Design, synthesis and insecticidal activity of novel anthranilic diamides with benzyl sulfide scaffold

Article abstract of DOI:10.1016/j.cclet.2013.04.047

A series of novel anthranilic diamides with benzyl sulfide scaffold were synthesized, in which N-pyridylpyrazole moiety generally regarded as key pharmacophore was abandoned. The target compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. The preliminary bioassays indicated that half of the title compounds were endowed with good insecticidal activities against armyworm (Mythimna sepatara) at the concentration of 500 mg/L. Exhilaratingly, the synthesized compound 3a was also active against Tetranychus cinnabarinus at 100 mg/L. The difference in activities between the target compounds was influenced by the substituents, which provided some hints for further investigation on structure modifications.

Full text of DOI:10.1016/j.cclet.2013.04.047

Chinese Chemical Letters 24 (2013) 673–676
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Design, synthesis and insecticidal activity of novel anthranilic diamides with
benzyl sulfide scaffold
*
Yin-Bo Chen, Ji-Ling Li, Xu-Sheng Shao, Xiao-Yong Xu, Zhong Li
Shanghai Key Lab of Chemistry Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of novel anthranilic diamides with benzyl sulfide scaffold were synthesized, in which N-
pyridylpyrazole moiety generally regarded as key pharmacophore was abandoned. The target
compounds were characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. The preliminary bioassays
indicated that half of the title compounds were endowed with good insecticidal activities against
armyworm (Mythimna sepatara) at the concentration of 500 mg/L. Exhilaratingly, the synthesized
compound 3a was also active against Tetranychus cinnabarinus at 100 mg/L. The difference in activities
between the target compounds was influenced by the substituents, which provided some hints for
further investigation on structure modifications.
Received 5 March 2013
Received in revised form 8 April 2013
Accepted 18 April 2013
Available online 31 May 2013
Keywords:
Anthranilic diamides
Benzyl sulfide
Synthesis
ß 2013 Zhong Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Insecticidal activity
1. Introduction
above observations, it was reasoned that the pyrazole heterocycle
in the N-pyridylpyrazole moiety (a) is a key pharmacophore in this
The current status of insecticide resistance and the underly-
ing resistance in target species is a serious problem in plant
protection [1]. Therefore, the exploration of novel insecticides
with new mode of action has attracted much interest. In the past
decade, the newest major class of insecticides, the diamides,
inaugurated the new era of insecticides. Chlorantraniliprole [2]
and flubendiamide [3] (Fig. 1), sharing a unique mode of action
on the insect ryanodine receptors with high potency and
remarkable selectivity, have been rocketed into a position of
great status in agrochemicals.
Anthranilic diamides, which acting on insect ryanodine
receptors (RyRs), are fasting growing class insecticides in modern
crop protection for their highly potent activity, low ecotoxicity and
broad insecticidal spectra [4]. According to the modified structures
of anthranilic diamides described in a sizable number of patents
and papers in recent years, the common molecular structural
features of anthranilic diamides can be categorized into three parts
(Fig. 2): the N-pyridylpyrazole moiety (a) [5–8], the anthraniloyl
moiety (b) [9–13] and aliphatic amide moiety (c) [14–17]. A major
emphasis on researching for novel anthranilic diamides involved
the modifications related to part (b) and (c). In previous studies, it
was found that replacing the N-pyridylpyrazole moiety with 1, 2,
3-thiadiazole or trizolopyrimidine ones [18,19], the anthranilic
diamides analogs showed no insecticidal activities. On the basis of
kind of compounds. Therefore, altering the N-pyridylpyrazole
moiety (a) by other substituents on the structural modifications
was seldom reported.
Element sulfur is undoubtedly linked to the pesticides in the
history of crop protection. Sulfide scaffold is a highly efficient
pharmacophore in the molecular design. The introduction of
sulfide scaffold contributed to higher activities and was responsi-
ble for low mammalian toxicity [20]. In recent years, the sulfide
scaffold is widely used in several commercialized insecticides, for
example, flubendiamide [3], thiacloprid [21] and sulfoxaflor [22]
(Fig. 3). Then, the program of incorporation of benzyl sulfide
scaffold into the anthraniloyl moiety (b) was initiated in this study.
Enlightened by all of intriguing reasons above, we herein designed
and synthesized a series of novel anthranilic diamides bearing
benzyl sulfide scaffold (Fig. 4).
2. Experimental
2.1. Experiments
Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Melting points (mp) were
recorded on Bu¨chi B540 apparatus and are uncorrected. 1H NMR,
19F NMR and 13C NMR spectra were recorded on Bruker AM-400
(400 MHz) spectrometer with DMSO-d6 as the solvent and TMS as
the internal standard. Chemical shifts are reported in
d (parts per
million) values. High-resolution mass spectra were recorded under
electron impact (70 eV) condition using a MicroMass GCT CA 055
* Corresponding author.
E-mail address: lizhong@ecust.edu.cn (Z. Li).
1001-8417/$ – see front matter ß 2013 Zhong Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.047

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Y.-B. Chen et al. / Chinese Chemical Letters 24 (2013) 673–676
3
Fig. 3. Commercialized insecticides with sulfides.
Fig. 1. Commercialized diamide insecticides.
instrument. Analytical thin-layer chromatography (TLC) was
carried out on precoated plates (silica gel 60 F254), and spots
were visualized with ultraviolet (UV) light.
a solution of the title compound 3b (1.0 mmol) in 10 mL DCM was
added m-chloroperoxy benzoic acid (MCPBA) (1.05 mmol). The
reaction was carried out at room temperature, and the progress of
the reaction was monitored by TLC. After completion, the mixture
was poured into water, and then extracted with DCM. The organic
layer was washed with aqueous sodium hydrosulfite and an
aqueous sodium carbonate solution respectively, and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
on silica gel with ethyl acetate–petroleum ether as eluent to afford
the title compound 4a.
Preparation of 2-amino-6-bromo-N-(3-bromo-2-(methylcarba-
moyl)phenyl)benzamide (1): A mixture of 2-amino-6-bromobenzoic
acid (1.0 mmol), methylamine water solution (1.5 mmol), EDCI
(2.0 mmol), HOBt (0.2 mmol) in DCM was stirred at room
temperature and monitored by TLC. After completion, the mixture
was diluted with DCM, washed with water twice, dried over
anhydrous Na2SO4, evaporated, and chromatographed (ethyl
acetate - petroleum ether) to afford the compound 1.
Preparation of 2-amino-N-(3-(benzylthio)-2-(methylcarbamoyl)-
phenyl)-6-bromobenzamide (2):
A
mixture of
1
(1.0 mmol),
2.2. Biological assay
thiobenzyl alcohol (1.2 mmol), K2CO3 (1.2 mmol) in DMF was
stirred at room temperature for 12 h. After completion, the mixture
was removed under reduced pressure and taken into DCM,
followed by extraction with water and brine. The organic phase
was then dried over anhydrous Na2SO4, and the solvent was
removed in vacuo to afford the crude product, which, upon further
purification by column chromatography (ethyl acetate-petroleum
ether), afforded intermediate 2.
General synthetic procedure for the title compound 3aSw: A
mixture of various carboxylic acids (1.0 mmol), an excess of thionyl
chrolide (5 mL) was refluxed for 2 h and concentrated in vacuo to
give corresponding acyl chloride (quant). The corresponding acyl
chloride was dissolved in 2 mL anhydrous DCM, then added
All bioassays were performed on representative test organisms
reared in the laboratory. The bioassay was repeated at (25 Æ 1) 8C
according to statistical requirements. All compounds were dissolved
in N,N-dimethylformamide (AP, Shanghai Chemical Reagent Co., Ltd.,
Shanghai, China) and diluted with distilled water containing Triton X-
100 (0.1 mg/L) to obtain two concentrations of 500.0 mg/L and
100.0 mg/L. For comparative purposes, avermectins as control was
tested under the same conditions.
Insecticidal test for armyworm (Mythimna sepatara): The
activities of the designed compounds against armyworm were
tested using previously reported procedures [23]. The insecticidal
activity against armyworm was tested by foliar application.
Individual corn (Zea mays) leaves were placed on moistened
pieces of filter paper in Petri dishes. The leaves were then sprayed
with the compounds solution and exposed to dry. The dishes were
infested with 10 third-instar larvae and placed in the conditioned
room. The mortality rates were evaluated 48 h after treatment.
Each treatment had three repetitions and the data were adjusted
and subjected to probit analysis as before.
dropwise to
a solution of compound 2 (1.0 mmol), DIPEA
(1.2 mmol) in 15 mL anhydrous DCM in an ice bath. The reaction
was then stirred at room temperature and monitored by TLC, after
completion, the solvent was evaporated under reduced pressure.
The residual solid was purified by column chromatography on
silica gel with ethyl acetate - petroleum ether as eluent to afford
the title compound 3a–w.
Preparation of N-(2-((3-(benzylsulfinyl)-2-(methylcarbamoyl)phe-
nyl)carbamoyl)-3-bromophenyl)-2-bromo-3-nitrobenzamide (4a): To
Insecticidal test for Tetranychus cinnabarinus: The activities of the
new compounds against T. cinnabarinus were assessed according to
the reported procedure [24]. Cut round sections from chemically
untreated broad bean leaves. Leaves must be in good condition.
Collect about 40 adult mites with the fine pointed brush onto each
[(Fig._2)TD$FIG]
[F(ig._4)TD$FIG]
Fig. 2. The chemical structure of anthranilic diamides.
Fig. 4. Design of novel anthranilic diamides with benzyl sulfide.

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Y.-B. Chen et al. / Chinese Chemical Letters 24 (2013) 673–676
675
Scheme 1. Reagents and conditions: (a) methylamine water solution (25.0 %–30.0 %), EDCI, HOBt, DCM, r.t.; (b) thiobenzyl alcohol, K2CO3, DMF, r.t.; (c) (i) SOCl2, reflux; (ii)
DIPEA, DCM, r.t.; (d) MCPBA, DCM, r.t.
leaf section. The leaf disk with mites placed under the Potter spray
tower, and then sprayed with test liquids (pressure 5 Ib/in2). The
test set with the highest concentrations of organic solvents Tween
water as a blank control. The leaf discs with mite are air dried and
placed at a room with temperature of 24–26 8C, photoperiod 14 h.
Using hand lens assess mortality after 96 h by checking each mite’s
ability to show movement in response to a touch with a small
brush. Express results as percentage mortality and correct for
untreated mortality using Abbott’s formula. Each process was
repeated for 3 times.
3. Results and discussion
3.1. Synthesis
The synthetic route of the title compounds was depicted in
Scheme 1. The target compounds 3a–w were synthesized by a
three-step procedure. In the first step, the treatment of 2-amino-6-
bromobenzoic acid with methylamine water solution in the
presence of EDCI and HOBt afforded compound 1 rather than
compound 5 in good yields, which was confirmed by 1H NMR. We
Table 1
Insecticidal activities of compounds 3a–w and 4a against armyworm (M. sepatara) and T. cinnabarinus.
O
Ph
S
O
Ph
S
O
N
H
N
H
NH
Br
NH
Br
O
O
[TD$INLINE]
HN
Br
HN
R
O2N
O
O
n
n=0,1
3a-w
4a
Compd.
R
n
Conc. (mg/L)
Mortality (%)
M. sepatara
T. cinnabarinus
3a
4-Cyano-3-fluorophenyl
0
500
100
500
500
500
500
500
500
500
500
500
100
500
500
500
500
500
500
500
500
500
100
500
500
500
500
500
500
100
100
0
100
60
90
80
0
3b
3c
3d
3e
3f
2-Bromo-3-nitrophenyl
2,5-Dimethoxyphenyl
4-Chlorophenyl
0
0
0
0
0
0
0
0
0
100
100
100
100
90
80
60
50
0
4-Bromo-2,3-difluorophenyl
6-Fluoropyridin
0
0
3g
3h
3i
2-Trifluoromethoxyphenyl
Styrene
0
0
3-Bromo-5-trifluoromethoxyphenyl
2-Bromo-4,5-difluorophenyl
0
3j
100
10
90
80
80
0
0
3k
3l
4-Trifluoromethylphenyl
2,4,5-Trifluoro-3-methoxyphenyl
2-Bromo-6-fluorophenyl
6-Trifluoromethylpyridin
Methyl
0
0
0
0
0
0
0
0
1
0
0
3m
3n
3o
3p
3q
3r
0
0
0
0
2-Iodophenyl
0
0
2-Fluoro-5-iodophenyl
2,3,4,5,6-Pentafluorophenyl
2-Bromo-4-trifluoromethylphenyl
0
0
0
0
3s
0
90
10
0
0
3t
2,4,6-Trifluorophenyl
1
1
1
1
0
0
3u
4-Nitrophenyl
90
90
90
0
0
3v
4-Methoxyphenyl
0
3w
Naphthalene
0
4a
–
–
0
Avermectins
ns
100
100
100
100

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Y.-B. Chen et al. / Chinese Chemical Letters 24 (2013) 673–676
proposed that compound 1 was prepared via self-condensation of
2-amino-6-bromobenzoic acid, and then coupled with methyl-
amine. With the key intermediate 1 in hand, conversion of 1–2 was
then carried out with thiobenzyl alcohol in the DMF using K2CO3 as
acid acceptor. Fortunately, owing to the electronic effect of
aromatic substitutes, the amino group deactivated the bromo
group in the same aromatic ring, so that compound 2 was the
major product with the yield of 65%, which was further convinced
by comparing 1H NMR data of compound 1 and 2 (see Supporting
information). Various carboxylic acids were treated with thionyl
chrolide and then coupled with intermediate 2 in the presence of
DIPEA to provide the title compounds of amide 3a–w in moderate
to good yields. By oxidation of the compound 3b with MCPBA,
compound 4a could be easily prepared in high yields.
compounds exhibited excellent insecticidal activities against T.
cinnabarinus, which showed some differences in activities com-
pared with anthranilic diamides analogs. Further studies on the
structural optimizations and the special activities of the title
compounds are in progress.
Acknowledgments
This work was financial supported by National Basic Research
Program of China (973 Program, No. 2010CB126100), National
High Technology Research and Development Program of China
(863 Program, No. 2011AA10A207). This work was also partly
supported by National Key Technology R&D Program of China (No.
2011BAE06B01).
3.2. Insecticidal activities
Appendix A. Supplementary data
To evaluate the overall insecticidal activities of anthranilic
diamides with benzyl sulfide, two representative insects from two
different orders (Lepidoptera and Acarina) were selected as the
target pest. The testing results against two insects were listed in
Table 1. For comparative purposes, avermectins as control was also
tested under the same conditions.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.04.047.
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4. Conclusion
In conclusion, a series of novel anthranilic diamides derivatives,
which altered N-pyridylpyrazole moiety and endowed with benzyl
sulfide scaffold, were designed and synthesized in this study.
The insecticidal activities of the title compounds against army-
worm (M. sepatara) at 500 mg/L were evaluated; activities were
significantly influenced by the substituents. In particular, the
preliminary bioassays indicated that one-third of the synthesized
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