Synthesis, insecticidal activities, and SAR studies of novel pyridylpyrazole acid derivatives based on amide bridge modification of anthranilic diamide insecticides

Article abstract of DOI:10.1021/jf4012467

Anthranilic diamides are one of the most important classes of modern agricultural insecticides. To discover new structure-modified compounds with high activity, series of novel carbonyl thioureas, carbonyl ureas, oxadiazoles, carbonyl thiophosphorylureas, oxadiazole-containing amides, and thiazoline-containing amides were designed through the modification of the amide bridge based on the structure of chlorantraniliprole and were synthesized, and bioassays were carried out. The compounds were characterized and confirmed by melting point, IR, ¹H NMR, and elemental analyses or HRMS. Preliminary bioassays indicated that some compounds exhibited significant insecticidal activities against oriental armyworm, diamondback moth, beet armyworm, corn borer, and mosquito. Among them, trifluoroethoxyl-containing carbonyl thiourea 20a showed best larvicidal activity against oriental armyworm, with LC₅₀ and LC₉₅ values of 0.1812 and 0.7767 mg/L, respectively. Meanwhile, 20c and 20e showed 86 and 57% death rates against diamondback moth at 0.005 mg/L, and the LC₅₀ values of the two compounds were 0.0017 and 0.0023 mg/L, respectively, which were lower than that of the control chlorantraniliprole. The relationship between structure and insecticidal activity was discussed, and the HF calculation results indicated that the carbonyl thiourea moiety plays an important role in the insecticidal activity. The present work demonstrated that the trifluoroethoxyl-containing carbonyl thioureas can be used as lead compounds for further development of novel insecticides.

Full text of DOI:10.1021/jf4012467

Article
pubs.acs.org/JAFC
Synthesis, Insecticidal Activities, and SAR Studies of Novel
Pyridylpyrazole Acid Derivatives Based on Amide Bridge
Modification of Anthranilic Diamide Insecticides
Bao-Lei Wang, Hong-Wei Zhu, Yi Ma, Li-Xia Xiong, Yong-Qiang Li, Yu Zhao, Ji-Feng Zhang,
You-Wei Chen, Sha Zhou, and Zheng-Ming Li*
State-Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
China
S
* Supporting Information
ABSTRACT: Anthranilic diamides are one of the most important classes of modern agricultural insecticides. To discover new
structure-modified compounds with high activity, series of novel carbonyl thioureas, carbonyl ureas, oxadiazoles, carbonyl
thiophosphorylureas, oxadiazole-containing amides, and thiazoline-containing amides were designed through the modification of
the amide bridge based on the structure of chlorantraniliprole and were synthesized, and bioassays were carried out. The
1
compounds were characterized and confirmed by melting point, IR, H NMR, and elemental analyses or HRMS. Preliminary
bioassays indicated that some compounds exhibited significant insecticidal activities against oriental armyworm, diamondback
moth, beet armyworm, corn borer, and mosquito. Among them, trifluoroethoxyl-containing carbonyl thiourea 20a showed best
larvicidal activity against oriental armyworm, with LC50 and LC95 values of 0.1812 and 0.7767 mg/L, respectively. Meanwhile,
20c and 20e showed 86 and 57% death rates against diamondback moth at 0.005 mg/L, and the LC50 values of the two
compounds were 0.0017 and 0.0023 mg/L, respectively, which were lower than that of the control chlorantraniliprole. The
relationship between structure and insecticidal activity was discussed, and the HF calculation results indicated that the carbonyl
thiourea moiety plays an important role in the insecticidal activity. The present work demonstrated that the trifluoroethoxyl-
containing carbonyl thioureas can be used as lead compounds for further development of novel insecticides.
KEYWORDS: pyridylpyrazole acid derivative, synthesis, insecticidal activity
INTRODUCTION
■
Synthetic pesticides play important roles for controlling pests
harmful to crop growth in the current agricultural system. To
overcome resistance and ecobiological problems associated with
conventional insecticides, there is an urgent need to discover
novel potent insecticides with new modes of action and
ecofriendly properties such as easy degradability to nontoxic
residues, harmlessness to human beings, and benefits in meeting
Figure 1. Chemical structures of anthranilic diamide insecticides.
the demands of crop protection.
The ryanodine receptor (RyR), also known as the calcium ion
chemical synthesis have attracted considerable attention.10,11
There are two amide moieties in the structures of flubendiamide
and chlorantraniliprole, respectively. In previous work, most
modifications for chlorantraniliprole were related to the benzene
moiety and the N-pyridylpyrazole heterocycle moiety. The most
successful example is cyantraniliprole (Cyazypyr),8 which
replaced a cyano group of the 4-Cl substituent of the former
chlorantraniliprole. However, the modification for the two amide
moieties was relatively seldom reported, especially the alteration
of the amide bridge, a key pharmacophore that links the benzene
ring and the N-pyridylpyrazole heterocycle, was not much
reported in previous patents. It is known that acylurea or
acylthiourea compounds, representing an important class of
channel receptor, has been regarded as one of the potential
targets for novel insecticide discovery since it was found that
natural ryanodine possessed insecticidal activity.1−3 In the past
decade, Nippon Kayaku Co., Ltd., found the phthalic diamide
insecticide flubendiamide targeting insect RyR.4 Also, DuPont
discovered the anthranilic diamides,5 which originated from the
insecticidal phthalic diamides as highly potent and selective
activators of the insect RyR.6 Until now, two representive
phthalic diamides, chlorantraniliprole (Rynaxypyr; DPX-E2Y45)
and cyantraniliprole (Cyazypyr) (Figure 1) have been
marketed.7,8 These compounds show exceptional insecticidal
activity on a broad range of Lepidoptera, Coleoptera, Diptera,
and Isoptera insects.6 In addition to larvicidal activity,
chlorantraniliprole has been found to have significant ovicidal
activity among some Lepidopteran pests.9
Received: March 22, 2013
Revised: May 17, 2013
Accepted: May 20, 2013
Since the discovery of phthalic diamides and anthranilic
diamides, compounds with such structural features and their
© XXXX American Chemical Society
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a
Scheme 1. Synthesis of Compounds 5a−c
a
Reagents and conditions: (a) diethyl maleate, NaOEt, EtOH, reflux; (b) POCl3 or POBr3, MeCN, 80 °C; (c) K2S2O8, H2SO4, MeCN, reflux; (d)
(i) aqueous NaOH, MeOH and (ii) aqueous HCl; and (e) CF3CH2I, K2CO3, DMF, 100 °C.
a
Scheme 2. Synthesis of Compound 5d
a
Reagents and conditions: (a) NaOCH3, ethyl trifluoroacetate,; (b) 3-chloro-2-hydrazinylpyridine (1), AcOH, reflux; and (c) KMnO4, acetone/
H2O, reflux.
Flash chromatography was performed with silica gel (200−300
mesh). Reagents were all analytically pure. All solvents and liquid
reagents were dried by standard methods in advance and distilled before
use. 5-Methyl-1H-tetrazole was purchased from Adamas Reagent Co.,
Ltd. 2-Aminoethanol and 1-amino-2-propanol were purchased from
Aladdin Reagent Database Inc. Commercial insecticides chlorantrani-
liprole and diflubenzuron were used only as contrast compounds and
synthesized according to the literature.16,17
Synthetic Procedures. 4-Amino-5-methyl-4H-1,2,4-triazole-3-
thiol was prepared according to the literature.18 The key intermediate
pyrazole carboxylic acid (5a−d) was synthesized from the material 3-
chloro-2-hydrazinylpyridine (1) or 2-acetylfuran (6) referring to the
literature15.19,20 (Schemes 1 and 2). 2-Amino-3,5-disubstituted-
benzamide derivatives (14a−g) were synthesized with 2-amino-3,5-
disubstituted-benzoic acids (12) as materials in moderate yield
according to the method reported by Dong et al.21 (Scheme 4).
biologically active molecules, such as benzoylphenylureas (e.g.,
diflubenzuron), are a familiar type of insect growth regulators
(IGRs), which have attracted considerable attention for decades
because of their unique mode of action and low toxicity to
nontarget organisms (beneficial arthropods).12−14 We also found
some N-pyridylpyrazole acylthioureas showed favorable insecti-
cidal activities in our preliminary research, which encouraged us
to further synthesize novel compounds with bridge-modified
structure.15 Heterocycles such as oxadiazole, thiazoline, and
other heterocycles are important pharmacophores for insectici-
dal molecular design. Given these considerations, series of novel
compounds were designed by changing the amide bridge to
carbonyl thiourea, carbonyl urea, oxadiazole, carbonyl thiophos-
phorylurea, and thiazoline amide moieties with a substituted N-
pyridylpyrazole ring based on the structure of chlorantraniliprole
and were synthesized successfully as shown in Schemes 1−9.
Their insecticidal activities against oriental armyworm, diamond-
back moth, beet armyworm, corn borer, and mosquito were
tested accordingly. The preliminary structure−activity relation-
ship (SAR) was also discussed.
Scheme 3. Synthesis of Compounds 10a−c
MATERIALS AND METHODS
■
Instruments and Materials. The melting points were determined
on an X-4 binocular microscope melting point apparatus (Beijing Tech
Instrument Co., Beijing, China) and were uncorrected. Infrared spectra
were recorded on a Nicolet MAGNA-560 spectrophotometer as KBr
tablets. 1H NMR spectra were recorded at 300 MHz using a Bruker AC-
P300 spectrometer or 400 MHz using a Bruker AV 400 spectrometer
(Bruker Co., Switzerland) in CDCl3 or DMSO-d6 solution with
tetramethylsilane as the internal standard, and chemical shift values (δ)
were given in parts per million (ppm). Elemental analyses were
performed on a Vario EL elemental analyzer. High-resolution mass
spectrometry (HRMS) data were obtained on a Varian QFT-ESI
instrument.
Synthesis of Intermediate Tetrazole Derivatives (10a−c).22
To a solution of benzonitrile (20 mmol) in N,N-dimethylformamide
(DMF) (25 mL) was added ammonium chloride (40 mmol) and
sodium azide (40 mmol), and the resultant slurry was vigorously stirred
at 120 °C for 2−3 h. After cooling to room temperature, the mixture was
filtered, and the solid was washed with DMF. The filtrates were
combined and the DMF was removed in vacuo. To the residue was
added water (30 mL), the mixture was adjusted to pH 2−3 with
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a
Scheme 4. Synthesis of Compounds 14a−g, 15a−e, and 16
a
Reagents and conditions: (a) SOCl2, reflux; (b) R2NH2, CH2Cl2; (c) 5-methyl-1H-tetrazole, Py, 100−110 °C; (d) compounds 10a−c, Py, 1,4-
dioxane, 100−110 °C; and (e) 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol, POCl3, reflux.
concentrated HCl, and the solid was collected by filtration and washed
with water and acetone successively to afford 5-phenyl-1H-tetrazole
(10a) as white crystals: yield 68%, mp 213−215 °C (lit.23 mp 215−216
°C).
3-Cyanopyridine was used as material to afford 3-(1H-tetrazol-5-
yl)pyridine (10b) as white crystals: yield 54%, mp 240−242 °C (lit.22
mp 239−241 °C).
Ph−H), 7.62−7.68 (m, 3H, Ph−H), 7.83 (d, J = 2.0 Hz, 1H, Ph−H),
8.19 (t, J = 2.0 Hz, 2H, Ph−H).
4-Chloro-2-methyl-6-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)aniline
(15d): yellow crystal; yield 84%; mp 202−205 °C; 1H NMR (400 MHz,
DMSO-d6) δ 2.22 (s, 3H, CH3), 6.75 (br, 0.85H, NH2), 7.30 (s, 1H,
Ph−H), 7.67 (dd, J1 = 8.0 Hz, J2 = 4.4 Hz, 1H, Py−H), 7.89 (s, 1H, Ph−
H), 8.57 (d, J = 7.6 Hz, 1H, Py−H), 8.83 (d, J = 4.4 Hz, 1H, Py−H), 9.37
(s, 1H, Py−H).
2-Chloro-3-cyanopyridine was used as material to afford 2-azido-3-
(1H-tetrazol-5-yl)pyridine (10c) as a light yellow solid: yield 52%; mp
245−247 °C; 1H NMR (CDCl3, 400 MHz) δ 7.68 (t, J = 7.2 Hz, 1H, Py-
H), 8.60 (d, J = 7.2 Hz, 1H, Py-H), 9.55 (d, J = 7.2 Hz, 1H, Py-H).
HRMS calcd for C6H4N8 ([M − H]−), 187.0481; found, 187.0490.
Synthesis of Oxadiazole-Containing Substituted Aniline
(15a, 15b). A mixture of 2-amino-5-halo-3-methylbenzoic acid (12,
10 mmol) with thionyl chloride (SOCl2) (15 mL) was refluxed for 3−5
h and condensed under reduced pressure to give the corresponding
crude carbonyl chloride (13), which was immediately dissolved in dry
toluene (10 mL) and added to a solution of 5-methyl-1H-tetrazole (9.5
mmol) in dry pyridine (20 mL) with stirring at room temperature. The
mixture was then stirred at 100−110 °C for 2−3 h, the solvent was
removed in vacuo, the residue was added to a 10% Na2CO3 solution (30
mL) and stirred for 5 min, and the solid was filtered, washed with water,
and recrystallized with 95% EtOH to give compound 15a or 15b.
4-Chloro-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)aniline
(15a): brown solid; yield 69%; mp 150−153 °C; 1H NMR (400 MHz,
DMSO-d6) δ 2.19 (s, 3H, CH3), 2.58 (s, 3H, CH3), 6.64 (br, 0.67H,
NH2), 7.24 (d, J = 1.6 Hz, 1H, Ph−H), 7.49 (d, J = 1.6 Hz, 1H, Ph−H).
4-Bromo-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)aniline
(15b): yellow solid; yield 72%; mp 133−136 °C; 1H NMR (400 MHz,
CDCl3) δ 2.22 (s, 3H, CH3), 2.62 (s, 3H, CH3), 5.91 (br, 2H, NH2),
7.27 (d, J = 2.0 Hz, 1H, Ph−H), 7.75 (d, J = 2.0 Hz, 1H, Ph−H).
Synthesis of Oxadiazole-Containing Substituted Aniline
(15c−e). A mixture of 2-amino-5-chloro-3-methylbenzoic acid (12a,
5 mmol) with SOCl2 (7 mL) was refluxed for 3 h and condensed under
reduced pressure to give a crude carbonyl chloride (13a), which was
immediately dissolved in 1,4-dioxane (5 mL) and added to a solution of
tetrazole derivative (10a−c, 4 mmol) in dry pyridine (10 mL) with
stirring. The mixture was further stirred at 100 °C for 4−6 h, the solvent
was removed in vacuo, the residue was added to a 10% Na2CO3 solution
(20 mL) and stirred for 5 min, and the solid was filtered, washed with
water, and recrystallized with a mixed solvent of EtOH and DMF to give
the product.
2-(5-(2-Azidopyridin-3-yl)-1,3,4-oxadiazol-2-yl)-4-chloro-6-meth-
1
ylaniline (15e): yellow solid; yield 78%; mp 254−256 °C; H NMR
(400 MHz, DMSO-d6) δ 2.24 (s, 3H, CH3), 6.82 (br, 2H, NH2), 7.34 (d,
J = 2.0 Hz, 1H, Ph−H), 7.67 (t, J = 7.2 Hz, 1H, Py−H), 7.85 (d, J = 2.0
Hz, 1H, Ph−H), 8.79 (d, J = 7.2 Hz, 1H, Py−H), 9.59 (d, J = 7.2 Hz, 1H,
Py−H). HRMS calcd for C14H10ClN7O ([M + Na]+), 350.0533; found,
350.0530.
Synthesis of 4-Chloro-2-methyl-6-(3-methyl-[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazol-6-yl)aniline (16). A mixture of 2-amino-5-
chloro-3-methylbenzoic acid (12a, 2 mmol), 4-amino-5-methyl-4H-
1,2,4-triazole-3-thiol (2 mmol), and phosphorus oxychloride (POCl3)
(7 mL) was refluxed for 5 h and condensed under reduced pressure. The
residue was poured into ice−water, and the mixture was adjusted to pH
10−11 with 30% sodium hydroxide solution. The solid was collected by
filtration, washed with water, and recrystallized with DMF−H2O to
afford compound 16 as a yellow solid: yield 47%; mp 266−268 °C; 1H
NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H, CH3), 2.67 (s, 3H, CH3),
6.56 (br, 2H, NH2), 7.31 (s, 1H, Ph−H), 7.36 (s, 1H, Ph−H).
Synthesis of 1-(3-Chloro-2-pyridyl)-3-(substituted)-1H-pyra-
zole-5-carbonyl chloride (17a−d). To a suspension of pyrazole
carboxylic acid (5) (1 mmol) in 25 mL of dichloromethane were added
successively oxalyl chloride (4 mmol) and two drops of DMF under
vigorous stirring. After stirring at room temperature for 3 h, the solution
was evaporated to dryness in vacuo, and the residue, that is, the crude
pyrazole carbonyl chloride, was obtained as a yellow powder (100%),
which was used directly in the next step without further purification.
General Synthetic Procedure for N′-(2,4,6-Trisubstituted-
phenyl)-N-(1-(3-chloro-2-pyridyl)-3-halo-1H-prazole-5-
carbonyl)thiourea (19a−n). To a mixture of 0.24 g (2.5 mmol) of
potassium thiocyanate (KSCN) in 15 mL of dry acetonitrile were added
two drops of polyethylene glycol-400 (PEG-400), and the mixture was
stirred at room temperature for 5 min to give a homogeneous solution;
then, the solution of crude pyrazole carbonyl chloride (17a or 17b) (1
mmol) in 5 mL of dry acetonitrile was added. After stirring at room
temperature for 40 min, the mixture was filtered to give the acetonitrile
solution of pyrazole carbonyl isothiocyanate (18a or 18b), and then the
2,4,6-trisubstituted aniline (0.85 mmol) was added. After stirring for a
further 3−4 h at room temperature, the reaction mixture was evaporated
4-Chloro-2-methyl-6-(5-phenyl-1,3,4-oxadiazol-2-yl)aniline (15c):
1
yellow crystal; yield 51%; mp 205−208 °C; H NMR (400 MHz,
DMSO-d6) δ 2.21 (s, 3H, CH3), 6.75 (br, 0.71H, NH2), 7.29 (s, 1H,
C
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in vacuo, and the residue was subjected to column chromatography on
silica gel with petroleum ether and ethyl acetate as solvents to give
product (19a−n).
to that of 26 using 93% spermine as amine material, and the solid filtered
was washed with 1,2-dichloroethane to give pure product.
General Synthetic Procedure for 2-(3-Bromo-1-(3-chloropyr-
idin-2-yl)-1H-pyrazol-5-yl)-5-substituted-1,3,4-oxadiazole (28,
29a−c). A mixture of pyrazole carboxylic acid (5b, 1.5 mmmol) with
SOCl2 (10 mL) was refluxed for 4 h and condensed under reduced
pressure to give carbonyl chloride (17b), which was immediately
dissolved in dry toluene (7 mL) and added to a solution of 5-methyl-1H-
tetrazole or compound 10 (1.2 mmol) in dry pyridine (10 mL) with
stirring. The mixture was further stirred at 100−110 °C for 2 h and
cooled to room temperature, and water (50 mL) was added. The
mixture was then extracted with ethyl acetate (10 mL × 4), and the
extracts were dried with anhydrous sodium sulfate. The solvent was
removed in vacuo, and the residue was recrystallized with 95% EtOH to
give product.
Synthesis of 6-(3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyra-
zol-5-yl)-3-methyl-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazole (30).
A mixture of pyrazole carboxylic acid (5b, 2 mmol) and 4-amino-5-
methyl-4H-1,2,4-triazole-3-thiol (2 mmol) in POCl3 (7 mL) was
refluxed for 5 h and condensed under reduced pressure. The residue was
poured into ice−water, and the mixture was adjusted to pH 10−11 with
30% sodium hydroxide solution. The solid was collected by filtration,
washed with water, and recrystallized with DMF−H2O to afford
compound 30 as pink crystals.
General Synthetic Procedure for N-(4-Halo-2-methyl-6-
(substituted-carbamoyl)phenylcarbamothioyl)-1-(3-chloropyr-
idin-2-yl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxa-
mide (20a−g). To a mixture of 0.24 g (2.5 mmol) of KSCN in 15 mL of
dry acetonitrile were added two drops of PEG-400, and the mixture was
stirred at room temperature for 5 min to give a homogeneous solution;
then, the solution of crude pyrazole carbonyl chloride (17c) (1 mmol)
in 5 mL of dry acetonitrile was added. After stirring at room temperature
for 40 min, the reaction was filtered to give the acetonitrile solution of
pyrazole carbonyl isothiocyanate (18c), and then the amino compound
(14a−g) (0.85 mmol) was added; after stirring at room temperature for
another 3−4 h, the reaction mixture was evaporated in vacuo, and the
residue was subjected to column chromatography on silica gel with
petroleum ether and ethyl acetate as solvents to give product.
General Synthetic Procedure for 3-Substituted-N-(4-halo-2-
methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloro-
pyridin-2-yl)-1H-pyrazole-5-carboxamide (21a−c). To a mixture
of oxadiazole-containing substituted aniline (15a or 15b) (0.95 mmol)
and triethylamine (1 mmol) in dichloromethane (15 mL) was added the
solution of pyrazole carbonyl chloride (17b or 17c, 1 mmol) in dry
dichloromethane (7 mL) at 0−5 °C. The reaction mixture was then
stirred at room temperature for 3−4 h and washed with 5% NaHCO3
solution and water successively. The organic layer was dried over
anhydrous sodium sulfate. The solvent was removed in vacuo, and the
residue was subjected to column chromatography on silica gel with
petroleum ether and ethyl acetate as solvents to give product.
General Synthetic Procedure for N-(2-(5-(2-Azidopyridin-3-
yl)-1,3,4-oxadiazol-2-yl)-4-chloro-6-methylphenyl)-3-bromo-1-
(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (22). The
synthesis was similar to that of compounds 21a−c. Using oxadiazole-
containing aniline (15e) and pyrazole carbonyl chloride (17b) as
materials, compound 22 was obtained as a yellow solid.
Synthesis of 1-(2-Hydroxyethyl/hyroxypropyl)-3-(2,4,6-tri-
substituted-phenyl)thiourea (32a−d). According to the method
in the literature,24 to a solution of 1,3,5-trisubstituted-2-isothiocyana-
tobenzene (31a−c, 4 mmol) in diethyl ether (15 mL) was added 2-
aminoethanol or 1-amino-2-propanol (4.5 mmol), and the mixture was
refluxed for 1−2 h. The produced precipitate was filtered and washed
with diethyl ether to give compound 32 as a white solid, which was used
for following reaction without purification.
Synthesis of 5-Substituted-N-(2,4,6-trisubstituted-phenyl)-
4,5-dihydrothiazol-2-amine (33a−d). The intermediate thiourea
(32, 3 mmol) was mixed with concentrated HCl (8 mL) and refluxed for
2 h. The reaction solution was diluted with water (15 mL) and
decolorized by activated charcoal. After cooling to room temperature,
the mixture was adjusted to pH ∼10 with aqueous sodium hydroxide (6
mol/L), and the solid was collected by filtration, washed with water and
recrystallized with EtOH−H2O to afford compound 33.
General Synthetic Procedure for N′-(4-Chloro-2-methyl-6-(5-
methyl-1,3,4-oxadiazol-2-yl)phenyl)-N-(1-(3-chloro-2-pyridyl)-
3-bromo-1H-prazole-5-carbonyl)thiourea (23). The procedure
was similar to those of 19 and 20. Using 15a as substituted aniline
material, compound 23 was obtained as a yellow solid.
33a: white crystal; yield 40%; mp 117−119 °C (lit.,25 mp 118−119
°C).
General Synthetic Procedure for 3-Halo-N-(4-chloro-2-meth-
yl-6-(5-aryl-1,3,4-oxadiazol-2-yl)phenylcarbamothioyl)-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (24a−c). The
synthesis was similar with those of 19 and 20. Using 15c or 15d as
substituted aniline material, compounds 24a−c were obtained.
Synthesis of 3-Substituted-1-(3-chloropyridin-2-yl)-1H-pyr-
azole-5-carboxamide (25a, 25b). To a suspension of pyrazole
carboxylic acid (5b or 5d) (8 mmol) in 50 mL of dichloromethane were
added successively oxalyl chloride (17 mmol) and two drops of DMF.
After stirring at room temperature for 3−4 h, the solution was
evaporated. The resulting carbonyl chloride was dissolved in 50 mL of
dry tetrahydrofuran (THF) and added to a mixture of aqueous ammonia
(25%) (40 mmol) and water (100 mL) at 0 °C. After stirring overnight, a
large amount of solid formed and was filtered, which was further purified
by a silica gel column eluted with petroleum ether and ethyl acetate to
give the pyrazole caboxamide. 25a: white solid; yield 84%; mp 200−202
°C. 25b: white solid; yield 77%; mp 183−185 °C.
General Synthetic Procedure for 3-Bromo-N-(4-chloro-2-
m e t h y l - 6 - ( 5 - s u b s t i t u t e d - 1 , 3 , 4 - o x a d i a z o l - 2 - y l ) -
phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-car-
boxamide (26a, 26b). A suspension of compound 25 (1 mmol) in 20
mL of 1,2-dichloroethane and oxalyl chloride (1.1 mmol) was heated to
reflux and kept for 2 h. After the mixture had cooled slightly, oxadiazole-
containing aniline (15a or 15d) was added, and the mixture was further
refluxed for 1−2 h. After cooling, the produced precipitate was filtered
and washed with 1,2-dichloroethane and ethyl acetate successively to
give product.
33b: white crystal; yield 46%; mp 124−126 °C (lit.,24 mp 124−125
°C).
33c: white crystal; yield 65%; mp 165−166 °C (lit.,24 mp 165.5−166
°C).
1
33d: white crystal; yield 42%; mp 122−123 °C; H NMR (CDCl3,
400 MHz) δ 1.44 (d, J = 6.8 Hz, 3H, CH3), 3.34 (dd, J1 = 10.0 Hz, J2 = 6.4
Hz, 1H, CH2), 3.78 (dd, J1 = 10.0 Hz, J2 = 6.4 Hz, 1H, CH2), 3.88 (m,
1H, CH), 6.80 (s, 1H, NH), 7.30 (s, 2H, Ph−H).
General Synthetic Procedure for 3-Substituted-1-(3-chlor-
opyridin-2-yl)-N-(5-substituted-4,5-dihydrothiazol-2-yl)-N-
(2,4,6-trisubstituted-phenyl)-1H-pyrazole-5-carboxamide
(34a−e). The synthesis was similar to the synthesis of compounds 21a−
c. Using thiazoline-containing aniline (33) and pyrazole carbonyl
chloride (compound 17b or 17c) as materials, compound 34 was
obtained.
Biological Assay. All bioassays were performed on representative
test organisms reared in the laboratory. The bioassay was repeated at 25
1 °C according to statistical requirements. Assessments were made on
a dead/alive basis, and mortality rates were corrected using Abbott’s
formula.26 Evaluations were based on a percentage scale of 0−100, in
which 0 = no activity and 100 = total kill. The standard deviations of the
tested biological values were 5%. LC50 and LC95 values were calculated
by probit analysis.27
Larvicidal Activity against Oriental Armyworm (Mythimna
separata Walker) and Corn Borer (Ostrinia nubilalis). The
larvicidal activity of the title compounds and contrast compounds
chlorantraniliprole and diflubenzuron against oriental armyworm and
corn borer was tested according to the leaf-dip method using the
reported procedure.28 Leaf disks (about 5 cm) were cut from fresh corn
General Synthetic Procedure for O,O-Dimethyl 3-Substi-
tuted-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonylcarba-
moylphosphoramidothioate (27a, 27b). The procedure was similar
D
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Table 1. Larvicidal Activity of Compounds and Chlorantraniliprole against Oriental Armyworm (Mythimna separata Walker) at
200 mg/L Concentration
compd larvicidal activity (%) compd larvicidal activity (%) compd larvicidal activity (%) compd larvicidal activity (%)
compd
larvicidal activity (%)
15a
15b
15c
15d
15e
16
20
19e
19f
10
20
10
0
20a
20b
20c
20d
20e
20f
100
100
100
100
100
100
100
100
100
22
100
100
0
29a
29b
29c
30
0
10
16.7
36.7
23.3
23
19g
19h
19i
24a
24b
24c
26a
26b
27a
27b
28
0
0
13.3
30
6.67
20
30
40
10
20
10
0
34a
34b
34c
34d
34e
10
20
19j
60
10
10
10
16.7
50
19a
19b
19c
19d
19k
19l
20g
21a
21b
21c
20
6.67
10
100
100
19m
19n
a
43.3
33.3
control
100
a
chlorantraniliprole.
Table 2. Larvicidal Activity of Compounds, Chlorantraniliprole, and Diflubenzuron against Oriental Armyworm (Mythimna
separata Walker)
larvicidal activity (%) at
compd
100 mg/L
50 mg/L
25 mg/L
10 mg/L
5 mg/L
2.5 mg/L
1 mg/L
100
0.5 mg/L
100
0.25 mg/L
40
19c
19d
20a
20b
20c
20d
20e
20f
20g
21a
21b
22
100
100
100
100
100
100
100
100
100
100
30
100
100
100
100
100
100
100
100
100
60
20
100
100
100
100
100
100
100
100
0
15
100
100
100
100
100
100
100
0
100
0
100
40
0
100
0
40
100
100
80
0
100
100
0
60
40
0
23
0
26a
34c
10
diflubenzuron
100
100
100
100
100
100
100
100
100
100
40
a
chlorantraniliprole
100
100
100
70
a
At a concentration of 0.1 mg/L.
Table 3. Larvicidal Activity of Compounds, Diflubenzuron, and Chlorantraniliprole against Diamondback Moth (Plutella xylostella
L.)
larvicidal activity (%) at
compd
50 mg/L
25 mg/L
10 mg/L
2.5 mg/L
1.25 mg/L
0.125 mg/L
0.1 mg/L
0.01 mg/L
0.005 mg/L
19c
19d
20a
20c
20e
20g
22
90
43
57
0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
86
71
100
100
71
43
100
71
29
86
57
0
30
100
100
29
60
60
23
26a
34c
29
diflubenzuron
29
0
chlorantraniliprole
100
100
100
86
100
86
57
leaves and then were dipped into the test solution for 3−5 s. After air
drying, the treated leaf disks were placed individually into a glass-surface
vessel (7 cm). Each dried treated leaf disk was infested with 10 third-
instar oriental armyworm or corn borer larvae. Percentage mortalities
were evaluated 4 days after treatment. Leaves treated with acetone were
provided as controls. Each treatment was performed three times. The
insecticidal activity is summarized in Tables 1, 2, and 4.
Larvicidal Activity against Diamondback Moth (Plutella
̈
xylostella L.) and Beet Armyworm (Laphygma exigua Hubner).
The larvicidal activity of the title compounds and contrast compounds
chlorantraniliprole and diflubenzuron against diamondback moth and
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were expressed by death percentage. For comparative purposes,
chlorantraniliprole and diflubenzuron were tested under the same
conditions.
Table 4. Larvicidal Activity of Compounds 20a, 20c, 20e, 20g,
Diflubenzuron, and Chlorantraniliprole against Beet
Armyworm (Laphygma exigua Hubner) and Corn Borer (O.
̈
Hartree−Fock (HF) Calculation. The structures of compounds
20a, 20c and chlorantraniliprole were selected as the initial structures,
whereas the HF/6-31G (d,p)32 method in the Gaussian 03 package33
was used to optimize their structures. Vibration analysis showed that the
optimized structures were in accordance with the minimum points on
the potential energy surfaces. All of the convergent precisions were the
system default values, and all of the calculations were carried out on the
NanKai-Star supercomputer.
nubilalis)
L. exigua Hubner
O. nubilalis
̈
concn
(mg/L)
larvicidal
activity (%)
concn
(mg/L)
larvicidal
activity (%)
compd
20a
20c
10
1
0
0
25
10
100
60
10
1
70
60
40
25
10
100
60
RESULTS AND DISCUSSION
■
Chemistry. The tetrazole compounds (10a, 10b) were
prepared according to the literature
0.1
22
by heating cyano-
20e
20g
10
1
80
60
40
25
10
100
60
containing compound 9 with 2 equiv of sodium azide and
ammonium chloride in DMF with satisfactory yields. When using
2-chloro-3-cyanopyridine as material, we did not obtain the
desired 2-chloro-3-(1H-tetrazol-5-yl)pyridine; however, 2-azido-
3-(1H-tetrazol-5-yl)pyridine (10c), which is a novel biheter-
ocyclic compound containing eight nitrogen atoms, was
obtained. This result indicated that the chloro atom in the 2-
position of pyridine can be substituted by nucleophilic reagent
0.1
10
1
20
0
25
25
30
20
diflubenzuron
10
1
0
0
−
N3 during cyclization of the cyano group with hydrazoic acid,
and the reactivity of the −Cl group may be increased by its
neighboring −CN group of the material or tetrazole group of its
product, so the −Cl group could be easier to leave. Tetrazole
compound (5-methyl-1H-tetrazole or 10a, 10b) reacted with
3,5-disubstituted-2-amino benzoyl chloride (13) in pyridine,
undergoing a Huisgen reaction to give oxadiazole-containing
substituted aniline (15a−d) with the amino group conserved.
Similarly, azido-containing tetrazole compound (10c) can also
undergo such reaction to afford corresponding oxadizole-
containing substituted aniline (15e). The azido group is not
affected in the following reactions, too, which can be confirmed
chlorantraniliprole
10
1
80
80
40
25
10
100
80
0.1
beet armyworm was tested by the leaf-dip method using the reported
procedure.29,30 Leaf disks (5 cm × 3 cm) were cut from fresh cabbage
leaves and then dipped into the test solution for 3 s. After air-drying, the
treated leaf disks were placed individually into boxes (80 cm). Each dried
treated leaf disk was infested with 30 third-instar beet armyworm or 30
second-instar diamondback moth larvae. Percentage mortalities were
evaluated 3 days after treatment. Leaves treated with water and acetone
were provided as controls. Each treatment was performed three times.
The insecticidal activity is summarized in Tables 3 and 4.
Larvicidal Activity against Mosquito (Culex pipiens pallens).
The larvicidal activity of the title compounds and contrast compounds
against mosquito were evaluated by using the reported procedure.31 The
compounds were prepared to different concentrations by dissolving the
compounds in acetone and adding distilled water. Then 20 fourth-instar
mosquito larvae were put into 10 mL of the test solution and raised for 8
days. Each treatment was performed three times. The biological data in
Table 5 were the average value of the three tested values. The results
1
by H NMR and HRMS of their products (22 and 29c).
Moreover, 2-amino-5-chloro-3-methylbenzoic acid (12a) and 4-
amino-5-methyl-4H-1,2,4-triazole-3-thiol refluxed in POCl3 to
successfully give corresponding fused heterocyclic substituted
aniline (16) via a cyclization reaction. The reaction of oxadiazole-
containing aniline (15a, 15b, 15e) with pyrazole carbonyl
chloride can give oxadiazole-containing amide (21a−c, 22),
whereas it is difficult for compound 16 to undergo this reaction
to afford acylation product, which may be because of the very
weak solubility and weak reactivity of fused heterocyclic aniline
16.
There are some common methods for synthesizing the
carbonyl thioureas, for example, carbonyl chloride compound
refluxes with thiocyanate in acetone34 or reacts with thiocyanate
catalyzed by PEG-600 in methane dichloride at room temper-
ature35 to produce carbonyl isothiocyanate, which further reacts
with amine to give carbonyl thiourea. In our experiments for the
syntheses of carbonyl thioureas (19, 20, 23, and 24a-c), a PEG-
400 PTC method was adopted (illustrated in Scheme 5 and
Scheme 6). Pyrazole carbonyl chloride (5) was prepared from
the reaction of pyrazole acid with oxalyl chloride, and it was
treated with potassium thiocyanate under the conditions of
solid−liquid phase transfer catalysis using a small amount of
PEG-400 as the catalyst to give pyrazole carbonyl isothiocyanate
(18) at room temperature. This compound does not need to be
isolated, and it was treated immediately with 2,4,6-trisubstituted
anilines or 2-amino-3-methylbenzamide derivatives (14a−g) to
give compound 19 or 20 in good to excellent yields.
Table 5. Larvicidal Activity of Compounds 19c, 19d, 20a−g,
Diflubenzuron, and Chlorantraniliprole against Mosquito
(Culex pipiens pallens)
larvicidal activity (%) at
compd
2 mg/L
1 mg/L
0.5 mg/L
0.25 mg/L
19c
19d
20a
20b
20c
20d
20e
20f
20
0
100
100
60
100
60
40
20
50
60
30
20g
50
diflubenzuron
100
100
100
100
30
chlorantraniliprole
100
100
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a
Scheme 5. Synthesis of Compounds 19a−n and 20a−g
a
Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2; (b) KSCN, PEG-400, CH3CN; (c) substituted aniline, CH3CN; and (d) compd 14a−g,
CH3CN.
a
Scheme 6. Synthesis of Compounds 21a−c, 22, 23, and 24a−c
a
Reagents and conditions: (a) compd 15a or 15b, Et3N, CH2Cl2; (b) compd 15e, Et3N, CH2Cl2; (c) KSCN, PEG-400, CH3CN; (d) compd 15a,
CH3CN; and (e) compd 15c or 15d, CH3CN
a
Scheme 7. Synthesis of Compounds 26a, 26b, 27a, and 27b
a
Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2; (b) NH3·H2O; (c) (i) (COCl)2, ClCH2CH2Cl, reflux, and (ii) compd 15a or 15d; and (d)
(i) (COCl)2, ClCH2CH2Cl, reflux, and (ii) 93% spermine.
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Compounds 26 were synthesized, as shown in Scheme 7.
Pyrazole carboxylic acid 5 was converted to amide 25 by reaction
with oxalyl chloride and then aqueous ammonia. Compound 25
was then refluxed with oxalyl chloride in 1,2-dichloroethane to
give its corresponding pyrazole carbonyl isocyanate derivative,
which coupled with amines 15 to afford the compounds 26.
Similarly, using 93% spermine as amine material the carbonyl
thiophosphorylureas 27 were obtained.
The reaction of tetrazole compound (5-methyl-1H-tetrazole
or 10) with pyrazole carbonyl chloride 17b in pyridine led to
oxadiazole compound (28, 29; Scheme 8) by a Huisgen reaction,
whereas pyrazole carboxylic acid 5b directly reacted with 4-
amino-5-methyl-4H-1,2,4-triazol-3-thiol in POCl3 to afford the
fused heterocyclic compound 30.
carbonyl thiourea compounds 19a, 20a−g, 23, and 24a−c
showed absorption bands at 3143−3446 cm−1 for N−H
stretching. The strong peaks at 1742−1579 cm−1 are ascribed
to the CO group and CN group of heterocyclic ring
skeleton as well. The characteristic stretching vibrations ν (C
S) and ν (CN) appeared at 1273−1369 and 1152−1167 cm−1,
respectively. In the 1H NMR spectra of compounds 19a−n and
20a−g, the proton signals of −NHCO− and −NHCS− on the
carbonyl thiourea bridge were observed at δ 9.73−10.42 and
11.08−12.48 as a singlet, respectively. The trifluoroethoxyl
protons (−OCH2CF3) of compounds 20a−g, 21c, and 34e
appeared at δ 4.65−4.92 as a quartet due to “F” splitting, whereas
the methoxyl protons ((CH3O)2P(=S)−) of compound 27
appeared at δ ∼3.85 as a doublet owing to “P” splitting. Another
NH proton signal of the amide moiety (−CONHR2) in
compounds 20a−g was observed at δ 6.32−6.64. As for
compounds 26 and 27, the two active proton signals (NH)
appeared at δ 9.67−9.93 and 10.75−11.53 as a singlet,
respectively.
a
Scheme 8. Synthesis of Compounds 28, 29a−c, and 30
Structure−Activity Relationship (SAR). Larvicidal Activ-
ity against Oriental Armyworm. The larvicidal activity of
compounds against oriental armyworm is summarized in Tables
1 and 2. All of the compounds were initially tested at a
concentration of 200 mg/L, and consequently the compounds
with high insecticidal potency were investigated further at low
concentration. From Table 1, we can see that at 200 mg/L,
carbonyl thiourea compounds 19c, 19d, 20a−g, and 23 showed
100% larvicidal activities, oxadiazole-containing amide com-
pounds 21a−c and 22 exhibited 43.3−100% activities, and
oxadiazole-containing carbonyl urea 26a and thiazoline-contain-
ing amide 34c possessed 60 and 50% activities, respectively.
Other compounds including novel carbonyl thiophosphorylur-
eas 27 and intermediates oxadiazole-containing or fused
heterocyclic substituted aniline 15 and 16 showed comparably
lower activity and were not tested further. From Table 2, we can
see that compounds 20a−g also showed 100% larvicidal activity
against oriental armyworm even at the concentration of 10 mg/L.
At lower concentration, for example, 2.5 mg/L, 20a and 20g still
exhibited excellent larvicidal activity (100%), and were more
potent than the contrast diflubenzuron (2.5 mg/L, 40%).
Especially, 20a showed 100 and 40% larvicidal activities at
concentrations of 0.5 and 0.25 mg/L, respectively. Its LC50 and
LC95 values correspondingly were 0.1812 and 0.7767 mg/L,
lower than those of chlorantraniliprole (0.0276 and 0.2004 mg/
L, respectively, Table 6). The bioactivity of compounds 20a−e,
when R1 was fixed as Cl, indicated the sequence of larvicidal
a
Reagents and conditions: (a) SOCl2, benzene, reflux; (b) 5-methyl-
1H-tetrazole, Py, 100−110 °C; (c) compd 10a−c, Py, 1,4-dioxane,
100−110 °C; and (d) 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol,
POCl3, reflux.
Referring to the literature method reported by He et al.,24
thiazoline amines (33) were prepared by a cyclization reaction in
a concentrated HCl solution of hydroxyethylthiourea or
hydroxypropylthiourea (32), which derived from the condensa-
tion of isothiocyanate (31) with 2-aminoethanol or 1-amino-2-
propanol. Then compound 33 reacted with pyrazole acyl
chloride (17) using Et3N as deacid reagent to give acylation
product (34; Scheme 9).
The novel structures of these title compounds have been
characterized by melting point, 1H NMR, and elemental analyses
or HRMS; several compounds with typical structures were also
characterized by IR spectra. All spectral and analytical data were
consistent with the assigned structures. The infrared spectrum of
a
Scheme 9. Synthesis of Compounds 34a−e
a
Reagents and conditions: (a) 2-aminoethanol or 1-amino-2-propanol, Et2O; (b) (i) concentrated HCl, reflux, and (ii) NaOH; and (c) compd 17b
or 17c, Et3N, dry THF.
H
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calculated the frontier molecular orbital of representative
compounds 20a and 20c that have good insecticidal activity
against oriental armyworm and diamondback moth with
chlorantraniliprole as contrast by means of HF (Hartree−Fock).
The energies of LUMO, HOMO, and HOMO-1 of 20a, 20c
and chlorantraniliprole are listed in Table 8 and the LUMO and
Table 6. LC50 and LC95 Values of Compound 20a and
Chlorantraniliprole against Oriental Armyworm
LC50
(mg/L)
LC95
compd
y = a + bx
R
(mg/L)
20a
chlorantraniliprole
y = 6.93 + 2.60x
y = 7.98 + 1.91x
0.98
0.91
0.1812
0.0276
0.7767
0.2004
Table 8. Energies of LUMO, HOMO, and HOMO-1 of 20a,
20c and Chlorantraniliprole (Hartree)
activity was CH3 > C(CH3)3 > CH(CH3)2 > CH3CH2CH2,
cyclopropyl in the aliphatic amide moiety (R2).
Larvicidal Activity against Diamondback Moth. Table 3
shows that the bioassay results against diamondback moth at 1.25
mg/L, compounds 20a, 20c, 20e, 20g were more effective than
diflubenzuron (2.5 mg/L, 0%). At 0.125 mg/L the four
compounds have the same or better larvicidal activity than
chlorantraniliprole (86−100%). Even at 0.005 mg/L, 20e
showed 57% activity and reached the same larvicidal level as
chlorantraniliprole. It was worth noting that 20c showed a death
rate of 86% at 0.005 mg/L, which is more effective than
chlorantraniliprole (57%) against diamondback moth. The LC50
value of 20a was 0.0054 mg/L, higher than that of
chlorantraniliprole (0.0045 mg/L, Table 7). The LC50 values
20a
20c
chlorantraniliprole
LUMO
−0.20895
−0.29959
−0.30856
−0.20902
−0.29961
−0.308448
−0.09190
−0.25188
−0.25569
HOMO
HOMO-1
HOMO maps of 20a, 20c and chlorantraniliprole are shown in
Figure 2. Taking HF calculation results, there is something in
common between 20a and 20c in the LUMO and HOMO maps.
In the HOMO of 20a and 20c, electrons are mainly delocalized
on the benzene ring and the thiourea group, especially the latter.
However, when electron transitions take place, some electrons in
the HOMO will enter into the LUMO;37 then, in the LUMO of
20a and 20c, the electrons will mainly be delocalized on the
aromatic rings [benzene ring, pyrazole ring (including O atom of
trifluoroethyloxyl group in the 3-position of pyrazole) and
pyridine ring] and the carbonyl thiourea group. It was observed
that the carbonyl thiourea moiety in both of the molecules (20a,
20c) makes a major contribution to the activity. These are largely
through hydrophobic interaction and are most obvious in the
HOMO maps (especially the S atom of the bridge). Comparing
with those of chlorantraniliprole, we can see that the LUMO of
chlorantraniliprole mainly contains three aromatic rings and the
amide bridge group, which is similar to that of 20a and 20c,
whereas the HOMO contains the pyrazole ring, the pyridine ring,
and a small part of the amide bridge (mainly the N atom). The
frontier molecular orbitals are located on the main groups, the
atoms of which can easily bind with the receptor.38 Thus, it can
be concluded that the three aromatic rings of compounds 20a
and 20c and chlorantraniliprole as well may contribute activity
through π−π and hydrophobic interactions; meanwhile, the
carbonyl thiourea bridge that links the benzene and pyrazole
rings of the compounds also plays an important role in the
insecticidal activity, like the amide bridge group of chloran-
traniliprole, which may contribute activity through hydrophobic
interaction.
In summary, series of novel amide bridge modified
compounds containing pyridylpyrazole were conveniently
synthesized on the basis of the structures of anthranilic diamide
insecticides, and their structures were characterized and
confirmed by melting point, IR, 1H NMR, and elemental
analyses or HRMS. The insecticidal activities against oriental
armyworm, diamondback moth, beet armyworm, corn borer, and
mosquito of these heterocycle compounds were evaluated. The
bioassay results indicated that carbonyl urea, oxadiazole,
carbonyl thiophosphorylurea, and thiazoline-containing amide
compounds showed weak insecticidal activity against oriental
armyworm, whereas part of the carbonyl thiourea and
oxadiazole-containing amide compounds exhibited significant
larvicidal activity against oriental armyworm, and some of them
showed favorable activity against mosquito, diamondback moth,
beet armyworm, and corn borer. In general, carbonyl thiourea
compounds 20a, 20c, and 20e exhibited comparably outstanding
activity compared with others, even prior to the contrasts. In
Table 7. LC50 Values of Compounds 20a, 20c, 20e, and
Chlorantraniliprole against Diamondback Moth
compd
y = a + bx
R
LC50(mg/L)
20a
20c
20e
y = 15.11 + 4.46x
y = 10.79 + 2.09x
y = 15.22 + 3.87x
y = 18.06 + 5.57x
0.99
0.97
0.92
0.97
0.0054
0.0017
0.0023
0.0045
chlorantraniliprole
of 20c and 20e were 0.0017 and 0.0023 mg/L, respectively, lower
than that of chlorantraniliprole (0.0045 mg/mL, Table 7), which
were in accordance with the results in Table 3. The activities of
compounds 20a, 20c, and 20e, where R1 was fixed as Cl,
indicated the trend CH(CH3)2 > C(CH3)3 > CH3 in the aliphatic
amide moiety (R2).
Larvicidal Activity against Beet Armyworm. The larvicidal
activity of 20a, 20c, 20e, and 20g against beet armyworm at
different concentrations is summarized in Table 4. It was found
that only 20c and 20e exhibited a 40% death rate at 0.1 mg/L,
similar to that of chlorantraniliprole. Surprisingly, 20a and 20g,
with excellent activity against oriental armyworm (100% at 2.5
mg/L), showed no activity against beet armyworm at 1 mg/L.
Larvicidal Activity against Corn Borer. From Table 4, it was
found that 20a, 20c, and 20e possessed 100% death rate against
corn borer at 25 mg/L, more effective than 20g (30%) and
diflubenzuron (20%) as well. All three compounds exhibited a
60% death rate at 10 mg/L, which was somewhat less effective
than chlorantraniliprole (80%).
Larvicidal Activity against Mosquito. The larvicidal activity
of 19c, 19d, and 20a−g against mosquitoes is summarized in
Table 5, from which we can see that 20a−g exhibited significant
larvicidal activity and showed a 30−100% death rate at 2 mg/L.
20a and 20b showed 40 and 20% activity against mosquitoes at
0.5 mg/L, respectively, lower than that of chlorantraniliprole but
similar to that of diflubenzuron (0.5 mg/L, 30%).
HF Calculation. According to the frontier molecular orbital
theory, HOMO and LUMO are the two most important factors
that affect the bioactivities of compounds. HOMO has the
priority to provide electrons, whereas LUMO accepts electrons
first.36−38 Thus, a study of the frontier orbital energy can provide
some useful information for the active mechanism. We therefore
I
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Journal of Agricultural and Food Chemistry
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Figure 2. LUMO and HOMO maps for compounds 20a, 20c, and chlorantraniliprole from HF calculations. The green parts represent positive
molecular orbital, and the red parts represent negative molecular orbital.
Notes
some cases, 20c and 20e had better larvicidal effects against
diamondback moth than chlorantraniliprole. The preliminary
structure−activity relationship of compounds was discussed, and
the HF calculation results indicated that the carbonyl thiourea
moiety of the compounds 20a and 20c plays an important role in
the insecticidal activity. It is worth noting that the change of the
amide bridge in chlorantraniliprole to carbonyl thiourea can keep
the insecticidal activities at a low concentration in our earlier
studies,15 whereas the introduction of both carbonyl thiourea and
trifluoroethoxyl moieties to such a structure can increase the
insecticidal activities in this study, such as in the case of 20c and
20e. The present work demonstrated that the trifluoroethoxy-
containing carbonyl thioureas can be used as lead compounds for
the development of new insecticidal structures.
The authors declare no competing financial interest.
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR, HRMS, or elemental analyses and melting point data
for compounds 19a−n, 20a−g, 21a−c, 22, 23, 24a−c, 26a, 26b,
27a, 27b, 28, 29a−c, 30, and 34a−e (31P NMR and IR data for
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AUTHOR INFORMATION
Corresponding Author
*Phone: +86-22-23503732. E-mail: nkzml@vip.163.com.
■
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Funding
This work was supported by the National Basic Research
Program of China (No. 2010CB126106), the National Key
Technologies Research and Development Program
(2011BAE06B05-3), the National Natural Science Foundation
of China (No. 20872069), and the Tianjin Natural Science
Foundation (No. 11JCYBJC04500).
J
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