Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings

Article abstract of DOI:10.1039/c3ob40345a

A series of anthranilic diamides analogs (3-11, 16-24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by ¹H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1, 2,4-oxadiazol-5-yl)-

Full text of DOI:10.1039/c3ob40345a

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Synthesis, insecticidal activity, and structure-activity relationship
(SAR) of anthranilic diamides analogous containing oxadiazole
ring
Yuhao Li,a Hongjun Zhu,a,* Kai Chen,a Rui Liu,a Abdalla Khallaf,a Xiangning Zhangb and
Jueping Nib
a Department of Applied Chemistry, College of Science, Nanjing University of Technology, Nanjing 210009, P R
China. Fax: 86 25 83587443; Tel: 86 25 83172358; Eꢀmail: zhuhjnjut@hotmail.com
b Jiangsu Pesticide Research Institute Co Ltd., Nanjing 210047, P R China.
† Electronic Supplementary Information (ESI) available: [General synthetic methods and schemes for intermediates 1aꢀ
1
1c and amidoximes M1-M7, crystal and structure refinement data of compound 18, and H NMR spectra for all target
compounds 3-24.]. See DOI: 10.1039/b000000x/
A series of anthranilic diamides analogous (3ꢀ11, 16ꢀ24) containing 1,2,4ꢀ or 1,3,4ꢀoxadiazole ring were synthesized
and characterized by 1H NMR and mass spectroscopy. The structure of 3ꢀbromoꢀNꢀ(2ꢀ(3ꢀ(4ꢀbromophenyl)ꢀ1,2,4ꢀ
oxadiazolꢀ5ꢀyl)ꢀ4ꢀchloroꢀ6ꢀmethylphenyl)ꢀ1ꢀ(3ꢀchloropyridinꢀ2ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxamide (18, CCDCꢀ924454)
was determined by Xꢀray diffraction crystallography. The insecticidal activities against Plutella xylostella and
Spodoptera exigua were evaluated. The results showed that most of title compounds presented good larvicidal activities
against P. xylostella, especially compound 3ꢀbromoꢀNꢀ(4ꢀchloroꢀ2ꢀmethylꢀ6ꢀ(5ꢀ(methylthio)ꢀ1,3,4ꢀoxadiazolꢀ2ꢀ
yl)phenyl)ꢀ1ꢀ(3ꢀchloropyridinꢀ2ꢀyl)ꢀ1Hꢀpyrazoleꢀ5ꢀcarboxamide (6) presented 71.43% activity against P. xylostella at
0.4 ꢀg mLꢀ1 and 33.33% against S. exigua at 1 ꢀg mLꢀ1. The structureꢀactivity relationship showed that compounds
decorated 1,3,4ꢀoxadiazole were more potent than compounds decorated 1,2,4ꢀoxadiazole, and different substitutes
attached on oxadiazole ring also affected the insecticidal activity. This work provided some hints for the further
structure modification and the enhancement of insecticidal activity.
Introduction
With the increase of food demands, a safe and efficient way to protect large monocultures in modern agriculture is
required indeed.1,2 The discovery of highly effective and selective pesticides is still one of the most crucial tools for
preventing disease transmission and pest management. Luckly, a new pathway to antiꢀinsect damage was found, which
is ryanodine receptor (RyR), a new biochemical target of nonꢀvoltageꢀgated calcium channel.3 This target has been
found to affect calcium ion uncontrolled release by locking channels in a partially opened state, which leads to a series
of poisoning symptoms like rapid feeding cessation, regurgitation, lethargy and contractile paralysis on lepidopteran
larvae.4ꢀ6 Since the first pyridine dicarboxamide chemical structure was found in 1993, the study of RyRs chemical
analogs has attracted more and more interest in this field.7ꢀ9
Flubendiamide (Fig. 1) belongs to the first generation of phthalic amide chemical structure, which was commercialized
in 2007.10 Chlorantraniliprole (RynaxypyrTM) and cyantraniliprole (CyazypyrTM) (Fig. 1) were developed as the second

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generation of commercialized anthranilic diamides structure later.11,12 All of these showed higher activities and lower
toxicities. Following, the large number of phthalic amide and anthranilic diamides structural modification have
emerged during past decade.13,14 However, few literatures showed the structureꢀinsecticidal activity relationships of
these compounds.15 Generally, the chemical structure of anthranilic diamides could be characterized by three parts (Fig.
2): aromatic bridge moiety (A), Nꢀpyridylpyrazole amide moiety (B) and aliphatic amide moiety (C).13 The most
successful example of bridge moiety (A) modification is cyantraniliprole, which shows higher insecticidal activities
than chlorantraniliprole.12 For the Nꢀpyridylpyrazole amide moiety (B), previous work indicated that it is a key
pharmacophore in this kind of compounds and changing heterocycles or substituents would decrease the larvicidal
activities.16 As to aliphatic amide moiety (C), most modifications kept carbonyl group and replaced acid amide group
by ester group, hydrazide group and etc.17
To prevent the resistance problem and find more high efficient pesticides, it is really necessary to develop new
structures of anthranilic diamides. Because of oxadiazole rings contain N and O atoms, which qualified high biological
activities and have been widely used in pesticide and medicine fields.18, 19 According to the bioisosteric relationship, the
aliphatic amide part (C) of anthranilic diamides could be hided in oxadiazole ring (Fig. 3), which means attached an oꢀ
heterocyclic phynylformamide structure not only keep the aliphatic amide part, but also introduce a high activity
heterocycle in the structure. Taking all these into account, we successfully designed and synthesized a series of oꢀ
heterocyclic phynylformamide derivatives which contain 1,2,4ꢀoxadiazole or 1,3,4ꢀoxadiazole ring (Fig. 3). The single
crystal structure of one target compound has been verified, which could stimulate a better understanding of the binding
nature of these compounds, and help to explore new structures to enhance their biological activities. Furthermore, the
larvicidal activities against Plutella xylostella (P. xylostella) and Spodoptera exigua (S. exigua) were tested accordingly,
and their preliminary structureꢀactivity relationships were also discussed.
Results and discussion
Synthesis
General synthetic routes for final compounds 3ꢀ11 and 16ꢀ24 were shown in Scheme 1 and Scheme 2. For synthesis of
compounds 3ꢀ9, the key intermediates 2b and 2c were afforded by 1b or 1c reacted with 85% hydrazine hydrate.
Following the ringꢀopening reaction, target compound 3 was obtained by 2b reacted with triphosgene under reflux
temperature and formed a 1,3,4ꢀoxadiazole ring with hydroxyl group. Compounds 4 or 5 can be prepared via 2b or 2c
reacted with carbon bisulfide with high yield and afford 1,3,4ꢀoxadiazole ring with hydrosulfide group. Further,
compound 4 or 5 and alkylating agent reacted at room temperature (r.t.) to afford compounds 6ꢀ9. In order to obtain
alkyl directly substituted 1,3,4ꢀoxadiazole ring, acethydrazide was allowed to react with 1a or 1b directly, which
suffered ringꢀopening and dehydration reaction in one pot, and afforded compounds 10 and 11 under the existence of
N,N’ꢀdimethyl formamide (DMF).
The desired compounds 16ꢀ24 can be prepared by two routes. One is via ringꢀopening reaction of compound 1b or 1c
with different Nꢀhydroxyamidines and a ringꢀclosing reaction in two separate steps. The other one is 1b or 1c directly
reacted with substituted Nꢀhydroxyamidines, while DMF was used as solvent, to afford final products in one step. In
this work, we followed the literature method20 (react at r.t, chloroform (CHCl3) as solvent), the obtained products were
not acid amide structure 25 (Scheme 2), but compounds 12ꢀ15 were separated. In principle, substituted Nꢀ
hydroxyamidine has two reactive groups (ꢀNH2 and ꢀOH), both of them could be reacted with 1 and formed ester or
acid amide structure. After characterizing 12ꢀ15 by 1H NMR (at 500 MHz in DMSOꢀd6 δ 6.88ꢀ6.97 (s, 2H, NH2)) and
comparing with substituted Nꢀhydroxyamidine 1H NMR (at 500 MHz in DMSOꢀd6 δ 8.64ꢀ9.70 (s, 1H, OH), 5.32ꢀ6.01

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(s, 2H, NH2)), the products were identified as esters. When the temperature was changed to reflux temperature, the
desired products 16ꢀ24 contained 1,2,4ꢀoxadiazole ring were formed in low yield. After extending the reaction time
from 30 h to 48 h, the conversion ratio was enhanced about 5% and the total yield is about 50%, which indicated a low
conversion ratio. However, using DMF as solvent instead of CHCl3, the reaction suffered a significant change and
1,2,4ꢀoxadiazole ring was formed, yields could reach up to 58ꢀ71%. When enhanced reaction temperature and
prolonged the reaction time, yields could not be observed obvious change. In addition, some compounds made from the
oneꢀpot method led to low yields, because most of starting materials did not react, although different conditions have
been attempted. For optimizing reaction conditions, Nꢀhydroxyꢀ2ꢀmethyl benzimidamide or Nꢀhydroxyꢀ4ꢀbromo
benzimidamide reacted with 1b were selected as a mode, and yields were listed in Table 1.
Structure
The structures of all synthesized title compounds were confirmed by 1H NMR, MS and elemental analysis. The single
1
peak appears at the lowest field of 10.64ꢀ9.95 ppm in the H NMR can be assigned to aromatic amide hydrogen (Phꢀ
NHꢀC=O) of target compounds. In addition, the crystal structure of 18 was determined by the single crystal Xꢀray
diffraction, which belongs to triclinic system, Pꢁ1 space group with unit cell parameters: a = 9.2290 (18) Å, b =
11.1420 (2) Å, c = 12.5260 (3) Å, α = 76.53 (3)°, β = 80.97 (3)° and γ = 86.17 (3)°. The detailed crystallographic data
for 18 can be found in the supporting information (Table S1).
The single crystal structure and packing diagram of 18 are shown in Fig. 4 and Fig. 5. The bridge benzene ring (C10 to
C15) and the terminal benzene ring (C19 to C24) were connected with 1,2,4ꢀoxadiazole ring, which twisted 3.91o and
5.28o respectively and three rings almost located in the same plane. This is consistent with the similar twist angles
reported in the literature.21 On the contrary, the pyrazole ring (C6/C7/C8/N1/N3) makes a dihedral angle of 68.99 o with
bridge benzene ring (C10 to C15) and 85.39 o with terminal pyridine ring (C1/C2/C3/C4/N1/C6). It is obvious that
three rings exist in different planes which is in line with the similar structure in the literature.13 The intramolecular
hydrogen bonds CꢀH...N, NꢀH...N and CꢀH...O resulted in the formation of two planar pseudo rings A
(C16/H16A/N4/C10/C15),
B
(C20/H20A/N5/C18/C19)
and
two
nonꢀplanar
pseudo
rings
C
(N4/H4A/N5/C17/C11/C10), D (C16/H16A/O1/C9/N4/C10/C15), respectively. In the molecular packing of 18,
intermolecular CꢀH…N hydrogen bonds link the molecules stacked along a axis. These crystallographic data could
provide a basis for elucidating the effect on their biological activities.
Biological activities and structure-activity relationships
The results of in vivo larvicidal activities of all compounds against P. xylostella at concentrations of 100 ꢀg mLꢀ1 and
10 ꢀg mLꢀ1 were listed in Table 2. To understand which oxadiazole heterocycle shows better activity, compounds 3ꢀ11
for 1,3,4ꢀoxadiazole and 16ꢀ24 for 1,2,4ꢀoxadiazole were investigated. It is difficult to build the same substituent for
both heterocycles, but it’s still showed that compounds attached 1,3,4ꢀoxadiazole presented a little higher larvicidal
activity trend than compounds attached 1,2,4ꢀoxadiazole. For instance, compounds 16ꢀ18, 24 attached 1,2,4ꢀoxadiazole
showed none larvicidal activity at low concentration, while compounds 3ꢀ11 showed a larvicidal activity at low
concentration more or less.
In order to investigate structureꢀactivity relationship of different groups linked with 1,3,4ꢀoxadiazole moiety and bridge
benzene ring, compounds 3ꢀ11 were substituted by ꢀOH, ꢀSH, ꢀSCH3, ꢀSCH2CH3, ꢀSCH(CH3)2 or ꢀCH3 attached on
1,3,4ꢀoxadiazole ring and ꢀH, ꢀCl, and ꢀBr attached on bridge benzene ring respectively. Although it is hard to construct
a clear structureꢀactivity relationship from the data shown in Table 2, we can also conclude that the general trend in

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larvicidal activity for the substituents on 1,3,4ꢀoxadiazole moiety was ꢀCH3 ≈ ꢀSCH3 > ꢀSH > ꢀOH ≈ ꢀSCH2CH3 ≈ ꢀ
SCH(CH3)2. For example, compound 4 (ꢀSH, 100%) displayed a higher insecticidal activity than compound 3 (ꢀOH,
90%) at 100 ꢀg mLꢀ1. For compounds 6 (ꢀSCH3) and 11 (ꢀCH3) exhibited remarkable 100% mortality at 10 ꢀg mLꢀ1,
while compound 4 (ꢀSH) only has 57.14% mortality at the same concentration. Compounds 3, 7, and 8 even showed
lower insecticidal activities below 15% at 10 ꢀg mLꢀ1. However, substituents on bridge benzene ring showed a clear
trend in larvicidal activity ꢀCl > ꢀBr > ꢀH. Compound 9 (ꢀBr) and 10 (ꢀH) exhibited less than 50% activity at 100 ꢀg
mLꢀ1 and 20% activity at 10 ꢀg mLꢀ1, while compound 11 (ꢀCl) exhibited exciting 100% activity at both 100 and 10 ꢀg
mLꢀ1 dose. Compound 4 (ꢀCl) and 5 (ꢀBr) also showed the same trend at the same concentration.
For investigating the influence of different substitutions on 1,2,4ꢀoxadiazole ring, final products 16ꢀ24 contained
different groups such as ꢀCH3, ꢀCH2Ph, ꢀ(2ꢀCH3)Ph, and etc. According to the concept of aliphatic and aromatic
substituents, compounds 16ꢀ24 could be divide into two types. Compounds 20 and 23 belong to aliphatic substituent
type, and 16-19, 21ꢀ22 and 24 belong to aromatic substituent type, which showed a clear trend that target compounds
contained aliphatic substituents on 1,2,4ꢀoxadiazole ring is significantly more potent than aromatic substituents. For
example, compound 20 (ꢀCH3) showed obvious insecticidal activity of 100% at 100 and 10 ꢀg mLꢀ1, while compounds
16ꢀ18, 21 and 24 showed none activities at 10 ꢀg mLꢀ1. The devitalization of activities at 10 ꢀg mLꢀ1 dose presented
more obviously than 1,3,4ꢀoxadiazole ring contained target compounds. Two couples of compounds 20 (ꢀCl, ꢀCH3) vs
23 (ꢀBr, ꢀCH3), and 18 (ꢀCl, ꢀ(4ꢀBr)Ph) vs 24 (ꢀBr, ꢀ(4ꢀBr)Ph) also confirmed that Cl atom is favorable to enhance
insecticidal activity on bridge benzene ring than Br or H atom.
Since compounds 6, 11 and 20 were the most active compounds which presented 100% larvicidal activities against P.
xylostella at 10 ꢀg mLꢀ1. The results indicate that these compounds displayed comparable larvicidal activities with
reference product i.e. chlorantraniliprole. Therefore, further insecticidal activity assay under lower concentration for 6,
11 and 20 were investigated. As shown in Table 2, it can be found that compound 6 (1,3,4ꢀoxadiazole, ꢀSCH3) still
have 71.43% activity at 0.4 ꢀg mLꢀ1, while chlorantraniliprole preserve 68.89% activity. Compounds 11 (1,3,4ꢀ
oxadiazole, ꢀCH3) and 20 (1,2,4ꢀoxadiazole, ꢀCH3) decreased to 45.45% and 4.76% activity, respectively. Furthermore,
the broad insecticidal activities of compound 6 was investigated against S. exigua. The test results are shown in Table 3.
Compound 6 presented more than 30% insecticidal activities at 1 ꢀg mLꢀ1, which showed the similar level with
chlorantraniliprole. From the study of lower concentration and broad insecticidal activity, it is obvious that the 1,3,4ꢀ
oxadiazole attached compound 6 presented a remarkable and comparable insecticidal activity against P. xylostella and
S. Exigua with commercial product chlorantraniliprole.
Materials and methods
Chemical synthesis
All solvents and reagents were obtained from commercial suppliers and used without further purification. Analytical
thin layer chromatography was performed on silica gel GF254. Silica gel (100ꢀ200 mesh) was used for flash column
chromatography. The melting points were measured on an Xꢀ4 microscope electrothermal apparatus (Taike China) and
were uncorrected. The 1H NMR spectra was recorded in CDCl3 or DMSOꢀd6 solvent on a Bruker AV 300, AV 500 or
Varian 400 NMR spectrophotometer with TMS as the internal standard. Mass spectra were recorded with an Agilent
1100 Series LC/MSD Trap SL. Elemental analysis were performed on a Vario EL III elemental analysis instrument and
the results were within 0.5% of the calculated value. Xꢀray intensity data were recorded on a Nonius CAD4 single
crystal diffraction. The synthetic procedures and detailed characterization data of intermediates 1aꢀ1c and different
amidoximes can be found in supporting information.

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General procedure for the synthesis of compounds 2b and 2c.16 A mixture of 1b or 1c (44 mmol), 85% hydrazine
monohydrate (120 mmol) and DMF (200 mL) were stirred at r.t. for 15 min. Then the mixture was poured into 800 mL
H2O to afford white solid and filtered. The resulting filter cake was washed with 200 mL H2O again and dissolved in
ethyl acetate, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain
corresponding product.
2-(((3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl)carbonyl)amino)-3-methyl-5-chloro-benzoicacid
hydrazide (2b). Yield 92.0%; mp 212ꢀ214 oC; 1H NMR (400 MHz, DMSOꢀd6) δ 10.21 (s, 1H, PhꢀNHꢀC=O), 9.49 (s,
1H, NHNH2), 8.45 (dd, J1 = 4.7 Hz, J2 = 1.5 Hz, 1H, PyꢀH), 8.12 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H, PyꢀH), 7.56 (dd, J1
= 8.1 Hz, J2 =4.7 Hz, 1H, PyꢀH), 7.43 (d, J = 1.9 Hz, 1H, ArꢀH), 7.34 (s, 1H, CHCBr), 7.26 (d, J = 2.3 Hz, 1H, ArꢀH),
4.32 (s, 2H, NHNH2), 2.10 (s, 3H, PhꢀCH3). MS m/z calcd for C17H13BrCl2N6O2 (M+H)+ 483.0, (M+H+2)+ 485.0.
Found (M+H)+ 483.1, (M+H+2)+ 485.1.
2-(((3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl)carbonyl)amino)-3-methyl-5-bromo-benzoicacid
o
hydrazide (2c). Yield 86.0%; mp 215ꢀ218 C; 1H NMR (300 MHz, DMSOꢀd6) δ 10.29 (s, 1H, PhꢀNHꢀC=O), 9.58 (s,
1H, NHNH2), 8.46 (d, J = 4.1 Hz, 1H, PyꢀH), 8.03 (d, J = 8.4 Hz, 1H, PyꢀH), 8.11 (s,1H, ArꢀH), 7.50 (q, J = 8.1 Hz, 1H,
PyꢀH), 7.45 (s, 1H, CHCBr), 7.36 (s, 1H, ArꢀH), 4.28 (s, 2H, NHNH2), 2.19 (s, 3H, PhꢀCH3). MS m/z calcd for
C17H13BrCl2N6O2 (M+H)+ 526.9, (M+H+2)+ 528.9. Found (M+H)+ 526.9, (M+H+2)+ 528.9.
3-bromo-N-(4-chloro-2-methyl-6-(5-hydroxy-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-
5-carboxamide (3).22 A mixture of compound 2b (2.07 mmol) and triphosgene (2.68 mmol) in toluene (20 mL) were
stirred and refluxed about 4 h. After removing the solvent, the residue was poured into ice water slowly and stirred for
2 h, filtered and washed the filter cake to pH = 7. The residue was recrystallized with ether to afford white solid. Yield
1
69.3%; mp 221ꢀ224 oC; H NMR (300 MHz, DMSOꢀd6) δ 12.56 (s, 1H, OH), 10.30 (s, 1H, PhꢀNHꢀC=O), 8.44 (s, 1H,
PyꢀH), 8.03 (s, 1H, PyꢀH), 7.36ꢀ7.69 (m, 3H, ArꢀH, PyꢀH), 7.32 (s, 1H, CHCBr), 2.26 (s, 3H, PhꢀCH3). MS m/z calcd
for C18H11BrCl2N6O3 (MꢀH)ꢀ 506.9, (MꢀH+2)ꢀ 508.9. Found (MꢀH)ꢀ 507.0, (MꢀH+2)ꢀ 509.0. Anal. calcd C 42.38, H
2.17, N 16.47, found C 41.90, H 2.50, N 16.07.
General procedure for the synthesis of compounds 4 and 5.23 A mixture of 2b or 2c (2 mmol), potassium hydroxide
(0.132 g, 2 mmol, 85%), carbon disulfide (0.52 g, 6.8 mmol) and ethanol (20 mL) were heated under reflux temperature
with stirred until the evolution of hydrogen sulfide ceased (about 8 h). Ethanol was distilled off under reduced pressure
and the residue was dissolved in H2O and then acidified with 10% hydrochloric acid aqua solution. The resulting
precipitate was extracted with ethyl acetate, washed with H2O, dried and removed solvent by reduced pressure. The
residue was purified by column chromatography (silica gel 100ꢀ200 mesh, hexane:ethyl acetate = 2:1, v/v) to afford
target compounds.
3-Bromo-N-(4-chloro-2-(5-mercapto-1,3,4-oxadiazol-2-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-
o
1
pyrazole-5-carboxamide (4). Yield 85.2%; mp 170ꢀ172 C; H NMR (500 MHz, DMSOꢀd6) δ 14.78 (s, 1H, SH),
10.46 (s, 1H, PhꢀNHꢀC=O), 8.49 (dd, 1H, J = 4.7 Hz, PyꢀH), 8.16 (dd, 1H, J = 8.1 Hz, PyꢀH), 7.70 (d, 1H, J = 2.3 Hz,
PhꢀH), 7.68 (d, 1H, J = 2.3 Hz, PhꢀH), 7.61 (q, 1H, J = 8.1 Hz, PyꢀH), 7.37 (s, 1H, CHCBr), 2.22 (s, 3H, PhꢀCH3). MS
m/z calcd for C18H11BrCl2N6O2S (MꢀH)ꢀ 522.9, (MꢀH+2)ꢀ 524.9. Found (MꢀH)ꢀ 523.0, (MꢀH+2)ꢀ 525.0. Anal. calcd C
41.09, H 2.11, N 15.97, found C 41.50, H 2.50, N 16.11.
3-Bromo-N-(4-bromo-2-(5-mercapto-1,3,4-oxadiazol-2-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-
o
1
pyrazole-5-carboxamide (5). Yield 81.9%; mp 245ꢀ248 C; H NMR (300 MHz, DMSOꢀd6) δ 14.80 (s, 1H, SH),
10.35 (s, 1H, PhꢀNHꢀC=O), 8.45 (dd, 1H, J = 4.2 Hz, PyꢀH), 7.95 (dd, 1H, J = 8.0 Hz, PyꢀH), 7.86 (d, 1H, J = 7.8 Hz,
PhꢀH), 7.74 (d, 1H, J = 2.4 Hz, PhꢀH), 7.54 (q, 1H, J = 8.0 Hz, PyꢀH), 7.11 (s, 1H, CHCBr), 2.26 (s, 3H, PhꢀCH3). MS

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m/z calcd for C18H11Br2ClN6O2S (MꢀH)ꢀ 566.9, (MꢀH+2)ꢀ 568.9. Found (MꢀH)ꢀ 567.0, (MꢀH+2)ꢀ 569.0. Anal. calcd C
37.89, H 1.94, N 14.73, found C 37.60, H 2.38, N 14.55.
General procedure for the synthesis of compounds 6ꢀ9.24 A mixture of compound 4 or 5 (1.16 mmol) in methanol
(20 mL) and sodium methoxide (0.096 g, 1.74 mmol, 98%), alkyl iodides (1.39 mmol) were added and stirred at r.t.
about 5 h. After the solvent was removed, 100 mL H2O was added and collected residue by filtration, and then the
residue was washed with 50 mL H2O and dried in vacuum to afford desired products.
3-Bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
o
1
pyrazole-5-carboxamide (6). Yield 84.7%; mp 165ꢀ167 C; H NMR (500 MHz, DMSOꢀd6) δ 10.47 (s, 1H, phꢀNHꢀ
C=O), 8.47 (dd, 1H, J = 4.7 Hz, pyꢀH), 8.16 (dd, 1H, J = 8.1 Hz, pyꢀH), 7.81 (d, 1H, J = 2.4 Hz, PhꢀH), 7.66 (d, 1H, J
= 2.4 Hz, phꢀH), 7.60 (q, 1H, J = 8.1 Hz, pyꢀH), 7.37 (s, 1H, CHCBr), 2.23 (s, 3H, PhꢀCH3), 1.99 (s, 3H, SCH3). MS
m/z calcd for C19H13BrCl2N6O2S (M+H)+ 538.9, (M+H+2)+ 540.9. Found (M+H)+ 539.1, (M+H+2)+ 541.1. Anal. calcd
C 42.24, H 2.43, N 15.56, found C 41.28, H 2.49, N 15.66.
3-Bromo-N-(4-chloro-2-methyl-6-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
o
1
pyrazole-5-carboxamide (7). Yield 82.6%; mp 175ꢀ177 C; H NMR (500 MHz, DMSOꢀd6) δ 10.46 (s, 1H, phꢀNHꢀ
C=O), 8.47 (dd, 1H, J = 4.7 Hz, pyꢀH), 8.15 (dd, 1H, J = 8.1 Hz, pyꢀH), 7.81 (d, 1H, J = 2.5 Hz, PhꢀH), 7.66 (d, 1H, J
= 2.5 Hz, phꢀH), 7.60 (q, 1H, J = 8.1 Hz, pyꢀH), 7.38 (s, 1H, CHCBr), 3.24 (q, J = 14.6 Hz, 2H, SCH2CH3), 2.23 (s, 3H,
PhꢀCH3),1.37 (t, J = 7.3 Hz, 3H, SCH2CH3). MS m/z calcd for C20H15BrCl2N6O2S (M+H)+ 553.0, (M+H+2)+ 555.0.
Found (M+H)+ 553.1, (M+H+2)+ 555.1. Anal. calcd C 43.34, H 2.73, N 15.16, found C 43.80, H 2.60, N 14.90.
3-Bromo-N-(4-chloro-2-methyl-6-(5-(isopropylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
o
1
pyrazole-5-carboxamide (8). Yield 80.0%; mp 230ꢀ232 C; H NMR (300 MHz, DMSOꢀd6) δ 10.31 (s, 1H, PhꢀNHꢀ
C=O), 8.38 (d, 1H, J = 4.0 Hz, PyꢀH), 8.05 (d, 1H, J = 7.9 Hz,), 7.62ꢀ7.88 (m, 2H, ArꢀH), 7.50ꢀ7.45 (m, 1H, PyꢀH),
7.21 (s, 1H, CHCBr), 3.80 (s, 1H, CH(CH3)2), 2.44 (s, 3H, PhꢀCH3), 2.12 (s, 3H, CH(CH3)2), 1.28 (s, 3H, CH(CH3)2).
MS m/z calcd for C21H17BrCl2N6O2S (M+H)+ 567.0, (M+H+2)+ 569.0. Found (M+H)+ 567.2, (M+H+2)+ 569.2. Anal.
calcd C 44.38, H 3.02, N 14.79, found C 44.79, H 3.50, N 14.50.
3-Bromo-N-(4-bromo-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
1
pyrazole-5-carboxamide (9). Yield 79.0%; mp 193ꢀ195 oC; H NMR (300 MHz, CDCl3) δ 9.95 (s, 1H, phꢀNHꢀC=O),
8.45 (d, 1H, J = 4.7 Hz, pyꢀH), 7.85 (m, 2H, PhꢀH, PyꢀH), 7.52 (d, J = 6.0 Hz, 1H, PhꢀH), 7.37 (m, 1H, pyꢀH), 7.19 (s,
1H, CHCBr), 2.81 (s, 3H, SCH3), 2.26 (s, 3H, PhꢀCH3). MS m/z calcd for C19H13BrCl2N6O2S (M+H)+ 582.9,
(M+H+2)+ 584.9. Found (M+H)+ 583.0, (M+H+2)+ 585.0. Anal. calcd C 39.03, H 2.24, N 14.37, found C 39.33, H 2.52,
N 14.11.
General procedure for the synthesis of compounds 10ꢀ11. A mixture of 1a or 1b (4 mmol), acethydrazide (4.2 mmol)
and DMF (20 mL) were stirred at r.t. for 12 h. Then the mixture was poured into 100 mL H2O and filtered to afford
solid. The residue was washed with 50 mL H2O again and dried to afford desired products.
3-Bromo-N-(2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
1
carboxamide (10). Yield 82.0%; mp 258ꢀ260 oC; H NMR (300 MHz, DMSOꢀd6) δ 10.20 (s, 1H, PhꢀNHꢀC=O), 8.56
(d, J = 4.2 Hz, 1H, PyꢀH), 7.95ꢀ8.06 (m, 2H, ArꢀH, PyꢀH), 7.45ꢀ7.58 (m, 2H, ArꢀH), 7.34ꢀ7.41 (m, 1H, PyꢀH), 7.25 (s,
1H, CHCBr), 1.83 (s, 3H, CH3), 1.56 (s, 3H, phꢀCH3). MS m/z calcd for C19H14BrClN6O2 (M+H)+ 473.0, (M+H+2)+
475.0. Found (M+H)+ 472.9, (M+H+2)+ 474.9. Anal. calcd C 48.17, H 2.98, N 17.74, found C 48.37, H 3.40, N 17.99.
3-Bromo-N-(4-chloro-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
1
carboxamide (11). Yield 83.5%; mp 202ꢀ204 oC; H NMR (300 MHz, DMSOꢀd6) δ 10.23 (s, 1H, PhꢀNHꢀC=O), 8.50
(d, J = 6.0 Hz, 1H, PyꢀH), 8.32 (d, J = 6.0 Hz, 1H, PyꢀH), 8.17 (s, 1H, ArꢀH), 7.59 (q, J = 6.0 Hz, 1H, PyꢀH), 7.43 (s,
1H, ArꢀH), 7.37 (s, 1H, CHCBr), 2.15 (s, 3H, CH3), 1.89 (s, 3H, PhꢀCH3). MS m/z calcd for C19H13Br2ClN6O2 (M+H)+

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507.0, (M+H+2)+ 509.0. Found (M+H)+ 507.1, (M+H+2)+ 509.1. Anal. calcd C 44.91, H 2.58, N 13.95, found C 45.22,
H 2.73, N 14.07.
General Procedure for the Synthesis of Compounds 12ꢀ15.24 The mixture of 1b (1.1 mmol) and substituted Nꢀ
hydroxyamidine (1.1 mmol) in chloroform (20 mL) was stirred at r.t. for 15 h. After removal of solvent, petroleum
ether (100 mL) was added into residue, the solid was filtered and collected. The crude product was purified by column
chromatography (silica gel 100ꢀ200 mesh, hexane:ethyl acetate = 1:1, v/v) to afford desired products.
3-Bromo-N-(2-((((amino(phenyl)methylene)amino)oxy)carbonyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-
1
2-yl)-1H-pyrazole-5-carboxamide (12). Yield 48.5%; H NMR (500 MHz, DMSOꢀd6) δ 10.36 (s, 1H, PhꢀNHꢀC=O),
8.48 (dd, J = 4.7 Hz, 1H, PyꢀH), 8.15 (d, J = 7.9 Hz, 1H, PyꢀH), 7.95 (d, J = 2.5 Hz, 1H, ArꢀH), 7.72ꢀ7.74 (m, 2H, Arꢀ
H), 7.64 (d, J = 2.4 Hz, 1H, ArꢀH), 7.59 (q, J = 8.1 Hz, 1H, PyꢀH), 7.51ꢀ7.54 (m, 1H, ArꢀH), 7.47 (t, J = 7.6 Hz, 1H,
ArꢀH), 7.34 (s, 1H, CHCBr), 7.37 (t, J = 3.2 Hz, 1H, ArꢀH), 6.89 (s, 2H, NH2), 2.20 (s, 3H, PhꢀCH3). MS m/z calcd for
C24H17BrCl2N6O3 (MꢀH)ꢀ 585.0, (MꢀH+2)ꢀ 587.0. Found (MꢀH)ꢀ 585.0, (MꢀH+2)ꢀ 587.0. Anal. calcd C 49.00, H 2.91, N
14.29, found C 49.21, H 3.05, N 14.40.
3-Bromo-N-(2-((((amino(2-tolyl)methylene)amino)oxy)carbonyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-
1
yl)-1H-pyrazole-5-carboxamide (13). Yield 70.8%; H NMR (500 MHz, DMSOꢀd6) δ 10.34 (s, 1H, phꢀNHꢀC=O),
8.48 (dd, J = 4.7 Hz, 1H, PyꢀH), 8.15 (dd, J = 8.1 Hz, 1H, PyꢀH), 7.91 (d, J = 2.4 Hz, 1H, ArꢀH), 7.63 (d, J = 2.1 Hz,
1H, ArꢀH), 7.60 (dd, J = 8.1 Hz, 1H, PyꢀH), 7.36ꢀ7.39 (m, 1H, ArꢀH), 7.33 (s, 1H, CHCBr), 7.25ꢀ7.32 (m, 2H, ArꢀH),
7.17ꢀ7.24 (m, 1H, ArꢀH), 6.88 (s, 2H, NH2), 2.34 (s, 3H, PhꢀCH3), 2.20 (s, 3H, PhꢀCH3). MS m/z calcd for
C25H19BrCl2N6O3 (MꢀH)ꢀ 599.0, (MꢀH+2)ꢀ 601.0. Found (MꢀH)ꢀ 598.9, (MꢀH+2)ꢀ 600.9. Anal. calcd C 49.86, H 3.18, N
13.95, found C 50.04, H 3.60, N 13.60.
3-Bromo-N-(2-((((amino(4-bromophenyl)methylene)amino)oxy)carbonyl)-4-chloro-6-methylphenyl)-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (14). Yield 42.2%; 1H NMR (500 MHz, DMSOꢀd6) δ 10.36 (s, 1H,
PhꢀNHꢀC=O), 8.48 (dd, 1H, J = 4.7 Hz, PyꢀH), 8.15 (dd, 1H, J = 8.1 Hz, PyꢀH), 7.95 (d, 1H, J = 2.3 Hz, ArꢀH), 7.69 (s,
4H, ArꢀH), 7.64 (d, 1H, J = 2.1 Hz, ArꢀH), 7.77 (q, 1H, J = 8.1 Hz, pyꢀH), 7.34 (s, 1H, CHCBr), 6.97 (s, 2H, NH2),
2.20 (s, 3H, PhꢀCH3). MS m/z calcd for C24H16Br2Cl2N6O3 (MꢀH)ꢀ 662.9, (MꢀH+2)ꢀ 664.9. Found (MꢀH)ꢀ 662.8, (Mꢀ
H+2)ꢀ 664.8. Anal. calcd C 43.21, H 2.42, N 12.60, found C 43.33, H 2.69, N 12.27.
3-Bromo-N-(2-((((1-amino-2-(4-nitrophenyl)ethylidene)amino)oxy)carbonyl)-4-chloro-6-methylphenyl)-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (15). Yield 48.6%; 1H NMR (300 MHz, DMSOꢀd6) δ 10.29 (s, 1H,
PhꢀNHꢀC=O), 8.49 (dd, J = 4.7 Hz, 1H, PyꢀH), 8.19 (dd, J = 8.7 Hz, 2H, ArꢀH), 8.15 (dd, J = 8.1 Hz, 1H, PyꢀH), 7.83
(d, J = 2.45 Hz, 1H, ArꢀH), 7.58ꢀ7.62 (m, 4H, ArꢀH, PyꢀH), 7.29 (s, 1H, CHCBr), 6.65 (s, 2H, NH2), 3.58 (s, 2H,
CH2Ph), 2.18 (s, 3H, PhꢀCH3). MS m/z calcd for C25H18BrCl2N7O5 (MꢀH)ꢀ 676.9, (MꢀH+2)ꢀ 678.9. Found (MꢀH)ꢀ 676.7,
(MꢀH+2)ꢀ 679.7. Anal. calcd C 46.39, H 2.80, N 15.15, found C 46.55, H 3.11, N 15.00.
General procedure for the Synthesis of Compounds 16ꢀ24. The mixture of 1b or 1c (1.1 mmol) and substituted Nꢀ
hydroxyamidine (1.1 mmol) in DMF (20 mL) was stirred at 50 oC. After 48 h, the mixture was added 100 mL H2O, the
solid was filtered and collected. The residue was purified by column chromatography (silica gel 100ꢀ200 mesh,
hexane:ethyl acetate = 1:1, v/v) to afford target compounds.
3-Bromo-N-(2-(3-benzyl-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
1
carboxamide (16). Yield 21.9%; H NMR (500 MHz, DMSOꢀd6) δ 10.47 (s, 1H, PhꢀNHꢀC=O), 8.42 (dd, 1H, J = 4.7
Hz, PyꢀH) , 8.13 (dd, 1H, J = 8.1 Hz, PyꢀH), 7.98ꢀ7.60 (m, 3H, ArꢀH), 7.57 (q, 1H, J = 8.1 Hz, PyꢀH), 7.47ꢀ7.51 (m, 2H,
ArꢀH), 7.41 (s, 1H, CHCBr), 7.38 (d, 1H, J = 7.5 Hz, ArꢀH), 7.29 (t. 1H, J = 7.6 Hz, ArꢀH), 2.30 (s, 3H, PhꢀCH3). MS
m/z calcd for C24H15BrCl2N6O2 (MꢀH)ꢀ 581.0, (MꢀH+2)ꢀ 583.0. Found (MꢀH)ꢀ 581.0, (MꢀH+2)ꢀ 583.0. Anal. calcd C
50.55, H 2.65, N 14.74, found C 50.75, H 2.90, N 15.07.

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3-Bromo-N-(2-(3-(2-tolyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-
5-carboxamide (17). Yield 58.5%; 1H NMR (500 MHz, DMSOꢀd6) δ 10.58 (s, 1H, PhꢀNHꢀC=O), 8.43 (dd, 1H, J = 4.7
Hz, PyꢀH) , 8.11 (dd, 1H, J = 8.1 Hz, PyꢀH), 8.02 (d, 1H, J = 2.5 Hz, ArꢀH), 7.89 (ds, 1H, J = 7.2 Hz, ArꢀH), 7.78 (d,
1H, J = 2.4 Hz, ArꢀH), 7.57 (q, 1H, J = 8.1 Hz, PyꢀH), 7.47ꢀ7.51 (m, 1H, ArꢀH), 7.44 (s, 1H, CHCBr), 7.42 (d, 1H, J =
7.5 Hz, ArꢀH), 7.33 (t. 1H, J = 7.6 Hz, ArꢀH), 2.50 (s, 3H, PhꢀCH3), 2.29 (s, 3H, PhꢀCH3). MS m/z calcd for
C25H17BrCl2N6O2 (MꢀH)ꢀ 581.0, (MꢀH+2)ꢀ 583.0, Found (MꢀH)ꢀ 580.9, (MꢀH+2)ꢀ 582.9. Anal.(M+H2O) calcd C 49.86,
H 3.18, N 13.95, found C 50.35, H 14.39, N 13.47.
3-Bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole -5-carboxamide (18). Yield 70.9%; 1H NMR (500 MHz, DMSOꢀd6) δ 10.59 (s, 1H, PhꢀNHꢀC=O), 8.42 (dd,
1H, J = 4.7 Hz, PyꢀH), 8.11 (dd, J = 8.1 Hz, 1H, PyꢀH), 8.00 (d, J = 2.4 Hz, 1H, ArꢀH), 7.94 (tt, J = 8.6 Hz, 2H, ArꢀH),
7.76ꢀ7.79 (m, 3H, ArꢀH), 7.57 (q, J = 8.1 Hz, 1H, PyꢀH), 7.43 (s, 1H, CHCBr), 2.29 (s, 3H, PhꢀCH3). MS m/z calcd for
C24H14Br2Cl2N6O2 (MꢀH)ꢀ 644.9, (MꢀH+2)ꢀ 646.9. Found (MꢀH)ꢀ 644.9, (MꢀH+2)ꢀ 646.9. Anal. calcd C 44.41, H 2.17,
N 12.95, found C 44.55, H 2.39, N. 12.80.
3-Bromo-N-(2-(3-(4-nitrobenzyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole -5-carboxamide (19). Yield 61.1%; 1H NMR (300 MHz, DMSOꢀd6) δ 10.28 (s, 1H, PhꢀNHꢀC=O), 8.49 (dd,
J = 4.7 Hz, 1H, PyꢀH), 8.19 (dd, J = 8.7 Hz, 2H, ArꢀH), 8.15 (dd, J = 8.1 Hz, 1H, PyꢀH), 7.83 (d, J = 2.45 Hz, 1H, Arꢀ
H), 7.56ꢀ7.64 (m, 4H, ArꢀH, PyꢀH), 7.28 (s, 1H, CHCBr), 3.57 (s, 2H, CH2Ph), 2.16 (s, 3H, PhꢀCH3). MS m/z calcd for
C25H16BrCl2N7O4 (MꢀH)ꢀ 626.0, (MꢀH+2)ꢀ 628.0. Found (MꢀH)ꢀ 625.9, (MꢀH+2)ꢀ 627.9. Anal. calcd C 47.72, H 2.56,
N 15.58, found C 47.80, H 2.59, N 15.30.
3-Bromo-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide (20). Yield 45.7%; 1H NMR (500 MHz, DMSOꢀd6) δ 10.59 (s, 1H, phꢀNHꢀC=O), 8.47 (dd, 1H, J = 4.7
Hz, PyꢀH), 8.17 (dd, 1H, J = 8.1 Hz, PyꢀH), 7.88 (d, 1H, J = 2.3 Hz, ArꢀH), 7.75 (d, 1H, J = 2.5 Hz, ArꢀH), 7.61 (q, 1H,
J = 8.1 Hz, PyꢀH), 7.36 (s, 1H, CHCBr), 2.50 (s, 3H, CH3), 2.26 (s, 3H, PhꢀCH3). MS m/z calcd for C19H13BrCl2N6O2
(MꢀH)ꢀ 505.0, (MꢀH+2)ꢀ 507.0. Found (MꢀH)ꢀ 505.0, (MꢀH+2)ꢀ 507.0. Anal. calcd C 44.91, H 2.58, N 16.54, found C
45.31, H 2.99, N 16.03.
3-Bromo-N-(2-(3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-
1
1H-pyrazole-5-carboxamide (21). Yield 10.1%; H NMR (300 MHz, DMSOꢀd6) δ 10.64 (s, 1H, PhꢀNHꢀC=O), 8.45
(dd, J = 4.7 Hz, 1H, PyꢀH), 8.13 (dd, J = 8.0 Hz, 1H, PyꢀH), 8.01 (d, J = 2.3 Hz, 1H, ArꢀH), 7.71 ꢀ 7.83 (m, 3H, ArꢀH),
7.59 (q, J = 8.0 Hz, 1H, PyꢀH), 7.44ꢀ7.45 (m, 1H, ArꢀH), 7.37 (s, 1H, CHCBr), 7.01ꢀ7.07 (m, 1H, ArꢀH), 2.29 (s, 3H,
PhꢀCH3). MS m/z calcd for C24H13BrCl2F2N6O2 (M+H)+ 605.0, (M+H+2)+ 607.0. Found (M+H)+ 605.1, (M+H+2)+
607.1. Anal. calcd C 47.55, H 2.16, N 13.86, found C 47.99, H 2.57, N 13.43.
3-Bromo-N-(2-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole -5-carboxamide (22). Yield 38.5%; 1H NMR (500 MHz, DMSOꢀd6) δ 10.61 (s, 1H, PhꢀNHꢀC=O), 9.16 (d, J
= 1.6 Hz, 1H, PyꢀH), 8.80 (dd, J = 4.8 Hz, 1H, PyꢀH), 8.41 (dd, J = 4.7 Hz, 1H, PyꢀH), 8.34 (tt, J = 8.1 Hz, 1H, PyꢀH),
8.12 (dd, J = 8.1 Hz, 1H, PyꢀH), 8.02 (d, J = 2.2 Hz, 1H, ArꢀH), 7.80 (d, J = 2.2 Hz, 1H, ArꢀH), 7.60ꢀ7.63 (q, J = 8.1
Hz, 1H, PyꢀH), 7.58ꢀ7.56 (q, J = 8.1 Hz, 1H, PyꢀH), 7.44 (s, 1H, CHCBr), 2.30 (s, 3H, PhꢀCH3). MS m/z calcd for
C23H14BrCl2N7O2 (MꢀH)ꢀ 568.0, (MꢀH+2)ꢀ 570.0. Found (MꢀH)ꢀ 568.0, (MꢀH+2)ꢀ 570.0. Anal. (M+hexane) calcd C
52.98, H 4.29, N 14.91, found C 53.23, H 4.70, N 14.67.
3-Bromo-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-4-bromo-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-
5-carboxamide (23). Yield 49.3%; 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H, PhꢀNHꢀC=O), 8.46 (d, J = 4.4 Hz, 1H,
PyꢀH), 8.09 (s, 1H, PyꢀH), 7.86 (d, J = 8.2 Hz, 1H, ArꢀH), 7.59 (s, 1H, ArꢀH), 7.41 (m, 1H, PyꢀH), 7.11 (s, 1H,

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CHCBr), 2.53 (s, 3H, CH3), 2.27 (s, 3H, PhꢀCH3). MS m/z calcd for C19H13Br2ClN6O2 (MꢀH)ꢀ 548.9, (MꢀH+2)ꢀ 550.9.
Found (MꢀH)ꢀ 548.7, (MꢀH+2)ꢀ 550.7. Anal. calcd C 41.30, H 2.37, N 15.21, found C 41.55, H 2.50, N 15.11.
3-Bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-bromo-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole -5-carboxamide (24). Yield 56.8%; 1H NMR (300 MHz, DMSOꢀd6) δ 10.60 (s, 1H, PhꢀNHꢀC=O), 8.43 (d, J
= 3.4 Hz, 1H, PyꢀH), 8.09ꢀ8.17 (m, 2H, ArꢀH, PyꢀH), 7.98ꢀ7.88 (m, 3H, ArꢀH, PyꢀH), 7.59ꢀ7.55 (m, 1H, ArꢀH), 7.43 (s,
1H, CHCBr), 2.20 (s, 3H, PhꢀCH3). MS m/z calcd for C24H14Br3ClN6O2 (MꢀH)ꢀ 688.8, (MꢀH+2)ꢀ 692.8. Found (MꢀH)ꢀ
688.7, (MꢀH+2)ꢀ 692.7. Anal. (M+1/2 hexane) calcd C 44.02, H 2.87, N 11.41, found C 44.45, H 3.10, N 11.30.
X-ray diffraction crystallography
A suitable single crystal of compound 18 was obtained by dissolving the compound in ethyl acetate and evaporating the
solvent slowly at r.t. for about 10 d. The diffraction data were collected on a Nonius CAD4 single crystal diffractometer
equipped with a graphiteꢀmono chromated MoKα radiation (λ = 0.71073 Å) by using a ω/2θ scan mode at 296 K. The
crystal structure was solved by the direct method and refined by the fullꢀmatrix leastꢀsquares procedure on F2 using
SHELXLꢀ97 program.25 All nonꢀhydrogen atoms were refined anisotropically, and the hydrogen atoms were
introduced at calculated positions.
Insecticidal activities assay
The larvicidal activities of the title compounds (3ꢀ24) against Plutella xylostella and Spodoptera exigua were evaluated
by dipping method according to the literature procedures.1,26 Cabbage leaf disks (8 cm in diameter) were dipped into a
test solution for 10 sec and airꢀdried on filter paper. The treated diet was released into the petri dish, and twenty thirdꢀ
instar P. xylostella or S. exigua were released into the petri dish. P. xylostella and S. exigua with abnormal symptoms
such as body contraction, feeding cessation or paralysis was included in the number of dead. The P. xylostella affected
by this treatment were assessed for 3 d after the treatment. The S. exigua affected by this treatment were assessed for 5
d after the treatment. The mortality percentage was expressed as the mean of values obtained in three independent
experiments. Chlorantraniliprole was used as a control.
Conclusions
In summary, by comparing two substituted heterocycle groups, a series of new type anthranilic diamides analogous
containing substituted 1,2,4ꢀ or 1,3,4ꢀoxadiazole ring were designed and synthesized. The crystal structure of 18 was
determined by single crystal Xꢀray diffraction analysis. The preliminary bioassays indicated that some of compounds
showed good larvicidal activities against P. xylostella at 100 ꢀg mLꢀ1 and 10 ꢀg mLꢀ1. The structureꢀactivity
relationship (SAR) showed that substituted 1,3,4ꢀoxadiazole compounds presented higher insecticidal activity than
substituted 1,2,4ꢀoxadiazole compounds. The SAR result also showed an enhanced activity trend of different
substituents attached on 1, 3, 4ꢀoxadiazole is ꢀCH3 ≈ ꢀSCH3 > ꢀSH > ꢀOH ≈ ꢀSCH2CH3 ≈ ꢀSCH(CH3)2, and different
substituent on bridge benzene ring is ꢀCl > ꢀBr > ꢀH, respectively. For the modified 1,2,4ꢀoxadiazole target compounds,
aliphatic substituents showed more higher insecticidal activity than aromatic substituents compounds. Compared with
chlorantraniliprole, compound 6 showed the similar insecticidal activity against P. Xylostella at 0.4 ꢀg mLꢀ1 and S.
exigua at 1 ꢀg mLꢀ1. Expecting to find more new types 1,3,4ꢀoxadiazole contained anthranilic diamides analogous,
further structural optimization and larvicidal activity test are under way.

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Acknowledgements
We thank the National key technology R&D program of the Ministry of Science and Technology (2011BAE06A07ꢀ04),
the Technology R&D Program of Jiangsu province (BE2012363), the Postgraduate innovation fund of Jiangsu province
(2010, CX10B_178Z1) for financial support and Jiangsu Pesticide Research Institute Co Ltd for the test of biological
activities.
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26 J. R. Busivine, Recommended Methods for Measurement of Pest Resistance to Pesticides; FAO Plant Production
and Protection Paper 21, Rome, Italy, 1980.

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Table 1. Optimized reaction conditions for preparation of compounds 13 or 17 and 14 or 18.
composition (%)
Time
(h)
T
R3
solvent
CHCl3
(oC)
ester
70.8
38.1
27.5
0
oxadiazole
5.0
2ꢀCH3Ph
15
30
48
15
15
48
15
30
48
15
15
48
30
reflux
reflux
30
19.8
24.5
54.9
55.5
58.5
6.0
DMF
CHCl3
DMF
50
0
50
0
4ꢀBrPh
30
42.2
30.8
22.5
0
reflux
reflux
30
18.9
25.0
66.1
67.0
70.9
50
0
50
0
Table2. Larvicidal activity against P. xylostella of compounds 3ꢀ24.
ring
(oxadiazole)
1,3,4ꢀ
concentration
mortality
3d (%)
90.48
14.29
100.00
57.14
100.00
42.86
100.00
100.00
95.24
80.95
71.43
100.00
5.00
compound
X
R
(ꢀg mLꢀ1)
100
10
Cl
OH
3
Cl
Br
Cl
1,3,4ꢀ
1,3,4ꢀ
1,3,4ꢀ
SH
SH
100
10
100
10
100
10
4
4
5
6
SCH3
1
0.4
100
10
100
10
100
10
100
10
100
10
4
1
100
10
Cl
Cl
Br
H
1,3,4ꢀ
1,3,4ꢀ
1,3,4ꢀ
1,3,4ꢀ
1,3,4ꢀ
SCH2CH3
SCH(CH3)2
SCH3
7
8
100.00
15.00
47.62
4.55
9
CH3
20.00
14.20
100.00
100.00
85.71
45.45
68.18
15.79
100.00
61.90
10
11
Cl
CH3
Cl
Cl
ꢀ
ꢀ
Ph
12
13
2ꢀCH3Ph
100
10

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Cl
Cl
Cl
Cl
Cl
Cl
Cl
ꢀ
4ꢀBrPh
CH2(4ꢀNO2Ph)
Ph
100
10
100
10
100
10
100
10
100
10
100
10
100
10
4
100.00
19.05
100.00
57.89
95.24
0.00
95.24
0.00
85.17
0.00
100.00
47.62
100.00
100.00
61.90
4.76
14
15
16
17
18
19
20
ꢀ
1,2,4ꢀ
1,2,4ꢀ
1,2,4ꢀ
1,2,4ꢀ
1,2,4ꢀ
2ꢀCH3Ph
4ꢀBrPh
CH2(4ꢀNO2Ph)
CH3
1
Cl
Cl
Br
Br
ꢀ
1,2,4ꢀ
1,2,4ꢀ
1,2,4ꢀ
1,2,4ꢀ
ꢀ
2,6ꢀ(F)2Ph
3ꢀPy
100
10
100
10
100
10
100
10
100
10
4
1
0.4
76.19
0.00
21
100.00
19.05
100.00
95.24
57.89
0.00
100.00
100.00
100.00
100.00
68.89
22
CH3
23
24
4ꢀBrPh
ꢀ
chlorantraniliprole
Table 3. Insecticidal activities against S. exigua of compound 6.
100a
40
10
4
1
83.33
100.00
77.78
100.00
66.67
100.00
38.89
ꢀ
33.33
30.00
6
Chlorantraniliprole
a the unit of concentration is ꢀg mLꢀ1
Fig. 1. The chemical structure of flubendiamide, chlorantraniliprole and cyantraniliprole.
Fig. 2. General structure of anthranilic diamides.
Fig. 3. Design strategy of the target compounds.
Fig. 4. A molecule structure of 18.
Fig. 5. A packing plot of 18 viewed along the crystallographic aꢀaxis.
Scheme 1. General synthetic route of compounds 3-11.

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Reagents and conditions: (a) 85% hydrazine hydrate, DMF, 30 min; (b) triphosgene, toluene, reflux, 4 h; (c) CS2, KOH,
EtOH, reflux, 8 h; (d) R1I, NaOH, MeOH, r.t., 5 h; (e) acethydrazide, DMF, r.t., 12 h.
Scheme 2. General synthetic route of compounds 12-24.
Reagents and conditions: (a) CHCl3, r.t., 15 h; (b) DMF, 30 oC, 15 h; (c) DMF, 50 oC, 48 h.

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Scheme 1

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Scheme 2

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Fig. 1
Fig. 2
Fig. 3

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Fig. 4
Fig. 5

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A table of contents:
A series of anthranilic diamides analogous containing substituted 1,2,4ꢀ or 1,3,4ꢀ oxadiazoleꢀring show good
insecticidal activities against P. xylostella and S. exigua
.