Design, synthesis and biological activities of novel anthranilic diamide insecticide containing trifluoroethyl ether

Article abstract of DOI:10.1002/cjoc.201200362

Two series of novel anthranilic diamide insecticide containing trifluoroethyl ether were designed and synthesized, and their structures were characterized by ¹H NMR spectroscopy, elemental analysis and single crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities. The insecticidal activities of compounds 19a, 19b, 19d, 19g, 19k and 19m against oriental armyworm at 2.5 mg·kg^-1 were 100%. The larvicidal activities of 19a, 19b, 19c, 19d, 19e, 19g and 19n against diamond-back moth were 100% at 0.1 mg·kg^-1. Surprisingly, most of them still exhibited perfect insecticidal activity against diamond-back moth when the concentration was reduced to 0.05 mg·kg^-1, which was higher than the commercialized Chlorantraniliprole.

Full text of DOI:10.1002/cjoc.201200362

FULL PAPER
DOI: 10.1002/cjoc.201200362
Design, Synthesis and Biological Activities of Novel An-
thranilic Diamide Insecticide Containing Trifluoroethyl Ether
Zhao, Yu(赵毓)
Li, Yongqiang(李永强)
Xiong, Lixia (熊丽霞)
Wang, Hongxue(王红学)
Li, Zhengming*(李正名)
National Pesticidal Engineering Centre (Tianjin), State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071, China
Two series of novel anthranilic diamide insecticide containing trifluoroethyl ether were designed and synthe-
sized, and their structures were characterized by 1H NMR spectroscopy, elemental analysis and single crystal X-ray
diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indi-
cated that some of these title compounds exhibited excellent insecticidal activities. The insecticidal activities of
compounds 19a, 19b, 19d, 19g, 19k and 19m against oriental armyworm at 2.5 mg•kg－1 were 100%. The larvicidal
－
1
activities of 19a, 19b, 19c, 19d, 19e, 19g and 19n against diamond-back moth were 100% at 0.1 mg•kg . Surpris-
ingly, most of them still exhibited perfect insecticidal activity against diamond-back moth when the concentration
－
1
was reduced to 0.05 mg•kg , which was higher than the commercialized Chlorantraniliprole.
Keywords anthranilic diamide, ryanodine receptor, trifluoroethyl ether, insecticidal activity
Introduction
vator of insect ryanodine receptors with exceptional ac-
tivity on a broad range of Lepidoptera. As the first new
insecticide from this class (Figure 1),[7] Chloran-
traniliprole demonstrates field use-rates that are signifi-
cantly less than current commercial standards, varying
from 50 g/ha to less than 1 g/ha and with good safety
toward beneficial insects. In addition to possessing ex-
tremely high levels of potency on insects, Chloran-
traniliprole shows remarkable safety to mammals as a
result of poor intrinsic activity on mammalian ryanodine
receptors with a margin of selectivity of the order of 103.
Resistance has often been a problem or a potential
problem for insecticide and is one of the most important
reasons why insecticides with a new mode of action
have been desired.[1] Recently, two new classes of in-
secticidal phthalic acid diamides and anthranilic dia-
mides have been discovered with exceptional insecti-
cidal activity on a range of Lepidoptera, which exhibit
their action by binding to ryanodine receptors and acti-
vating the uncontrolled release of calcium stores.[2]
Since then diamides have be the focus of synthesis ac-
tivities within the agrochemical industry. Anthranilic
diamides and their chemistry have recently attracted
considerable attention in the field of novel agricultural
insecticides, owing to their prominent insecticidal activ-
ity, unique modes of action and good environmental
profiles.[3,4] Anthranilic diamides act on the sarcosplas-
mic reticulum of cardiac and skeletal muscle cells to
open internal calcium stores causing muscle contraction,
paralysis, and death.[5,6]
Anthranilic diamide insecticide is characterized by a
three-part chemical structure as shown in Figure 1: (A) an
anthraniloyl moiety, (B) an aromatic acyl moiety and (C)
an aliphatic amide moiety. Notably, anthranilic diamides
containing N-pyridylpyrazole in the second section (B)
showed significantly better activity than other heterocyc-
lic derivatives. Work in this area has led to the discovery
of Chlorantraniliprole, a highly potent and selective acti-
H
Br
N
O
N
O
H
N
X
Me
Cl
(B)
(C)
Ar
H
N
N
N
R1
R2
O
Cl
Me
N
O
(A)
(RynaxypyrTM
CF3
)
H
N
O
H
N
N
N
O
Cl
Cl
Me
N
DP-23
Figure 1 Chemical structures of anthranilic diamides insecti-
cides.
*
E-mail: nkzml@vip.163.com; Tel.: 0086-022-23503732; Fax: 0086-022-23505948
Received April 15, 2012; accepted May 11, 2012.
1748
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Chin. J. Chem. 2012, 30, 1748—1758

Design, Synthesis and Biological Activities of Novel Anthranilic Diamide Insecticide
Recently, anthranilic diamides derivatives have
drawn much attention in insecticidal research due to
their significant bioactivity. In addition, many investi-
gations have indicated that introducing the F or CF3
group into heterocyclic molecules mostly results in the
improvement of physical, chemical and biological
properties.[8-11] It was reported that a series of fluori-
nated derivatives of anthranilic diamides displayed an
insecticidal activity comparable or superior to that of
Chlorantraniliprole. The synthesis and insecticidal
evaluation of DP-23 have been reported and the results
of bioassay showed that it exhibit excellent larvicidal
activity (Figure 1).[12]
Encouraged by these reports, an idea was developed
that the introduction of a trifluoroethyl ether substituent
into the Chlorantraniliprole molecules by substituting
the halogen atoms on the pyrazole ring could improve
biological properties. Therefore, in a search for new
anthranilic diamide insecticides with improved profiles,
two series of anthranilic diamide derivatives containing
trifluoroethyl ether were designed and synthesized.
Tech Instruments Co., Beijing, China) and were uncor-
rected. All solvents and liquid reagents were dried by
standard methods and distilled before use.
General procedures
Chlorantraniliprole was prepared according to the
route shown in Scheme 1. The title compounds 19 and
20 were synthesized from compound 18 and the appro-
priate intermediate 14 or 15 (obtained from the interme-
diate 13 and corresponding alcohol or amine – see Table
1) in dry tetrahydrofuran using triethylamine as base as
shown in Scheme 2.
Synthetic procedure for 2-amino-3-methyl-benzoic
acid (4)
Compounds 4 was prepared according to the litera-
ture.[13] Chloralhydrate (8.1 g, 55 mmol, 1.1 equiv.) and
Na2SO4 (71.0 g, 0.5 mol, 10 equiv.) were dissolved in
water (200 mL) in a three-neck 500 mL round-bottom
flask. The solution was stirred with a mechanical stirrer
and heated to 40 ℃ until the mixture became clear. A
warm solution of the commercial o-toluidine 1 (5.4 g,
50 mmol) in water (50 mL) and an aqueous solution of
concentrated HCl (5.32 g, 4.5 mL, 52.5 mmol, 1.05
equiv.) were added, followed by a warm solution of
hydroxylamine hydrochloride (10.4 g, 0.15 mol, 3.0
equiv.) in water (45 mL). The mixture was heated to
reflux under vigorous stirring, allowed to reflux for 10
min, and then cooled to room temperature. The product
precipitated out of solution, and after standing overnight,
the solid were collected and dried to obtain 2-hydroxy-
imino-N-o-tolyl-acetamide.
Experimental
Materials and methods
1H NMR spectra were obtained at 400 MHz using a
Bruker AV400 spectrometer or Varian Mercury Plus400
spectrometer in CDCl3 solution with tetramethylsilane
as the internal standard. Elemental analyses were deter-
mined on a Yanaco CHN Corder MT-3 elemental ana-
lyzer. The melting points were determined on an X-4
binocular microscope melting point apparatus (Beijing
Scheme 1
H
NH2
OH
NCS
N
NaOH, H2O2
Cl3CCH(OH)2
O
H2SO4
OH
O
N
.
NH2OH HCl
N
NH2
H
O
O
2
1
3
4
NH2
NH2
SOCl2
THF, CH3NH2
H
O
N
Cl
N
H
Cl
CH3
O
O
5
6
Br
O
H2N
Cl
N
NH
POBr3
NH
EtOOC
K2S2O8, H2SO4
N
EtOOC
N
Cl
N2H4
Diethyl maleate
Cl
Cl
N
Cl
N
N
7
8
10
9
H
N
Br
Br
N
O
Br
N
Me
Cl
H
N
N
HOOC
N
(COCl)2, CH2Cl2
N
EtOOC
NaOH
MeOH
N
Cl
O
Cl
Me
6
Cl
N
N
N
(RynaxypyrTM
)
12
11
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Zhao et al.
FULL PAPER
Scheme 2
R1
NH2
H
N
R3 NH2
R2
R3
R1
O
NH2
OH
14a 14n
R1
R2
NH2
R3
OH
O
13
O
R2
R3
O
15a 15b
O
O
O
CH2CF3
NaOH
NH
NH
K2S2O8 EtOOC
H2SO4
N
EtOOC
N
CF3CH2I
EtOOC
N
N
Cl
Cl
Cl
N
N
N
16
17
9
H
N
O CH2CF3
O
R3
H
N
N
14
N
Cl
O
O
CH2CF3
R2
R1
N
19a 19n
N
HOOC
N
O CH2CF3
Cl
O
O
N
R3
R2
H
N
N
15
N
18
Cl
O
R1
N
20a 20b
Sulfuric acid (60 mL) was heated in a three-neck 250
mL round-bottom flask to 60 ℃ and then removed.
The dry 2-hydroxyimino-N-o-tolyl-acetamide (2) was
added in portions with stirring over 30 min so that the
temperature did not exceed 70 ℃. The mixture was
then heated to 80 ℃ for 20 min, then allowed to cool
to room temperature. The reaction mixture was poured
over crushed ice (100 g) and left to stand for 1 h,
yielding a crude precipitate that was collected by suction
filtration. The product was washed with water (50 mL×
2) and filtered to give crude 7-methyl-1H-indole-2,3-
dione, which was directly used for the next step without
further purification.
J＝7.0 Hz, 1H, Ph-H), 6.48—6.51 (m, 1H, Ph-H), 2.09
(s, 3H, CH3).
Synthetic procedure for 2-amino-5-chloro-3-methyl-
benzoic acid (5)
2-amino-5-chloro-3-methylbenzoic acid (5) was
prepared according to the literature.[14] To a solution of
2-amino-3-methylbenzoic acid (10 g, 66 mmol) in DMF
(40 mL) was added N-chlorosuccinimide (8.8 g, 66
mmol) and the reaction mixture was heated to 100 ℃
for 40 min. The reaction was cooled to room tempera-
ture and let stand overnight. The reaction mixture was
then slowly poured into ice-water (150 mL) to precipi-
tate a white solid. The solid was filtered and washed
with water (50 mL×3) and then taken up in ethyl ace-
tate (600 mL). The ethyl acetate solution was dried over
magnesium sulfate, evaporated under reduced pressure
and the residual solid was washed with ether (30 mL×3)
to afford intermediate 2-amino-5-chloro-3-methylben-
zoic acid (5): White solid, m.p. 196—197 ℃ (dec.),
yield 76.0%; 1H NMR (DMSO, 400 MHz) δ: 7.53 (s, 1H,
Ph-H), 7.21 (s, 1H, Ph-H), 2.09 (s, 3H, CH3).
To a stirred suspension of compound 3 in a 5%
aqueous sodium hydroxide solution (150 mL), this mix-
ture was cooled to 0 ℃, and added dropwise a 30%
aqueous hydrogen peroxide solution (150 mL). The re-
action mixture was stirred at 50 ℃ for 30 min and then
allowed to reach room temperature. The filtered solution
was acidified to pH 4 with an aqueous 1 mol•L－ hy-
1
drochloric acid solution, and a tan precipitate was col-
lected by filtration, washed thoroughly with cold water,
and dried under vacuum to afford 2-amino-3-
methyl-benzoic acid (4). The overall yield of compound
Synthesis of intermediates N-methyl 2-amino-5-
chloro-3-methyl-benzamide (6)
1
4 was 25.6%, m.p. 173—174 ℃. H NMR (DMSO-d6,
400 MHz) δ: 7.61 (d, J＝8.0 Hz, 1H, Ph-H), 7.15 (d,
N-Methyl 2-amino-5-chloro-3-methyl-benzamide (6)
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1748—1758

Design, Synthesis and Biological Activities of Novel Anthranilic Diamide Insecticide
was prepared according to the literature.[15] To a 100 mL
round-bottomed flask was placed 2-amino-5-chloro-3-
methylbenzoic acid (5) (3.7 g, 20 mmol) and then was
added 50 mL of thionyl chloride. The resulting mixture
was refluxed for 3 h. The mixture was evaporated in
vacuo to dryness and then 60 mL of THF was added. To
this solution was added dropwise 50 g of 25% aqueous
methylamine solution under an ice bath. The resulting
solution was allowed to stir at room temperature for 12
h and then water (200 mL) was added. The yellow pre-
cipitate was collected by filtration and dried to give 2.36
g (59.3%) of compound 6, m.p. 130—132 ℃; 1H NMR
(CDCl3, 400 MHz) δ: 7.16 (d, J＝2.2 Hz, 1H, Ph-H),
7.09 (d, J＝1.6 Hz, 1H, Ph-H), 6.01 (br s, 1H, NH), 5.52
(br s, 2H, NH2), 2.95 (d, J＝4.8 Hz, 3H, NHCH3), 2.13
(s, 3H, CH3).
5-Bromo-2-(3-chloro-pyridin-2-yl)-3,4-dihydro-2H-
pyrazole-3-carboxylic acid ethyl ester (10)
To a solution of 2-(3-chloro-pyridin-2-yl)-5-oxo-
pyrazolidine-3-carboxylic acid ethyl ester (9) (27 g, 0.1
mol) in acetonitrile (300 mL) was added phosphorous
oxybromide (34.4 g, 0.12 mmol). The reaction mixture
was refluxed for 5 h, then 250 mL of solvent was re-
moved by distillation. The concentrated reaction mixture
was slowly poured into saturated aq. Na2CO3 (250 mL)
and was stirred vigorously for 30 min. The resulting
mixture was extracted with CH2Cl2 (250 mL×2), the
organic extract was separated, dried, filtered, concen-
trated and purified by silica gel chromatography to af-
ford
5-bromo-2-(3-chloro-pyridin-2-yl)-3,4-dihydro-
2H-pyrazole-3-carboxylic acid ethyl ester (10) (31.0 g,
1
93.0%), m.p. 59—60 ℃; H NMR (DMSO-d6, 400
MHz) δ: 8.10 (d, J＝4.4 Hz, 1H, pyridyl-H), 7.83 (d,
J＝7.7 Hz, 1H, pyridyl-H), 6.98 (dd, J＝4.4, 7.7 Hz, 1H,
pyridyl-H), 5.17 (dd, J＝8.7, 11.8 Hz, 1H, CH), 4.08 (q,
J＝7.0 Hz, 2H, OCH2), 3.27 (dd, J＝8.7, 17.6 Hz, 1H,
CH2-H), 3.57 (dd, J＝11.8, 17.6 Hz,, 1H, CH2-H), 1.12
(t, J＝7.0 Hz, 3H, CH3).
Synthetic procedure for (3-chloro-pyridin-2-yl)-
hydrazine (8)
To a suspension of 2,3-dichloropyridine 7 (100.0 g,
0.676 mol) in anhydrous ethanol (420 mL) was added
50% hydrazine hydrate (280 mL, 2.884 mol). The re-
sulting mixture was refluxed for 36 h, and then cooled
to room temperature. The product precipitated out of
solution, the white crystal was collected by filtration,
washed thoroughly with cold ethanol and dried to give
Synthetic procedure for 5-bromo-2-(3-chloro-pyri-
din-2-yl)-2H-pyrazole-3-carboxylic acid ethyl ester
(11)
1
white crystals (74.4 g, 76.8%), m.p. 163—164 ℃; H
To a solution of 5-bromo-2-(3-chloro-pyridin-2-
yl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid ethyl
ester (10) (17 g, 51 mmol) in acetonitrile (250 mL) was
added sulfuric acid (98%, 10 g, 102 mmol). After being
stirred for several minutes, the reaction mixture was
treated with K2S2O8 (21 g, 76.5 mmol) and was refluxed
for 4.5 h. After being cooled to 60 ℃, the mixture was
filtered, the filter cake was washed with acetonitrile (30
mL). The filtrate was concentrated to 100 mL, then was
added slowly to water (250 mL) under stirring. The
solid was collected by filtration, washed with acetoni-
trile (30 mL×3), water (30 mL), and then dried to give
5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-car-
boxylic acid ethyl ester (11) (15.6 g, 92.7%), m.p. 117
NMR (CDCl3, 300 MHz) δ: 8.09 (d, J＝3.9 Hz, 1H,
pyridyl-H), 7.47 (d, J＝8.1 Hz, 1H, pyridyl-H), 6.64 (dd,
J＝3.9, 8.1 Hz, 1H, pyridyl-H), 6.21 (s, 1H, NH), 3.97
(br s, 2H, NH2).
Synthetic procedure for 2-(3-chloro-pyridin-2-yl)-5-
oxo-pyrazolidine-3-carboxylic acid ethyl ester (9)
To 200 mL of absolute ethanol in a 500 mL
three-necked round-bottomed flask was added 6.9 g (0.3
mol) of sodium cut in pieces of suitable size. When all
the sodium has reacted, the mixture was heated to reflux
and (3-chloro-pyridin-2-yl)-hydrazine (8) (39.82 g,
0.277 mol) was added. The mixture was refluxed for 10
min, then diethyl maleate (51.65 g, 0.3 mol) was added
dropwise. The resulting orange-red solution was held at
reflux for 30 min. After being cooled to 65 ℃, the reac-
tion mixture was treated with glacial acetic acid (30 g,
0.51 mol). The mixture was diluted with water (30 mL).
After removal of most solvent, the residue was treated
with water (300 mL). The slurry formed was dissolved
in aqueous ethanol (70%, 200 mL) and was stirred
thoroughly. The solid was collected by filtration,
washed with aqueous ethanol (50%, 50 mL×3) to give
2-(3-chloro-pyridin-2-yl)-5-oxo-pyrazolidine-3-carboxy-
lic acid ethyl ester (9) (36.6 g, 49.0%), m.p. 132—134
1
—118 ℃; H NMR (CDCl3, 300 MHz) δ: 8.52 (d, J＝
4.8 Hz, 1H, pyridyl-H), 7.92 (d, J＝8.1 Hz, 1H, pyridyl-
H), 7.45 (dd, J＝4.8, 8.1 Hz, 1H, pyridyl-H), 6.95 (s, 1H,
pyrazolyl-H), 4.24 (q, J＝7.2 Hz, 2H, CH2), 1.21 (t, J＝
7.2 Hz, 3H, CH3).
Synthetic procedure for 5-bromo-2-(3-chloro-
pyridin-2-yl)-2H-pyrazole-3-carboxylic acid (12)
To a mixture of the ethyl 5-bromo-2-(3-chloro-pyri-
din-2-yl)-2H-pyrazole-3-carboxylic acid ethyl ester (11)
(15.6 g, 47.2 mmol) in methanol (120 mL) was added
－
1
1
aqueous sodium hydroxide solution (60 mL, 1 mol•L ).
The solution was stirred at room temperature for 6 h,
then was concentrated in vacuo to about 50 mL. The
concentrated mixture was diluted with H2O (150 mL),
and washed with ethyl acetate (150 mL). The aqueous
solution was acidified using concentrated hydrochloric
acid to pH＝2. The solid was collected by filtration,
℃; H NMR (DMSO-d6, 400 MHz) δ: 10.18 (s, 1H,
NH), 8.25 (d, J＝4.8 Hz, 1H, pyridyl-H), 7.91 (d, J＝
7.4 Hz, 1H, pyridyl-H), 7.18 (dd, J＝4.8, 7.4 Hz, 1H,
pyridyl-H), 4.81 (d, J＝9.8 Hz, 1H, CH), 4.17 (q, J＝7.0
Hz, 2H, OCH2), 2.89 (dd, J＝9.8, 16.8 Hz, 1H, CH2-H),
2.34 (d, J＝16.8 Hz, 1H, CH2-H), 1.20 (t, J＝7.0 Hz, 3H,
CH3).
Chin. J. Chem. 2012, 30, 1748—1758
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1751

Zhao et al.
FULL PAPER
washed with ether (30 mL), and then dried to give
5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-car-
boxylic acid (12) (12.75 g, 89.3%), m.p. 197—200 ℃;
1H NMR (CDCl3, 300 MHz) δ: 8.52 (dd, J＝1.5, 4.8 Hz,
1H, pyridyl-H), 7.94 (dd, J＝1.5, 8.1 Hz, 1H, pyridyl-H),
7.48 (dd, J＝4.8, 8.1 Hz, 1H, pyridyl-H), 7.10 (s, 1H,
pyrazolyl-H).
Table 1 Melting points and yields of the compounds 14a—14n
and 15a—15b
Compd.
14a
14b
14c
14d
14e
14f
R1
R2
R3
m.p./℃
Yield/%
88.0
92.4
77.9
68.1
89.2
79.3
58.0
61.9
66.4
56.9
70.2
70.2
80.0
69.6
52.9
47.6
CH3 Cl
CH3 Cl
CH3 Cl
CH3 Cl
CH3 Cl
n-propyl
119—121
cyclopropyl 122—124
n-butyl
i-butyl
87—88
117—122
Synthetic procedure for Chlorantraniliprole
cyclohexyl 167—168
Chlorantraniliprole was prepared according to the
literatures.[16,17] To a suspension of N-pyridylpyrazole
acid 12 (0.30 g, 1 mmol) in dichloromethane (20 mL)
was added oxalyl chloride (0.38 g, 3 mmol), followed
by dimethylformamide (2 drops). The solution was
stirred at room temperature. After 6 h the mixture was
concentrated in vacuo to obtain the crude acid chloride.
The crude acid chloride in dichloromethane (20 mL)
was added slowly to a stirred solution of 2-amino-5-
chloro-3-N-dimethyl-benzamide (6) (0.24 g, 1.2 mmol)
in dichloromethane (20 mL) in an ice bath. After 20 min,
ethyl-diisopropyl-amine (0.13 g, 1 mmol) was added
dropwise. The solution was warmed to room tempera-
ture and stirred for 12 h. The solution was diluted with
H
Cl
Cl
Cl
Cl
Cl
H
n-propyl
i-propyl
120—122
161—162
14g
14h
14i
H
H
cyclopropyl 143—145
n-butyl 108—110
cyclohexyl 179—181
H
14j
H
14k
14l
CH3
CH3
CH3
CH3
n-propyl
i-propyl
88—90
H
137—139
14m
14n
15a
15b
H
cyclopropyl 118—120
cyclohexyl 158—159
H
CH3 Cl
CH3 Br
methyl
methyl
33—35
50—53
CH2Cl2 (20 mL), and washed with 1 mol•L－ aq. HCl
1
solution (10 mL), saturated aq. NaHCO3 (10 mL), and
brine (10 mL). The organic extract was separated, dried,
filtered, and concentrated and purified by silica gel
chromatography to afford the Chlorantraniliprole. (0.43
Synthetic procedure for 2-(3-chloro-pyridin-2-yl)-5-
oxo-2,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl
ester (16)
1
To a solution of 2-(3-chloro-pyridin-2-yl)-5-oxo-
pyrazolidine-3-carboxylic acid ethyl ester (9) (10 g, 37
mmol) in acetonitrile (150 mL) was added sulfuric acid
(98%, 7.2 g, 74 mmol). After being stirred for several
min, the reaction mixture was treated with K2S2O8 (15g,
56 mmol) and was refluxed for 4.5 h. After being cooled
to 60 ℃, the mixture was filtered, the filter cake was
washed with acetonitrile (30 mL). The filtrate was con-
centrated and poured into ice water (200 mL). The
aqueous layer was extracted with dichloromethane (150
mL×3). The organic layer was washed with water (100
mL×3) and dried over anhydrous sodium sulfate. Then
the ethyl acetate was concentrated. The residue was pu-
rified by column chromatography over silica gel using
petroleum ether (60—90 ℃) and ethyl acetate as the
eluent to afford the 2-(3-chloro-pyridin-2-yl)-5-oxo-
2,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester
g, 89.3%), m.p. 197—200 ℃; H NMR (CDCl3, 400
MHz) δ: 10.10 (br s, 1H, NH), 8.46 (dd, J＝1.6, 4.8 Hz,
1H, pyridyl-H), 7.85 (dd, J＝1.6, 8.0 Hz, 1H, pyridyl-H),
7.38 (dd, J＝4.8, 8.0 Hz, 1H, pyridyl-H), 7.24 (d, J＝2.0
Hz, 1H, Ph-H), 7.21 (d, J＝2.0 Hz, 1H, Ph-H), 7.11 (s,
1H, pyrazolyl-H), 6.15—6.18 (m, 1H, NHCO), 2.95 (d,
J＝4.9 Hz, 2H, NHCH3), 2.17 (s, 3H, CH3).
Synthetic procedure for 2-amino-5-chloro-3-methyl-
N-propyl-benzamide (14a)
To a 100 mL round-bottomed flask was placed 2-
amino-5-chloro-3-methylbenzoic acid (5) (5.0 g, 27
mmol) and then was added 50 mL of thionyl chloride.
The resulting mixture was refluxed for 3 h. The mixture
was evaporated in vacuo to dryness and then 40 mL of
THF was added. The solution was added slowly to a
stirred solution of propylamine (15.8 g, 270 mmol) in
tetrahydrofuran (40 mL) in an ice bath. The resulting
solution was allowed to stir at room temperature for 12
h. Then the solution was concentrated in vacuo and di-
luted with ethyl acetate (150 mL), and washed with wa-
ter (50 mL×3). The organic extract was separated,
dried, filtered, and concentrated and purified by silica
gel chromatography to afford the desired title compound
14a.
1
(16). (6.2 g, 62.4%), m.p. 136—138 ℃; H NMR
(CDCl3, 400 MHz) δ: 9.35 (s, 1H, NH), 8.52 (d, J＝4.4
Hz, 1H, pyridyl-H), 7.90 (d, J＝8.0 Hz, 1H, pyridyl-H),
7.43 (dd, J＝4.4, 8.0 Hz, 1H, pyridyl-H), 6.36 (s, 1H,
pyrazolyl-H), 4.19 (q, J＝7.2 Hz, 2H, CH2), 1.19 (t, J＝
7.2 Hz, 3H, CH3).
Synthetic procedure for 2-(3-chloro-pyridin-2-yl)-5-
(2,2,2-trifluoro-ethoxy)-2,5-dihydro-1H-pyrazole-3-
carboxylic acid ethyl ester (17)
Compounds 14b—14n and 15a—15b were prepared
by similar method above using the appropriate sub-
strates. The melting points and yields of compounds 14
and 15 are listed in Table 1. The 1H NMR data are listed
in Table 2.
The ester 17 was prepared according to the litera-
ture.[7] Compound 16 (1.0 g, 3.7 mmol) was dissolved in
30 mL of dry dimethylformamide, and potassium
1752
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1748—1758

Design, Synthesis and Biological Activities of Novel Anthranilic Diamide Insecticide
Table 2 1H NMR of the compounds 14a—14n and 15a—15b
Compd.
1H NMR δ
(400 MHz, DMSO-d6) δ: 8.37 (br s, 1H, CONH), 7.41 (d, J＝1.8 Hz, 1H, Ph-H), 7.13 (d, J＝1.8 Hz, 1H, Ph-H), 6.32 (s, 2H,
PhNH2), 3.14—3.17 (m, 2H, NHCH2), 2.08 (s, 3H, PhCH3), 1.50—1.52 (m, 2H, CH2CH3), 0.88 (t, J＝7.4 Hz, 3H, CH2CH3)
14a
(400 MHz, CDCl3) δ: 7.08—7.10 (m, 2H, Ph-H), 6.10 (br s, 1H, NH), 5.60 (br s, 2H, NH2), 2.80—2.86 (m, 1H, cyclopropyl-H),
2.13 (s, 3H, CH3), 0.84—0.87 (m, 2H, cyclopropyl-H), 0.58—0.62 (m, 2H, cyclopropyl-H)
14b
14c
(400 MHz, DMSO-d6) δ: 8.34 (br s, 1H, CONH), 7.41 (d, J＝1.8 Hz, 1H, Ph-H), 7.12 (d, J＝1.8 Hz, 1H, Ph-H), 6.32 (s, 2H,
PhNH2), 3.19—3.22 (m, 2H, NHCH2), 2.08 (s, 3H, PhCH3), 1.45—1.52 (m, 2H, CH2), 1.29—1.36 (m, 2H, CH2CH3), 0.89 (t, J＝
7.3 Hz, 3H, CH2CH3)
(400 MHz, DMSO-d6) δ: 8.38 (br s, 1H, CONH), 7.42 (d, J＝2.0 Hz, 1H, Ph-H), 7.14 (d, J＝2.0 Hz, 1H, Ph-H), 6.29 (s, 2H,
PhNH2), 3.01—3.03 (m, 2H, NHCH2), 2.08 (s, 3H, PhCH3), 1.77—1.88 (m, 1H, CH(CH3)2), 0.88 (d, J＝6.6 Hz, 6H, CH(CH3)2)
14d
14e
(400 MHz, CDCl3) δ: 7.05—7.14 (m, 2H, Ph-H), 5.81 (br s, 1H, NH), 5.46 (br s, 2H, NH2), 3.82—3.94 (m, 1H, cyclohexyl-H),
2.13 (s, 3H, CH3), 1.18—2.04 (m, 10H, cyclohexyl-H)
(400 MHz, DMSO-d6) δ: 8.34—8.36 (m, 1H, CONH), 7.53 (d, J＝2.4 Hz, 1H, Ph-H), 7.15 (dd, J＝8.7, 2.4 Hz, 1H, Ph-H), 6.70
(d, J＝8.7 Hz, 1H, Ph-H), 6.54 (s, 2H, PhNH2), 3.13—3.16 (m, 2H, NHCH2), 1.46—1.53 (m, 2H, CH2CH3), 0.87 (t, J＝7.2 Hz,
3H, CH2CH3)
14f
14g
14h
(400 MHz, DMSO-d6) δ: 8.11—8.13 (m, 1H, CONH), 7.54 (d, J＝2.4 Hz, 1H, Ph-H), 7.15 (dd, J＝8.8, 2.4 Hz, 1H, Ph-H), 6.70
(d, J＝8.8 Hz, 1H, Ph-H), 6.50 (s, 2H, PhNH2), 4.01—4.09 (m, 1H, CH), 1.14 (d, J＝6.6 Hz, 6H, CH(CH3)2)
(400 MHz, DMSO-d6) δ: 8.35—8.37 (m,1H, CONH), 7.53 (d, J＝2.4 Hz, 1H, Ph-H), 7.20 (dd, J＝8.8, 4.8 Hz, 1H, Ph-H), 6.76
(d, J＝8.8 Hz, 1H, Ph-H), 6.61 (s, 2H, PhNH2), 2.82—2.88 (m, 1H, cyclopropyl-H), 0.69—0.74 (m, 2H, cyclopropyl-H), 0.58—
0.62 (m, 2H, cyclopropyl-H)
(400 MHz, DMSO-d6) δ: 8.30—8.32 (m, 1H, CONH), 7.51 (d, J＝2.0 Hz, 1H, Ph-H), 7.15 (dd, J＝8.7, 2.0 Hz, 1H, Ph-H), 6.70
(d, J＝8.7 Hz, 1H, Ph-H), 6.53 (s, 2H, PhNH2), 3.17—3.19 (m, 2H, NHCH2 ), 1.42—1.51 (m, 2H, CH2CH2), 1.26—1.35 (m, 2H,
CH2CH3), 0.89 (t, J＝7.2 Hz, 3H, CH2CH3)
14i
(400 MHz, DMSO-d6) δ: 8.10—8.12 (m, 1H, CONH), 7.52 (d, J＝2.0 Hz, 1H, Ph-H), 7.14 (dd, J＝8.7, 2.0 Hz, 1H, Ph-H), 6.69
(d, J＝8.7 Hz, 1H, Ph-H), 6.47 (s, 2H, PhNH2), 3.67—3.70 (m, 1H, NHCH ), 1.08—1.79 (m, 10H, cyclohexyl-H)
14j
(400 MHz, DMSO-d6) δ: 8.20—8.22 (m, 1H, CONH), 7.35 (d, J＝7.6 Hz, 1H, Ph-H), 7.06 (d, J＝7.2 Hz, 1H, Ph-H), 6.45—6.49
(m, 1H, Ph-H), 6.18 (s, 2H, PhNH2), 3.14—3.19 (m, 2H, NHCH2), 2.07 (s, 3H, PhCH3), 1.46—1.55 (m, 2H, CH2CH3), 0.88 (t,
J＝7.4 Hz, 3H, CH2CH3)
14k
14l
(400 MHz, DMSO-d6) δ: 8.19—8.21 (m, 1H, CONH), 7.33 (d, J＝7.6 Hz, 1H, Ph-H), 7.05 (d, J＝7.0 Hz, 1H, Ph-H), 6.46—6.49
(m,1H, Ph-H), 6.11 (s, 2H, PhNH2), 4.22—4.30 (m, 1H, CH), 2.18 (s, 3H, CH3), 1.25 (d, J＝6.6 Hz, 6H, CH(CH3)2)
(400 MHz, DMSO-d6) δ: 8.18 (s, 1H, CONH), 7.30 (d, J＝7.6 Hz, 1H, Ph-H), 7.05 (d, J＝6.8 Hz, 1H, Ph-H), 6.43—6.47 (m, 1H,
Ph-H), 6.21 (s, 2H, PhNH2), 2.78—2.80 (m, 1H, cyclopropyl-H), 2.07 (s, 3H, PhCH3), 0.65—0.67 (m, 2H, CH2CH2, cyclopropyl-
H), 0.53—0.55 (m, 2H, CH2CH2, cyclopropyl-H)
14m
14n
(400 MHz, CDCl3) δ: 6.56—7.19 (m, 3H, Ph-H), 5.90 (br s, 1H, NH), 5.53 (br s, 2H, NH2), 3.88—3.97 (m, 1H, cyclohexyl-H),
2.15 (s, 3H, CH3), 1.15—2.03 (m, 10H, cyclohexyl-H)
(400 MHz, DMSO-d6) δ: 7.56 (s, 1H, Ph-H), 7.26 (s, 1H, Ph-H), 6.33 (br s, 2H, NH2), 3.79 (s, 3H, OCH3), 2.12 (s, 3H, CH3)
(400 MHz, DMSO-d6) δ: 7.80 (s, 1H, Ph-H), 7.21 (s,1H, Ph-H), 5.78 (br s, 2H, NH2), 3.84 (s, 3H, OCH3), 2.29 (s, 3H, CH3)
15a
15b
1
carbonate (0.76 g, 5.5 mmol) was added. The mixture
was heated to 100 ℃. The 2,2,2-trifluoroiodoethane
(0.94 g, 4.4 mmol) in dry dimethylformamide (5 mL)
was added slowly to the mixture. The solution was
warmed at 100 ℃ and stirred for 3 h and poured into
ice water (50 mL). The aqueous layer was extracted
with ethyl acetate (40 mL×3). The organic layer was
washed with water (40 mL×3) and dried over anhy-
drous sodium sulfate. Then the ethyl acetate was con-
centrated. The residue was purified by column chroma-
tography on a silica gel using petroleum ether (60—90
℃) and ethyl acetate as the eluent to afford the
2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-
2,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester
(17). (1.28 g, 99%), m.p. 63—65 ℃; H NMR (CDCl3,
400 MHz) δ: 8.52 (dd, J＝1.6, 4.8 Hz, 1H, pyridyl-H),
7.91 (dd, J＝1.6, 8.0 Hz, 1H, pyridyl-H), 7.43 (dd, 1H,
J＝4.8, 8.0 Hz, 1H, pyridyl-H), 6.54 (s, 1H, pyrazolyl-
H), 4.66 (q, J＝16.4 Hz, 2H, CH2CF3), 4.20 (q, J＝7.2
Hz, 2H, CH2), 1.22 (t, J＝7.2 Hz, 3H, CH3).
Synthetic procedure for 2-(3-chloro-pyridin-2-yl)-
5-(2,2,2-trifluoro-ethoxy)-2,5-dihydro-1H-pyrazole-
3-carboxylic acid (18)
To a mixture of the compound 17 (1.28 g, 3.6 mmol)
in methanol (20 mL) was added aqueous sodium hy-
droxide solution (5 mL, 1 mol•L ). The solution was
stirred at room temperature for 6 h, then was concen-
－
1
Chin. J. Chem. 2012, 30, 1748—1758
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1753

Zhao et al.
FULL PAPER
trated in vacuo to about 5 mL. The concentrated mixture
was diluted with H2O (40 mL), and washed with ethyl
acetate (20 mL). The aqueous solution was acidified
using concentrated hydrochloric acid to pH＝2. The
solid was collected by filtration, washed with ether (10
mL), and then dried to give 2-(3-chloro-pyridin-2-yl)-5-
(2,2,2-trifluoro-ethoxy)-2,5-dihydro-1H-pyrazole-3-car-
boxylic acid (18) (0.84 g, 71.3%), m.p. 165—167 ℃.
1H NMR (CDCl3, 300 MHz) δ: 8.51 (dd, J＝1.6, 4.8 Hz,
1H, pyridyl-H); 7.92 (dd, J＝1.6, 8.0 Hz, 1H, pyridyl-H);
7.44 (dd, 1H, J＝4.8, 8.0 Hz, pyridyl-H); 6.59 (s, 1H,
pyrazolyl-H); 4.65 (q, J＝16.4 Hz, 2H, CH2CF3).
organisms reared in the laboratory. The bioassay was re-
peated at (25±1) ℃ according to statistical require-
ments. Assessments were made on a dead/alive basis, and
mortality rates were corrected using Abbott’s formula.
Evaluations are based on a percentage scale of 0—100 in
which 0 equals no activity and 100 equals total kill.
Insecticidal activity against oriental armyworm
(Mythimna separata) The insecticidal activities of the
title compounds 19a—19n and 20a—20b against orien-
tal armyworm were evaluated using the reported proce-
dure.[18,19] 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. The dishes were
infested 10 fourth-instar Oriental armyworm larvae.
Percentage mortalities were evaluated 2 d after treat-
ment. Each treatment was performed three times. For
comparative purposes, Chlorantraniliprole was tested
under the same conditions. The results were summarized
in Table 5.
Insecticidal activity against diamond-back moth
(Plutella xylostella Linnaeus) The insecticidal activi-
ties of the title compounds 19a—19n against diamond-
back moth were evaluated using the leaf disc assay.[20]
The leaf discs (5 cm×3 cm) were cut from fresh cab-
bage leaves and then dipped into the test solution for 15
s. After air-drying, the treated leaf discs were placed
individually into boxes (80 cm3), and then the sec-
ond-instar diamondback moth larvae were transferred to
the Petri dish. Three replicates (seven larvae per repli-
cate) were carried out. The commercial insecticide
Chlorantraniliprole was used as a standard. The results
were summarized in Table 6.
Synthetic procedure for the title compounds 19 and 20
To a suspension of N-pyridylpyrazole acid 18 (1
mmol) in dichloromethane (20 mL) was added oxalyl
chloride (3 mmol) and dimethylformamide (2 drops). The
solution was stirred at ambient temperature for 4 h. Then
the mixture was concentrated in vacuo to give the crude
acid chloride. The crude acid chloride in tetrahydrofuran
(25 mL) was added slowly to a stirred solution of 14 or
15 (1.2 mmol) and triethylamine (1.2 mmol) in tetrahy-
drofuran (15 mL). The mixture was stirred at ambient
temperature for 8 h. Then the solution was concentrated
in vacuo and diluted with CH2Cl2 (60 mL), and washed
with 1 mol•L－ aq. HCl solution (15 mL), saturated aq.
1
NaHCO3 (15 mL), and brine (15 mL). The organic extract
was separated, dried, filtered, and concentrated and puri-
fied by silica gel chromatography to afford the desired
title compounds 19 and 20. The melting points, yields,
and elemental analyses of compounds 19 and 20 are listed
in Table 3. The 1H NMR data are listed in Table 4.
Biological assay
All bioassays were performed on representative test
Table 3 The melting points, yields and elemental analyses of the title compounds 19 and 20
Elemental analysis (%) calcd. (found)
H
Compd.
R1
R2 R3
m.p./℃
Yield/%
C
N
19a
19b
19c
19d
19e
19f
CH3 Cl n-propyl
CH3 Cl cyclopropyl
CH3 Cl n-butyl
CH3 Cl i-butyl
200—201
211—213
173—175
220—221
160—162
102—104
186—188
198—199
96—98
59.9
62.7
67.6
63.9
58.7
60.5
70.1
56.9
63.2
66.7
67.0
69.3
54.8
64.7
69.1
65.4
49.82 (49.66)
50.02 (49.92)
50.75 (50.56)
50.75 (50.81)
52.64 (52.54)
48.85 (48.77)
48.85 (48.79)
49.04 (49.40)
49.82 (49.70)
51.81 (51.93)
53.29 (53.41)
53.29 (53.22)
53.50 (53.25)
56.03 (56.07)
47.73 (47.99)
43.86 (43.90)
3.80 (3.92)
3.43 (3.78)
4.07 (3.99)
4.07 (4.11)
4.24 (4.41)
3.51 (3.55)
3.51 (3.46)
3.14 (3.47)
3.80 (3.84)
3.99 (4.06)
4.27 (4.11)
4.27 (4.35)
3.88 (4.09)
4.70 (4.60)
3.00 (2.85)
2.76 (3.02)
13.21 (13.22)
13.26 (13.21)
12.87 (12.98)
12.87 (12.81)
12.28 (12.24)
13.56 (13.29)
13.56 (13.40)
13.62 (13.07)
13.21 (13.10)
12.59 (13.45)
14.12 (13.97)
14.12 (14.40)
14.18 (13.94)
13.07 (13.08)
11.13 (11.01)
10.23 (10.45)
CH3 Cl cyclohexyl
H
Cl n-propyl
Cl i-propyl
19g
19h
19i
H
H
Cl cyclopropyl
Cl n-butyl
H
19j
H
Cl cyclohexyl
145—146
185—187
177—179
172—173
147—149
50—52
19k
19l
CH3
CH3
CH3
CH3
H
H
H
H
n-propyl
i-propyl
19m
19n
20a
20b
cyclopropyl
cyclohexyl
CH3 Cl methyl
CH3 Br methyl
40—42
1754
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1748—1758

Design, Synthesis and Biological Activities of Novel Anthranilic Diamide Insecticide
Table 4 1H NMR of the title compounds 19a—19n and 20a—20b
1H NMR (400 MHz, CDCl3) δ
Compd.
9.97 (s, 1H, CONH), 8.38 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 7.75 (dd, J＝8.0, 1.6 Hz, 1H, pyridyl-H), 7.27 (dd, J＝8.0, 4.8 Hz,
1H, pyridyl-H, 1H), 7.14 (s, 1H, Ph-H), 7.10 (s, 1H, Ph-H), 6.58 (s, 1H, pyrazolyl-H), 6.09—6.11 (m, 1H, NHCH2), 4.60 (q, J＝
8.2 Hz, 2H, CH2CF3), 3.23—3.25 (m, 2H, CH2NH), 2.10 (s, 3H, PhCH3), 1.47—1.48 (m, 2H, CH2CH3), 0.87 (t, J＝7.0 Hz, 3H,
CH2CH3)
19a
10.02 (s, 1H, CONH), 8.45 (dd, J＝4.4, 1.6 Hz, 1H, pyridyl-H), 7.82 (dd, J＝8.0, 1.6 Hz, 1H, pyridyl-H, 1H), 7.34 (dd, J＝8.0,
4.4 Hz, 1H, pyridyl-H, 1H), 7.17 (s, 1H, Ph-H), 7.10 (s, 1H, Ph-H), 6.74 (s, 1H, pyrazolyl-H), 6.42—6.44 (m, 1H, PhCONH),
4.67 (q, J＝8.2 Hz, 2H, CH2CF3), 2.77—2.79 (m, 1H, CH), 2.15 (s, 3H, PhCH3), 0.82—0.84 (m, 2H, CH2CH2), 0.53—0.55 (m,
2H, CH2CH2)
19b
19c
19d
9.99 (s, 1H, CONH), 8.39 (dd, J＝4.4, 1.2 Hz, 1H, pyridyl-H), 7.77 (dd, J＝8.0, 1.6 Hz, 1H, pyridyl-H), 7.29 (dd, J＝8.0, 4.4 Hz,
1H, pyridyl-H), 7.27 (s, 1H, Ph-H), 7.15 (s, 1H, Ph-H), 6.55 (s, 1H, pyrazolyl-H), 6.10—6.12 (m, 1H, PhCONH), 4.60 (q, J＝8.2
Hz, 2H, CH2CF3), 3.30—3.32 (m, 2H, NHCH2), 2.14 (s, 3H, PhCH3), 1.53—1.55 (m, 2H, CH2CH2), 1.32—1.34 (m, 2H,
CH2CH3), 0.89 (t, J＝7.2 Hz, 3H, CH2CH3)
10.04 (s, 1H, CONH), 8.47 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 7.84 (dd, J＝8.0, 1.6 Hz, 1H, pyridyl-H), 7.36 (dd, J＝8.0, 4.8
Hz, 1H, pyridyl-H), 7.27 (s, 1H, Ph-H), 7.22 (s, 1H, Ph-H), 6.59 (s, 1H, pyrazolyl-H), 6.19—6.21 (m, 1H, PhCONH), 4.68 (q,
J＝8.2 Hz, 2H, CH2CF3), 3.21—3.23 (m, 2H, CH2NH), 2.19 (s, 3H, PhCH3), 1.84—1.86 (m, 1H, CH), 0.95 (d, J＝6.7 Hz, 6H,
CH(CH3)2)
10.06 (s, 1H, CONH), 8.47 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 7.84 (dd, J＝8.0, 1.6 Hz, 1H, pyridyl-H), 7.35 (dd, J＝8.0, 4.8
Hz, 1H, pyridyl-H), 7.26 (s, 1H, Ph-H), 7.20 (s, 1H, Ph-H), 6.60 (s, 1H, pyrazolyl-H), 5.95—5.97 (m, 1H, PhCONH), 4.69 (q,
J＝8.2 Hz, 2H, CH2CF3), 3.85—3.87 (m, 1H, CH), 2.19 (s, 3H, PhCH3), 1.96—1.98 (m, 2H, cyclohexanyl-H), 1.73—1.75 (m,
2H, cyclohexanyl-H), 1.63—1.65 (m, 2H, cyclohexanyl-H), 1.38—1.40 (m, 2H, cyclohexanyl-H), 1.18—1.21 (m, 2H,
cyclohexanyl-H)
19e
12.24 (s, 1H, CONHPh), 8.52 (d, J＝4.0 Hz, 1H, pyridyl-H), 8.46—8.48 (m, 1H, Ph-H), 7.92 (d, J＝6.8 Hz, 1H, pyridyl-H), 7.37
—7.48 (m, 3H, pyridyl-H, Ph-H), 6.61 (s, 1H, pyrazolyl-H), 6.33—6.35 (m, 1H, PhCONH), 4.69 (q, J＝8.2 Hz, 2H, CH2CF3),
3.44—3.46 (m, 2H, NHCH2), 1.66—1.68 (m, 2H, CH2CH2), 1.01 (t, J＝6.8 Hz, 3H, CH2CH3)
19f
12.26 (s, 1H, CONHPh), 8.50 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 8.47 (d, J＝8.9 Hz, 1H, Ph-H), 7.92 (d, J＝8.0 Hz, 1H,
pyridyl-H), 7.42—7.45 (m, 2H, pyridyl-H, Ph-H), 7.34 (d, J＝9.0 Hz, 1H, Ph-H), 6.58 (s, 1H, pyrazolyl-H), 6.05—6.06 (m, 1H,
PhCONH), 4.66 (q, J＝8.2 Hz, 2H, CH2CF3), 4.27—4.29 (m, 1H, CH), 1.30 (d, J＝6.4 Hz, 6H, CH(CH3)2)
19g
12.27 (s, 1H, CONHPh), 8.52 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 8.46 (d, J＝8.9 Hz, 1H, Ph-H), 7.93 (d, J＝8.0 Hz, 1H,
pyridyl-H), 7.44—7.48 (m, 2H, pyridyl-H, Ph-H), 7.35 (d, J＝9.0 Hz, 1H, Ph-H), 6.62 (s, 1H, pyrazolyl-H), 6.37—6.39 (m, 1H,
PhCONH), 4.68 (q, J＝8.2 Hz, 2H, CH2CF3), 4.27—4.29 (m, 1H, CH), 0.95—0.99 (m, 2H, CH2CH2), 0.66—0.69 (m, 2H,
CH2CH2)
19h
19i
12.15 (s, 1H, CONHPh), 8.52 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 8.45 (d, J＝8.9 Hz, 1H, Ph-H), 7.93 (d, J＝8.0 Hz, 1H,
pyridyl-H), 7.42—7.46 (m, 2H, pyridyl-H, Ph-H), 7.33—7.35 (m, 1H, Ph-H), 6.51 (s, 1H, pyrazolyl-H), 6.14—6.16 (m, 1H,
PhCONH), 4.60 (q, J＝8.2 Hz, 2H, CH2CF3), 3.31—3.33 (m, 2H, NHCH2), 1.53—1.56 (m, 2H, CH2CH2), 1.32—1.37 (m, 2H,
CH2CH3), 0.90 (t, J＝7.2 Hz, 3H, CH2CH3)
12.26 (s, 1H, CONH), 8.52 (dd, J＝4.8, 1.6 Hz, 1H, pyridyl-H), 8.48 (d, J＝9.0 Hz, 1H, Ph-H), 7.89 (d, J＝1.2 Hz, 1H, pyridyl-
H), 7.40—7.45 (m, 2H, pyridyl-H, Ph-H), 7.33—7.35 (m, 1H, Ph-H), 6.60 (s, 1H, pyrazolyl-H), 6.20—6.23 (m, 1H, PhCONH),
4.68 (q, J = 8.2 Hz, 2H, CH2CF3), 3.95—3.97 (m, 1H, CH), 1.78—1.81 (m, 2H, cyclohexanyl-H), 1.68—1.70 (m, 2H,
cyclohexanyl-H), 1.43—1.45 (m, 2H, cyclohexanyl-H), 1.28—1.30 (m, 2H, cyclohexanyl-H), 1.19—1.22 (m, 2H,
cyclohexanyl-H)
19j
10.10 (s, 1H, CONH), 8.39 (dd, J＝4.7, 1.5 Hz, 1H, pyridyl-H), 7.75 (dd, J＝8.0, 1.5 Hz, 1H, pyridyl-H), 7.36 (dd, J＝8.0, 4.7
Hz, 1H, pyridyl-H), 7.25—7.28 (m, 1H, Ph-H), 7.17—7.20 (m, 1H, Ph-H), 7.07—7.10 (m, 1H, Ph-H), 6.48 (s, 1H, pyrazolyl-H),
6.05—6.08 (m, 1H, PhCONH), 4.61 (q, J＝8.2 Hz, 2H, CH2CF3), 3.26—3.28 (m, 2H, CH2NH), 2.15 (s, 3H, PhCH3), 1.51—1.55
(m, 2H, CH2CH3), 0.89 (t, J＝7.2 Hz, 3H, CH2CH3)
19k
19l
8.54 (s, 1H, CONH), 8.38 (dd, J＝4.7, 1.4 Hz, 1H, pyridyl-H), 7.92 (dd, J＝8.0, 1.4 Hz, 1H, pyridyl-H), 7.53—7.55 (m, 1H,
Ph-H), 7.42—7.45 (m, 1H, Ph-H), 7.39 (dd, J＝8.0, 4.7 Hz, 1H, pyridyl-H), 7.21—7.23 (m, 1H, Ph-H), 6.54 (s, 1H, pyrazolyl-
H), 6.03—6.06 (m, 1H, PhCONH), 4.69 (q, J＝8.3 Hz, 2H, CH2CF3), 4.20—4.22 (m, 1H, CH), 2.30 (s, 3H, PhCH3), 1.16 (d, J＝
6.6 Hz, 6H, CH(CH3)2))
10.16 (s, 1H, CONH), 8.38 (d, J＝4.8 Hz, 1H, pyridyl-H), 7.76 (d, J＝8.0 Hz, 1H, pyridyl-H), 7.27 (dd, J＝4.8, 8.0 Hz, 1H,
pyridyl-H), 7.13—7.15 (m, 1H, Ph-H), 7.00—7.05 (m, 2H, Ph-H), 6.57 (s, 1H, pyrazolyl-H), 6.44—6.46 (m, 1H, PhCONH), 4.61
(q, J＝8.2 Hz, 2H, CH2CF3), 2.64—2.65 (m, 1H, CH), 2.10 (s, 3H, PhCH3), 0.72—0.74 (m, 2H, CH2CH2), 0.40—0.43 (m, 2H,
CH2CH2)
19m
Chin. J. Chem. 2012, 30, 1748—1758
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1755

Zhao et al.
FULL PAPER
Continued
Compd.
1H NMR (400 MHz, CDCl3) δ
10.22 (s, 1H, CONH), 8.47 (dd, J＝4.7, 1.5 Hz, 1H, pyridyl-H), 7.83 (dd, J＝8.0, 1.5 Hz, 1H, pyridyl-H), 7.34 (dd, J＝8.0, 4.7
Hz, 1H, pyridyl-H), 7.26—7.27 (m, 1H), 7.22—7.25 (m, 1H), 7.14—7.15 (m, 1H), 6.61 (s, 1H, pyrazolyl-H), 6.21—6.23 (m, 1H,
PhCONH), 4.69 (q, J＝8.2 Hz, 2H, CH2CF3), 3.86—3.88 (m, 1H CH), 2.23 (s, 3H, PhCH3), 1.94—1.96 (m, 2H, cyclohexanyl-
H), 1.73—1.75 (m, 2H, cyclohexanyl-H), 1.63—1.66 (m, 2H, cyclohexanyl-H), 1.38—1.40 (m, 2H, cyclohexanyl-H), 1.18—1.21
(m, 2H, cyclohexanyl-H)
19n
10.02 (s, 1H, CONH), 8.45 (d, J＝4.5 Hz, 1H, pyridyl-H), 7.80 (d, J＝1.7 Hz, 1H, pyridyl-H), 7.34—7.37 (m, 3H, pyridyl-H,
Ph-H), 6.56 (s, 1H, pyrazolyl-H), 6.54—6.57 (m, 1H, PhCONH), 4.68 (q, J＝8.2 Hz, 2H, CH2CF3), 3.91 (s, 3H, OCH3), 2.21 (s,
3H, PhCH3)
20a
20b
10.03 (s, 1H, CONH), 8.45 (dd, J＝4.6, 1.4 Hz, 1H, pyridyl-H), 7.92—7.94 (m, 1H, Ph-H), 7.84 (dd, J＝7.8, 1.4 Hz, 1H,
pyridyl-H), 7.51—7.53 (m, 1H, Ph-H), 7.36 (dd, J＝4.6, 1.4 Hz, 1H, pyridyl-H), 6.56 (s, 1H, pyrazolyl-H), 4.69 (q, J＝8.2 Hz,
2H, CH2CF3), 3.91 (s, 3H, OCH3 ), 2.20 (s, 3H, PhCH3)
Table 5 Insecticidal activities against oriental armyworm of the
title compounds 19a—19n, 20a—20b and Chlorantraniliprole
Table 6 Insecticidal activities against diamond-back moth of the
title compounds 19a—19n and Chlorantraniliprole
－
－
larvicidal activity (%) at conc (mg•kg )
1
1
larvicidal activity (%) at conc (mg•kg )
200 100 50 25 10 5 2.5 1 0.5 0.25
100 100 100 100 100 100 100 40
100 100 100 100 100 100 100 100 100 40
100 100 100 100 100 100 70 0
100 100 100 100 100 100 100 50
100 100 100 100 100 100 30
100 100 100 40
Compd.
Compd.
50 20 10
5
1
0.5 0.25 0.1 0.05
19a
19b
19c
19d
19e
19f
19a
100 100 100 100 100 100 100 100 100
100 100 100 100 100 100 100 100 100
100 100 100 100 100 100 100 100 100
100 100 100 100 100 100 100 100 100
100 100 100 100 100 100 100 100 100
19b
19c
19d
19e
19f
100 100 100 100 40
100 100 100 100 100 100
100 100 100 100 0
100 100 57
19g
19h
19i
100 100 100 100 100 100 100 80 0
100 100 100 100 100 80 0
80 20
19g
19h
19i
100 100 100 0
100 100 60 80
0
0
19j
20
19j
19k
19l
100 100 100 100 100 100 100 40
100 100 100 100 0
19k
100 100 100 100 100 100 43
100 100 100 0
19l
0
19m
19n
20a
20b
100 100 100 100 100 100 100 100 20
100 100 100 100 100 50
100 90 30
19m
100 100 100 100 100 100 100 43
19n
100 100 100 100 100 100 100 100 100
Chlorantraniliprole
100 100 100 100 100 100 100 43 0
90 10
Chlorantraniliprole 100 100 100 100 100 100 100 100 100 100
Results and Discussion
Synthesis
Insecticidal activity against beet armyworm
(Laphygma exigua Hubner) The insecticidal activi-
ties of the title compounds 19a—19n against beet
armyworm were tested by the leaf-dip method using the
reported procedure.[21] Leaf discs (1.8 cm diameter)
were cut from fresh cabbage leaves and then were
dipped into the test solution for 15 s. After air-drying,
the treated leaf discs were placed in a Petri dish (9 cm
diameter). Each dried treated leaf disc was infested with
seven third-instar beet armyworm larvae. Percentage
mortalities were evaluated 3 d after treatment. Leaves
treated with water and acetone were provided as con-
trols. Each treatment was performed three times. For
comparative purposes, Chlorantraniliprole was tested
under the same conditions. The results were summarized
in Table 7.
In the present work, the synthesis of two series of
novel anthranilic diamide derivatives as well as their
insecticidal activities against three lepidopterous pests
were studied. The target trifluoroethyl ether compounds
19 and 20 were synthesized by a simple and convenient
four-step procedure starting from the key intermediate
2-(3-chloro-pyridin-2-yl)-5-oxo-pyrazolidine-3-car-
boxylic acid ethyl ester (9). Compound 9 was oxidized
to give pyrazolone 16 in low yield. The compound 16
was reacted with 2,2,2-trifluoroiodoethane in dry di-
methylformamide to yield 1-(2-chloro-5-pyridyl-
methyl)-2-cyanoiminoimidazolidine (17). Then com-
pound 17 was hydrolyzed to give the key intermediate
2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-
2,5-dihydro-1H-pyrazole-3-carboxylic acid (18). The
title compounds 19 and 20 were synthesized from
1756
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1748—1758

Design, Synthesis and Biological Activities of Novel Anthranilic Diamide Insecticide
Table 7 Insecticidal activities against beet armyworm of the
title compounds 19a—19n and Chlorantraniliprole
(p1), the pyridine ring C(17)-C(21)-N(5) (p2), and the
pyrazole ring (p3). The dihedral angel between the plane
of the pyridine ring p2 and the plane of the pyrazole ring
p3 is about 44.0°. The crystal packing structure of this
compound is shown in Figure 3.
－
larvicidal activity (%) at conc (mg•kg )
1
Compd.
20
5
2
1
0.5
57
86
19a
100
100
100
100
100
100
100
100
0
100
100
100
83
100
100
28
100
100
19b
19c
19d
19e
83
19f
50
19g
100
100
57
71
19h
19i
19j
0
19k
67
19l
0
19m
100
50
100
100
86
19n
Chlorantraniliprole
100
100
100
100
Figure 3 Packing diagram of the compound 19g
Biological activity
compound 18 and the appropriate intermediate 14 or 15
(obtained from the intermediate 13 and corresponding
alcohol or amine – see Table 1) in dry tetrahydrofuran
using triethylamine as base.
Table 5 shows the insecticidal activities of the title
compounds 19a—19n and 20a—20b and Chloran-
traniliprole against oriental armyworm. The results of
insecticidal activities given in Table 5 indicated that
most of the title compounds exhibited excellent activity
against oriental armyworm comparable to the commer-
cialized Chlorantraniliprole. For instance, the insecti-
cidal activities of compounds 19a, 19b, 19d, 19g, 19k
Crystal structure analysis
Compound 19g was recrystallized from ethyl ace-
tate/petroleum ether to give colorless crystal suitable for
X-ray single-crystal diffraction with the following crys-
tallographic parameters: a＝11.976(2) Å, b＝14.274(3)
Å, c＝14.350(3) Å, α＝90°, β＝111.73(3)°, γ＝90°, μ＝
and 19m against oriental armyworm at 2.5 mg•kg－
1
were 100%. Moreover, some of them still exhibited
good insecticidal activity against oriental armyworm
－
1
0.344 mm , V＝2278.6(8) Å3, Z＝4, Dx＝1.505 Mg•
－
3
－
1
m , F(000)＝1056, T＝113(2) K, 3.06°≤θ≤25.02°,
and the final R factor, R1＝0.0431, wR2＝0.1048. The
crystal is monoclinic.
when the concentration was reduced to 1 mg•kg .
Table 6 shows the insecticidal activities of the title
compounds 19a—19n and Chlorantraniliprole against
diamond-back moth. The results indicate that the title
compounds 19 have excellent insecticidal activities
against diamond-back moth and that some of the title
compounds 19 exhibit higher larvicidal activities than
the commercialized Chlorantraniliprole. For example,
the larvicidal activities of 19a, 19b, 19c, 19d, 19e, 19g,
and 19n against diamond-back moth were 100% at 0.1
－
1
mg•kg , whereas the corresponding commercial insec-
ticide Chlorantraniliprole caused 43% mortality at this
concentration. Surprisingly, most of them still exhibited
perfect insecticidal activity against diamond-back moth
－
1
when the concentration was reduced to 0.05 mg•kg ,
which was higher than the commercialized Chloran-
traniliprole.
Table 7 shows the insecticidal activities of the title
compounds 19a—19n and Chlorantraniliprole against
beet armyworm. The results indicated that most of the
title compounds exhibited good activity against beet
armyworm. Compounds 19b exhibited moderate insec-
Figure 2 Molecular structure of the compound 19 g
The molecular structure of 19g contains the follow-
ing three-plane subunit: the benzene ring C(1)—C(6)
Chin. J. Chem. 2012, 30, 1748—1758
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1757

Zhao et al.
FULL PAPER
K.; Fujioka, S.; Kodama, H.; Hirooka, T.; Nishimatsu, T. J. Pestic.
Sci. 2005, 30, 354.
ticide activity against beet armyworm and had ＞80%
mortality at 0.5 mg•kg .
－
1
[2] Ebbinghaus-Kintscher, U.; Luemmena, P.; Lobitz, N.; Schulte, T.;
Funke, C.; Fischer, R.; Masaki, T.; Yasokawa, N.; Tohnishi, M. Cell
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From the data presented in Table 5, we found that
the bioactivities of the second series 20 were weaker
than that of the first series 19. Therefore the amide-sub-
stituted analogue showed a higher insecticidal activity
than did the corresponding ester-substituted analogue.
Among those compounds, replacing the nitrogen atom
with oxygen atom resulted in decreased insecticidal ac-
tivity. From Tables 5—7, we can also see that the lar-
vicidal activities of the title compounds appeared to be
strongly associated with the substituent R and its posi-
tion on the benzene. Methyl-substituted at ortho and
chloro-substituted at para are very important for in-
creasing activity. Further studies on structural optimiza-
tion and structure-activity relationships of these an-
thranilic diamide derivatives are in progress.
[3] Gewehr, M.; Puhl, M.; Dickhaut, J.; Bastiaans, H. M. M.; Anspaugh,
D. D.; Kuhn, D. G.; Oloumi-Sadeghi, H.; Armes, N. WO
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1
and synthesized with structures characterized by H
NMR spectroscopy, single crystal X-ray diffraction
analysis and elemental analysis. The insecticidal activi-
ties of the new compounds were evaluated. The results
of bioassays indicated that some of these title com-
pounds exhibited excellent insecticidal activities. Sur-
prisingly, most of them still exhibited perfect insecti-
cidal activity against diamond-back moth when the
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Acknowledgement
This work was supported by the National Basic Re-
search Program of China (No. 2010CB126106), the
Fundamental Research Funds for the Central Universi-
ties and the Specialized Research Fund for the Doctoral
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1758
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1748—1758