal activity: The in vivo fungicidal results of all
of the compounds against Rhizoctonia solani, Pseudoperonospora
cubensis, Sphaerotheca fuliginea and Botrytis cinerea were

Vol. 25, No. 7 (2013)
Synthesis and Biological Activities of N-Substituted Phenyl Cyclopropanecarboxamide 4073
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
and Botrytis cinerea. Surprisingly, compound 4a exhibited
good activity against Botrytis cinerea (61.2 %). As shown in
Table-1, compound displayed moderate activity against
Botrytis cinerea. For the Sphaerotheca fuliginea and Rhizoctonia
solani, it was found that most of them had low activity.
ACKNOWLEDGEMENTS
The project was supported by the Program of National
Natural Science Foundation of China (21102131).
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TABLE-1
FUNGICIDAL ACTIVITIES OF 4 (INHIBITION/%)
Sphaerotheca Pseudoperonospora Botrytis Rhizoctonia
Compd.
fuliginea
cubensis
15.6
8.9
cinerea
61.2
23.5
solani
19.8
6.3
6.9
9.2
0
16.3
8.5
6.8
7.8
0
4a
4b
4c
4d
4e
4f
7.8
3.6
0
2.1
36.8
20.1
15.6
10.8
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0
0
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ounds 4 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 4b displayed moderate insecticidal activity
against Mythimna separate (48.5 %).
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TABLE-2
INSECTICIDAL ACTIVITIES OF 4 (MORTALITY/%)
Nilaparvata Mythimna Tetranychus
legen
5.3
Aphis
cinnabarnus medicagini
Compd.
separate
16.3
0
16.1
4.6
3.1
0
0
0
0
0
0
0
4a
4b
4c
4d
4e
4f
10.1
0
48.5
18.4
8.3
26.4
7.1
36.1
13.5
20.3
7.8