Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold

Article abstract of DOI:10.1007/s00706-017-2060-3

Abstract: A new series of 1,3,4-oxadiazole derivatives with a 3-chloropyridin-2-yl-1H-pyrazole moiety was designed, synthesized, and characterized. The results of bioassay against Helicoverpa armigera and Plutella xylostella indicated that some of the synthesized compounds showed remarkable larvicidal activity. In particular, the LC₅₀ values of the most active compounds against P. xylostella were 46.5, 23.9, and 13.9?mg/dm³, and against Helicoverpa armigera were 88.3 and 69.5?mg/dm³, the latter being slightly better than commercial chlorpyrifos (LC₅₀ 103.77?mg/dm³). Preliminary SAR was also discussed. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-017-2060-3

Monatsh Chem
DOI 10.1007/s00706-017-2060-3
ORIGINAL PAPER
Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives
containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold
Yanyan Wang1 Xiumian Lu1 Jun Shi1 Jiahong Xu1 Fenghua Wang1 Xiao Yang1
•
•
•
•
•
•
Gang Yu1 Zhiqian Liu1 Chuanhui Li1 Ali Dai1 Yonghui Zhao2 Jian Wu1
•
•
•
•
•
Received: 22 June 2017 / Accepted: 11 September 2017
Ó Springer-Verlag GmbH Austria 2018
Keywords 1,3,4-Oxadiazole derivatives Á
3-Chloropyridin-2-yl-1H-pyrazole Á Synthesis Á
Larvicidal activity
Abstract A new series of 1,3,4-oxadiazole derivatives with
a 3-chloropyridin-2-yl-1H-pyrazole moiety was designed,
synthesized, and characterized. The results of bioassay
against Helicoverpa armigera and Plutella xylostella indi-
cated that some of the synthesized compounds showed
remarkable larvicidal activity. In particular, the LC50 values
of the most active compounds against P. xylostella were
46.5, 23.9, and 13.9 mg/dm3, and against Helicoverpa
armigera were 88.3 and 69.5 mg/dm3, the latter being
slightly better than commercial chlorpyrifos (LC50
103.77 mg/dm3). Preliminary SAR was also discussed.
Graphical abstract
Introduction
In recent years, because of the continued warming weather
and the resistance of insecticide, the pests in agriculture
have become more and more difficult to prevent and
control, which brought about enormous economic losses
all over the world annually [1]. For example, the dia-
mondback moth (Plutella xylostella) is a seriously harmful
pest in many countries [2] and has caused a significant
loss to oilseed plants and crucifers [3]. Hence, the dis-
covery of novel molecules with excellent insecticidal
activity has been attracting more and more attention in
recent years.
1,3,4-Oxadiazole, a highly active pharmacophore, is
widely used in pesticide design. Many compounds con-
taining such a scaffold with excellent activity have been
reported as insecticides (such as compounds 1–5 in Fig. 1)
[4–14], fungicides [15–17], and herbicides [18–21]. For
example, Liu and co-workers developed a series of
anthranilic diamides analogs containing 1,3,4-oxadiazole
that showed excellent insecticidal activity against P.
xylostella [11]. As well as some insecticidal sarisan ana-
logues with an 1,3,4-oxadiazole scaffold were developed
by Guo et al. [4–6].
Yanyan Wang and Xiumian Lu are Co-first authors.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-2060-3) contains supplementary
material, which is available to authorized users.
& Jian Wu
jwu6@gzu.edu.cn
3-Chloropyridin-2-yl-1H-pyrazole is another important
heterocyclic group and appears in many insecticidal
molecules [22–27], the commercial chlorantraniliprole
[22], cyantraniliprole [23, 24], and SYP-9080 (Fig. 2) [25]
containing this type of scaffold. And in recent years, a large
number of 3-chloropyridin-2-yl-1H-pyrazole derivatives
1
Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Research and
Development Center for Fine Chemicals, Guizhou
University, Guiyang 550025, China
2
Institute for the Control of Agrochemicals, Ministry of
Agriculture, Beijing 100125, China
123

Y. Wang et al.
Fig. 1 The structures of insecticidal molecules containing a structure of 1,3,4-oxadiazole
Fig. 2 The structures of commercial insecticides and insecticidal molecules containing the substructures of 3-chloropyridin-2-yl-1H-pyrazole
with excellent larvicidal activity were reported (such as
compounds 5, 6 in Fig. 1 and compounds 6–10 in Fig. 2)
[9, 10, 25–27]. Most of them are anthranilic diamide
derivatives and shown excellent insecticidal activities
against various pests including diamondback moth, cotton
bollworm, beet armyworm, oriental leafworm moth, etc. in
our previous work [28–33]. A series of diamide derivatives
containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold
and 1,3,4-oxadiazole substructure has been developed;
some of them (such compounds 9 and 10 in Fig. 2) showed
excellent larvicidal activity against not only lepidoptera but
also diptera and homoptera.
Encouraged by above reports and as a continuation of
work on finding potential insecticidal molecule, an attempt
was made in this work by incorporation of the scaffolds of
3-chloropyridin-2-yl-1H-pyrazole and 1,3,4-oxadiazole,
then structural variation by the introduction of different
kinds of moiety via an ether linkage, resulting in 1,3,4-
123

Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-…
oxadiazole derivatives containing a 3-chloropyridin-2-yl-
1H-pyrazole scaffold with good insecticidal activity
(Fig. 3). Structures of the synthesized compounds were
In the 1H NMR spectra, the proton at position 5 of
pyridine ring appeared as a doublet of doublets near
d = 8.45 ppm due to the coupling coefficients from the
protons at positions 3 and 4 of the pyridine; the coupling
constants were 4.6 and 1.5 Hz, respectively. Pyrazole-H
exhibited a singlet near 7.15 ppm. The two protons (–CH2–)
appeared as a singlet near 5.10 ppm; in the 13C NMR of
F-contained compound, because of the coupling coefficient
from F, the carbon was split into multiplet. For instance,
the carbon connected to F resonance frequency is near
d = 155 ppm as a doublet and with the coupling constant
(1JC–F) range from 240 to 250 Hz; and the carbon at ortho
position of fluorine atom was also split into doublet with
coupling constant (2JC–F) ranged from 20 to 26 Hz; for the
compound with a group of trifluoromethyl (–CF3), the
carbon (in –CF3) was split as a quartet, the coupling coef-
ficient ranged from 256 to 275 Hz, as well as the carbon
linked to –CF3 was split into a quartet with 2JF–C was about
31 Hz. The properties, 1H NMR, 13C NMR, 19F NMR, and
HR-MS data of the synthesized compounds 16a to 16ad are
summarized in more detail in the ‘‘Experimental’’.
1
characterized by H NMR, 19F NMR, 13C NMR, and HR-
MS. Results of larvicidal assays indicated that some of
synthesized compounds exhibited good larvicidal activi-
ties. In particular, the compounds 16u, 16v, and 16w
exhibited good larvicidal activities against P. xylostella and
H. armigera; the LC50 values of them against P. xylostella
were 46.5, 23.9, and 13.9 mg/dm3, respectively, and the
LC50 values of compounds 16u, 16v against H. armigera
were 88.3, 69.5 mg/dm3, respectively.
Results and discussion
Synthesis
The synthetic route for the title compounds are depicted in
Scheme 1. First, the key intermediates substituted ethyl
2-phenoxyacetates 13 were easily obtained in good yield
via reactions of ethyl 2-chloroacetate with different sub-
stituted phenols in the present of K2CO3 in solvent of
acetonitrile, which further reacted with hydrazine hydrate
(80%) to yield substituted 2-phenoxyacetohydrazides 14
in [ 90% yields. Subsequent treatment of substituted
2-phenoxyacetohydrazides 14, with 3-bromo-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (15,
prepared according to reported protocols [19, 26, 27]) in
the presence of phosphorus oxychloride at refluxing tem-
perature afforded the title compounds 16 with excellent
yield by employed known protocol [34].
Insecticidal activity
The larvicidal activities of the synthesized compounds
against both H. armigera and P. xylostella were evaluated
using procedures reported previously [29, 30, 33, 35, 36]
and summarized in Tables 1 and 2, respectively.
The results listed in Table 1 revealed that some of the
synthesized compounds showed weak to good larvicidal
activity against H. armigera at the corresponding concen-
tration. For example, the larvicidal activities of compounds
Fig. 3 The design of title compound
123

Y. Wang et al.
16i, 16 s, 16u-16w, 16z, and 16ab were [ 50% at 500 mg/
dm3 and the larvicidal activities of compounds 16u, 16v,
16w, and 16ab were 80.0, 83.3, 66.7, and 70.0%, respec-
tively. Whereas the concentration was 100 mg/dm3, the
mortalities of compounds 16u and 16w were still over
50%. These results indicated that compounds 16u and 16w
showed equivalent activity to that of commercial
chlorpyrifos.
benzene. When R was a hydrogen (16ac), the compound
showed very weak larvicidal activity, and the activity could
be further deceased by introduction of a monosubstitution
group at 4 position of benzene (such as compounds 16a,
16c, 16d, 16n, and 16q), as well as the compounds con-
taining a monosubstitution at 3 position of benzene showed
weak activities (e.g. compounds 16b, 16g, 16o, 16p, and
16q etc.). In addition, the activity was disfavored when
benzene was substituted by two groups at 3 and 5 positions,
as well as decreased by introducing other substituents, such
as 2-fluorine-5-(trifluoromethyl), 3,4-difluorine, and
3-bromine-4-fluorine. However, the activities could be
slightly improved by introducing an appropriate bulky
group at 4 position (16i [ 16c, 16q [ 16ad) or 2 position
(16v [ 16t) of benzene, but a much larger group was not
favored (16i [ 16n). Moreover, the introduction of a
methoxyl (16x) could slightly improve the activity, and the
methylthio (16ab) was much more favored than methoxyl.
Furthermore, the larvicidal activity could be enhanced by
two fluorines at 2 and 4 positions (16u) or three chlorines at
2, 3, and 5 positions (16w) on benzene ring, simultane-
ously. And a compound containing a 4-(2-phenylpropan-2-
yl) (16aa) was found to show moderate larvicidal activity.
As shown in Table 2, some of the synthesized com-
pounds showed no or weak larvicidal activity against P.
xylostella. But several title compounds showed moderate to
good larvicidal activity, for instance, the larvicidal activi-
ties of compounds 16f, 16i, 16k, 16l, 16r, 16s, 16u, 16v,
16w, 16aa, and 16ab at 500 mg/dm3 were 63.3, 80.0, 76.7,
73.3, 83.3, 90.0, 96.7, 100, 100, 63.3, and 93.3%, respec-
tively. And compounds 16u, 16v, 16w showed [ 70%
activities at 100 mg/dm3. In particularly, the activity of
compound 16w was up to 93.3%. When the concentration
decreased to 50 mg/dm3, the activities of compounds 16u,
16v, and 16w were 56.7, 73.3, and 80%, respectively. And
compounds 16v, 16w showed moderated larvicidal activity
at 25 mg/dm3.
The median lethal concentrations (LC50) for parts of the
synthesized compounds were further evaluated by using
previous protocols [33, 35, 36]. For comparison, the LC50
value of chlorpyrifos (a commonly used insecticide) was
also evaluated. The LC50 values given in Table 3 indicated
that the compounds 16r, 16s, 16u, 16v, 16w, 16ab against
P. xylostella were 162.5, 100.6, 46.5, 23.9, 13.9, 69.7 mg/
dm3, respectively. And the LC50 values of compounds 16u,
16v, 16w were 88.3, 69.5, and 190.1 mg/dm3, in particu-
larly, compounds 16u and 16v showed slightly better
activity than commercial chlorpyrifos.
Conclusions
Thirty novel 1,3,4-oxadiazole derivatives containing a
3-chloropyridin-2-yl-1H-pyrazole scaffold (16a–16ad)
were designed and synthesized based on combination of
the sub-structures of chlorantraniliprole and 1,3,4-oxadia-
zole. The structures of these compounds were characterized
and confirmed by 1H NMR, 19F NMR, 13C NMR, HR-MS.
A preliminary evaluation of the larvicidal activities of the
synthesized compounds against both H. armigera and P.
As revealed by data in Tables 1 and 2, the larvicidal
activity of the title compound was affected by R group on
123

Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-…
Table 1 Larvicidal activity of compounds 16a–16ad against H. armigera
Comp.
Insecticidal activity/% at different concentrations/mg dm-3
500
200
100
50
25
16a
0.0
–
–
–
–
16b
0.0
–
–
–
–
16c
0.0
–
–
–
–
16e
16.7
33.3
0.0
–
–
–
–
16f
5.6
–
–
–
–
16g
–
–
–
16h
0.0
–
–
–
–
16i
50.0
0.0
27.8
–
22.2
–
–
–
16j
–
–
16k
37.5
33.3
0.0
11.1
5.6
–
5.6
–
–
–
16l
–
–
16m
–
–
–
16n
0.0
–
–
–
–
16o
0.0
–
–
–
–
16p
0.0
–
–
–
–
16q
4.2
–
–
–
–
16r
41.7
50.0
0.0
16.7
27.8
–
11.1
22.2
–
–
–
16s
6.7
–
–
16t
–
16u
80.0
83.3
66.7
8.3
66.7
72.2
50.0
–
50.0
56.7
30.0
–
30.0
40.0
20
–
16.7
23.3
6.7
–
16v
16w
16x
16y
16.7
54.2
33.3
70.0
4.2
–
–
16z
33.3
5.6
56.7
–
27.8
0.0
40.0
–
6.7
–
16aa
–
16ab
23.3
–
6.7
–
16ac
16ad
0.0
–
–
–
–
Chlorantraniliprole
Chlorpyrifos
Avermectins
100
100
100
100
83.3
100
100
66.7
100
100
36.7
100
100
20
100
xylostella was conducted. The results indicated that some
of the synthesized compounds exhibited good larvicidal
activity against the tested pests. In particular, the LC50
values of compounds 16r, 16s, 16u, 16v, 16w, and 16ab
against P. xylostella were 162.5, 100.6, 46.5, 23.9, 13.9,
and 69.7 mg/dm3, respectively. And the LC50 values of
compounds 16u, 16v, and 16w against H. armigera were
88.3, 69.5, and 190.1 mg/dm3, respectively. Compounds
16u and 16v showed slightly better activity against H.
armigera than commercial chlorpyrifos (LC50 103.77 mg/
dm3). Preliminary SAR study revealed that an appropriate
bulky group at 4 position or 2 position of benzene can
slightly improve the activities, and the larvicidal activity
could be enhanced by 2,4-difluorine and 2,3,5-trichlorine
on benzene ring. Further structural modifications and bio-
logical evaluation to explore the full potential of this kind
of 1,3,4-oxadiazole derivatives containing a 3-chloropy-
ridin-2-yl-1H-pyrazole scaffold are currently in progress in
our laboratory.
Experimental
All chemical reagents were of analytical grade and pur-
chased from Accela ChemBio Co., Ltd. (Shanghai, China).
Melting points were determined using a XT-4 melt point
123

Y. Wang et al.
Table 2 Larvicidal activity of compounds 16a–16ad against P. xylostella
Comp.
Insecticidal activity/% at different concentrations/mg dm-3
500
200
100
50
25
16a
20.0
20.0
16.7
30
–
–
–
–
–
–
–
–
–
–
16b
–
16c
3.3
16d
16e
16.7
63.3
0.0
0
–
–
–
16f
30
6.7
–
–
–
16g
–
–
–
16h
0.0
–
–
–
–
16i
80.0
0.0
57.8
–
42.2
–
–
–
16j
–
–
16k
76.7
73.3
13.3
0.0
53.3
25.6
–
36.7
6.7
–
26.7
–
3.3
–
16l
16m
–
–
16n
–
–
–
–
16o
3.3
–
–
–
–
16p
0.0
–
–
–
–
16q
4.2
0.0
56.7
70.0
–
0.0
33.3
43.3
–
–
–
16r
83.3
90.0
6.7
20.0
30
–
3.3
16.7
–
16s
16t
16u
96.7
100
100
28.3
56.7
50.0
63.3
93.3
14.2
25.0
100
100
86.7
96.7
100
13.3
30.0
33.3
35.6
76.7
4.0
6.7
100
100
70.0
86.7
93.3
–
56.7
73.3
80
–
30
56.7
67.7
–
16v
16w
16x
16y
6.7
27.8
20.0
60.0
1.0
–
16z
16aa
6.7
40
–
16ab
23.3
–
16ac
16ad
–
–
Chlorpyrifos
Chlorantraniliprole
100
100
90
100
83
100
1
(1.2 mmol) in acetonitrile was stirred in refluxing for 2 h
(the course of the reactions was monitored by TLC), then
filtered, and the mother liquid was evaporated in vacuo to
afford corresponding substituted ethyl 2-phenoxyacetates,
which were then reacted with hydrazine hydrate (80%) to
yield substituted 2-phenoxyacetohydrazides 14 in [ 90%
yield.
instrument (Beijing Tech Instrument Co., China). H and
13C NMR were gauged on an AVANCE III HD 400 M
NMR (Bruker corporation, Switzerland) or JEOL ECX 500
NMR spectrometer (JEOL Ltd., Japan) operating at room
temperature using DMSO-d6 or CDCl3 as solvents. HR-MS
was collected on an Orbitrap LC–MS instrument (Q-Exa-
tive, Thermo ScientificTM, American). The course of the
reactions was monitored by TLC.
General procedure for the synthesis of title compounds
16a–16ad
Different fresh substituted 2-phenoxyacetohydrazides 14
General procedure for intermediates 14
Intermediates 14 were prepared by following the known
procedure [22, 29, 30]. The mixture of ethyl 2-chloroac-
etate (1 mmol), substituted phenols (1 mmol), and K2CO3
(0.5 mmol),
3-bromo-1-(3-chloropyridin-2-yl)-1H-pyra-
zole-5-carboxylic acid (0.5 mmol), and phosphorus
123

Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-…
Table 3 IC50 values of parts of the title compounds and chlorpyrifos against P. xylostella and H. armigera
Insects
Comp.
IC50/mg dm-3
y = a ? bx
r
P. xylostella
16r
162.5
100.6
46.5
y = 0.4463 ? 2.0598x
y = 1.5190 ? 1.7383x
y = 2.05354 ? 1.7674x
y = 2.3172 ? 1.94551x
y = 3.0665 ? 1.6907x
y = 1.8632 ? 1.7020x
y = 3.730 ? 1.44x
0.99
0.99
0.99
0.99
0.99
0.99
0.98
0.98
0.98
0.97
0.98
16s
16u
16v
23.9
16w
13.9
16ab
Chlorpyrifos
16u
69.7
7.6
H. armigera
88.3
y = 2.802 ? 1.130x
y = 2.787 ? 1.202x
y = 2.722 ? 1.000x
y = 2.228 ? 1.375x
16v
69.5
16w
190.1
103.77
Chlorpyrifos
oxychloride (3 cm3) were added to a flask. The resulting
mixture was stirred for 120 min at refluxing temperature;
the resulting mixture was poured into crushed ice, neutral-
ized with 10% NaOH, and then filtered and recrystallized
from ethanol in good yield.
128.24, 123.29 (q, J = 272.6 Hz), 119.74, 119.04, 119.01,
112.91, 112.11, 112.08, 60.19, 40.53, 40.36, 40.19, 40.03,
39.86, 39.69, 39.53 ppm; HR-MS (ESI?): m/z calcd for
C18H10BrClF3N5O2
499.97275.
([M?H]?)
499.97313,
found
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(4-chlorophenoxy)methyl]-1,3,4-oxadiazole
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(4-fluorophenoxy)methyl]-1,3,4-oxadiazole
(16a, C17H10BrCl2N5O2)
(16c, C17H10BrClFN5O2)
Yield 78.2%; white solid; m.p.: 82–83 °C; 1H NMR
(500 MHz, CDCl3): d = 8.44 (dd, 3J = 4.6 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.90 (dd, 3J = 8.1 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.46 (dd, 3J = 8.1 Hz,
4J = 4.6 Hz, 1H, pyridine-H), 7.26 (d, J = 7.0 Hz, 2H,
benzene-H), 7.11 (s, 1H, pyrazole-H), 6.87 (d, J = 7.0 Hz,
2H, benzene-H), 5.20 (s, 2H, –CH2–) ppm; 13C NMR
(126 MHz, CDCl3): d = 162.16, 156.59, 155.95, 147.86,
147.31, 139.71, 129.92, 129.78, 129.45, 128.99, 127.54,
126.66, 116.20, 112.58, 59.90 ppm; HR-MS (ESI?): m/
z calcd for C17H10BrCl2N5O2 ([M?H]?) 465.94677, found
465.94672.
Yield 78.2%; white solid; m.p.: 85–87 °C; 1H NMR
(500 MHz, CDCl3): d = 8.45 (dd, 3J = 4.7 Hz,
4J = 1.6 Hz, 1H), 7.90 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz,
1H), 7.44 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H), 7.11 (s, 1H,
pyrazole-H), 7.00-6.95 (m, 2H, benzene-H), 6.91-6.87 (m,
2H, benzene-H), 5.19 (s, 2H, –CH2–) ppm; 19F NMR
(471 MHz, CDCl3): d = -121.29 ppm; 13C NMR
(126 MHz,
CDCl3):
d = 162.33,
159.18,
(d,
J = 240.8 Hz), 156.56, 153.50, 147.91, 147.31, 139.68,
129.97, 129.72 (d, J = 63.9 Hz), 128.96, 126.62, 116.42,
116.29, 116.23, 112.52, 60.42 ppm; HR-MS (ESI?): m/
z calcd for C17H10BrClFN5O2 ([M?H]?) 499.97632, found
499.97635.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(3-(trifluoromethyl)phenoxy]methyl)-1,3,4-oxadiazole
(16b, C18H10BrClF3N5O2)
4-[[5-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-
yl]-1,3,4-oxadiazol-2-yl]methoxy]benzonitrile
Yield 78.2%; white solid; m.p.: 97–98 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.51 (dd, 3J = 4.7 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 8.25 (dd, 3J = 8.1 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 7.69 (dd, 3J = 8.1 Hz,
(16d, C18H10BrClN6O2)
Yield 78.2%; white solid; m.p.: 88–90 °C; 1H NMR
(400 MHz, CDCl3): d = 8.47 (dd, 3J = 4.7 Hz,
4J = 1.5 Hz, 1H), 7.93 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz,
1H), 7.62 (d, 3J = 8.9 Hz, 2H, benzene-H), 7.47 (dd,
4
4J = 4.7 Hz, 1H, pyridine-H), 7.55 (d, J = 3.3 Hz, 1H,
3
benzene-H), 7.53 (t, J = 8.3 Hz, 1H, benzene-H), 7.36-
4
3J = 8.1 Hz, J = 4.7 Hz, 1H), 7.12 (s, 1H, pyrazole-H),
7.33 (m, 2H, benzene-H ? pyrazole-H), 7.29 (dd,
4
7.05 (d, 3J = 8.9 Hz, 2H, benzene-H) ppm; 13C NMR
(126 MHz, CDCl3): d = 164.60, 162.63, 161.57, 156.66,
147.84, 139.72, 129.84, 129.41, 128.96, 126.70, 112.62,
99.00, 98.77, 98.16, 97.96, 59.92 ppm; HR-MS (ESI?): m/
z calcd for C18H10BrClN6O2 ([M?H]?) 446.98099, found
446.98092.
3J = 8.1 Hz, J = 2.2 Hz, 1H, benzene-H), 5.52 (s, 2H,
–CH2–) ppm; 19F NMR (471 MHz, DMSO-d6):
d = -61.01 ppm; 13C NMR (126 MHz, DMSO-d6):
d = 163.23, 157.91, 156.17, 148.28, 147.49, 140.70,
131.45, 131.06 (q, J = 31.7 Hz), 130.25, 128.88, 128.71,
123

Y. Wang et al.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(2,3-difluorophenoxy)methyl]-1,3,4-oxadiazole
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(5-fluoro-2-methylphenoxy)methyl]-1,3,4-oxadiazole
(16h, C18H12BrClFN5O2)
(16e, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 103–104 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.54 (dd, 3J = 4.6 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 8.26 (dd, 3J = 8.1 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 7.69 (dd, 3J = 8.1 Hz,
4J = 4.6 Hz, 1H, pyridine-H), 7.58–7.51 (m, 1H, ben-
zene-H, pyridine-H), 7.17–6.98 (m, 3H, benzene-H), 5.53
(s, 2H, –CH2–) ppm; 19F NMR (471 MHz, DMSO-d6):
d = -137.60, -159.54 ppm; 13C NMR (126 MHz,
DMSO-d6): d = 162.99, 156.24, 150.97 (dd, J = 245.1,
10.1 Hz), 148.28, 147.47, 140.83 (dd, J = 246.3, 14.6 Hz),
140.71, 130.21, 128.92, 128.70, 124.82 (d, J = 8.8 Hz),
124.78, 112.99, 111.77, 111.74, 111.07 (d, J = 17.2 Hz),
61.20 ppm; HR-MS (ESI?): m/z calcd for C17H9BrClF2-
N5O2 ([M?H]?) 467.96690, found 467.96698.
Yield 78.2%; white solid; m.p.: 95–97 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.49 (dd, 3J = 4.7 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 8.24 (dd, 3J = 8.1 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.68 (dd, 3J = 8.1 Hz,
4J = 4.7 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H),
3
4
7.16 (dd, JF–H = 11.3 Hz, JH–H = 4.0 Hz, 1H, benzene-
3
4
H), 6.95 (dd, JF–H = 11.1 Hz, JH–H = 2.5 Hz, 1H,
3
4
benzene-H), 6.72 (td, JH–H = 8.4 Hz, JH–H = 2.5 Hz,
1H, benzene-H), 5.43 (s, 2H, –CH2–), 2.04 (s, 3H, –CH3)
ppm; 19F NMR (471 MHz, DMSO-d6): d = -114.33 ppm;
13C NMR (126 MHz, DMSO-d6): d = 161.70 (d,
J = 244.2 Hz), 162.22, 156.59, 156.12, 156.04, 147.86,
147.30, 139.71, 131.58, 131.50, 129.98, 129.41, 128.98,
126.66, 122.74, 122.71, 112.57, 108.44 (d, J = 20.7 Hz),
100.08 (d, J = 25.9 Hz), 59.95, 15.64 ppm; HR-MS
(ESI?): m/z calcd for C18H12BrClFN5O2 ([M?H]?)
463.99197, found 463.99213.
4-[[5-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-
yl]-1,3,4-oxadiazol-2-yl]methoxy]-2,6-difluorobenzonitrile
(16f, C18H8BrClF2N6O2)
Yield 78.2%; white solid; m.p.: 76–77 °C; 1H NMR
(500 MHz, CDCl3): d = 8.48 (dd, 3J = 4.5 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.87 (d, 3J = 8.0 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.40 (dd, 3J = 8.0 Hz,
4J = 4.6 Hz, 1H, pyridine-H), 7.07 (s, 1H, pyrazole-H),
6.64 (s, 1H, benzene-H), 6.62 (s, 1H, benzene-H), 4.87 (s,
2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3):
d = -101.86 ppm; 13C NMR (126 MHz, CDCl3):
d = 163.74 (d, J = 247.9 Hz), 163.62 (d, J = 247.9 Hz),
159.04 (t, J = 13.5 Hz), 156.66, 147.84, 147.32, 139.72,
129.84, 129.41, 128.96, 126.70, 115.17, 112.62, 98.98 (d,
J = 7.2 Hz), 98.81 (d, J = 7.2 Hz), 98.37, 98.16, 97.96,
59.92 ppm; HR-MS (ESI?): m/z calcd for C18H8BrClF2-
N6O2 ([M?H]?) 492.96215, found 492.96211.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(4-(trifluoromethyl)phenoxy]methyl)-1,3,4-oxadiazole
(16i, C18H10BrClF3N5O2)
Yield 78.2%; white solid; m.p.: 97–98 °C; 1H NMR
(500 MHz, CDCl3): d = 8.44 (dd, 3J = 4.6 Hz,
4J = 1.3 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.0 Hz,
3
4J = 1.3 Hz, 1H, pyridine-H), 7.56 (d, J = 8.6 Hz, 2H,
benzene-H), 7.42 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H,
pyridine-H), 7.11 (s, 1H, pyrazole-H), 7.02 (d,
3J = 8.6 Hz, 2H, benzene-H), 5.27 (s, 2H, –CH2–) ppm;
19F NMR (471 MHz, CDCl3): d = -61.60 ppm; 13C NMR
(126 MHz, CDCl3): d = 161.84, 159.67, 156.66, 147.86,
147.29, 139.69, 129.86, 129.42, 128.97, 127.34, 127.31,
126.65,
124.68
(q,
J = 32.8 Hz),
124.17 (d,
J = 271.2 Hz), 114.85, 112.61, 59.59 ppm; HR-MS
(ESI?): m/z calcd for C18H10BrClF3N5O2 ([M?H]?)
499.97313, found 499.97339.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(3,5-difluorophenoxy)methyl]-1,3,4-oxadiazole
(16g, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 91–92 °C; 1H NMR
(500 MHz, CDCl3): d = 8.43 (dd, 3J = 4.6 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 7.90 (d, 3J = 8.1 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 7.44 (dd, 3J = 8.1 Hz,
4J = 4.6 Hz, 1H, pyridine-H), 7.10 (s, 1H, pyrazole-H),
6.51–6.39 (m, 3H, benzene-H), 5.18 (s, 2H, –CH2–) ppm;
19F NMR (471 MHz, CDCl3): d = -107.64 ppm; 13C
NMR (126 MHz, CDCl3): d = 163.74 (d, J = 247.9 Hz),
163.62 (d, J = 247.9 Hz), 159.04 (t, J = 13.5 Hz), 156.66,
147.84, 147.32, 139.72, 129.84, 129.41, 128.96, 126.70,
112.62, 98.97 (d, J = 7.2 Hz), 98.80 (d, J = 7.2 Hz),
98.37, 98.16, 97.96, 59.92 ppm; HR-MS (ESI?): m/z calcd
for C17H9BrClF2N5O2 ([M?H]?) 467.96690, found
467.96698.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(3-bromo-4-fluorophenoxy)methyl]-1,3,4-oxadiazole
(16j, C17H9Br2ClFN5O2)
Yield 78.2%; white solid; m.p.: 117–118 °C; 1H NMR
(500 MHz, CDCl3): d = 8.44 (dd, 3J = 4.6 Hz,
4J = 1.5 Hz, 1H), 7.90 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz,
3
4
1H), 7.44 (dd, J = 8.1 Hz, J = 4.6 Hz, 1H), 7.12 (dd,
4
3J = 5.4 Hz, J = 3.1 Hz, 1H), 7.11 (s, 1H, pyrazole-H),
7.03 (t, J = 8.5 Hz, 1H, benzene-H), 6.85 (dt, J = 9.0,
3.4 Hz, 1H, benzene-H), 5.18 (s, 2H, –CH2–) ppm; 13C
NMR (126 MHz, CDCl3): d = 161.87, 156.61, 154.82 (d,
J = 242.2 Hz), 153.68, 147.85, 147.32, 139.71, 129.88,
129.42, 128.97, 126.67, 119.99, 116.98 (d, J = 24.3 Hz),
115.26, 112.60, 109.51 (d, J = 22.9 Hz), 60.42 ppm; HR-
123

Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-…
MS (ESI?): m/z calcd for C17H9Br2ClFN5O2 ([M?H]?)
J = 249.2, 14.0 Hz), 147.84, 147.32, 146.05 (dd,
527.88683, found 527.88596.
J = 242.6, 12.6 Hz), 139.72, 129.89, 129.42, 128.93,
126.72, 117.74, 117.66 (d, J = 18.6 Hz), 112.56, 110.26,
105.15 (d, J = 20.6 Hz), 60.33 ppm; HR-MS (ESI?): m/z
calcd for C17H9BrClF2N5O2 ([M ? H]?) 467.96690, found
467.96674.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[4-fluoro-3-(trifluoromethyl)phenoxy]methyl]-1,3,4-oxa-
diazole (16k, C18H9BrClF4N5O2)
Yield 78.2%; white solid; m.p.: 86–88 °C; 1H NMR
(500 MHz, CDCl3): d = 8.43 (dd, 3J = 4.5 Hz,
4J = 1.7 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.0 Hz,
4J = 1.7 Hz, 1H, pyridine-H), 7.43 (dd, 3J = 8.0 Hz,
4J = 4.6 Hz, 1H, pyridine-H), 7.15 (s, 1H, pyrazole-H),
7.13–7.05 (m, 3H, benzene-H), 5.22 (s, 2H, –CH2–) ppm;
19F NMR (471 MHz, CDCl3): d = -61.50, -122.78 ppm;
13C NMR (126 MHz, CDCl3): d = 161.72, 156.64, 154.87
(d, J = 249.6 Hz), 153.07, 147.83, 147.32, 139.73, 129.84,
129.42, 128.95, 126.73, 122.16 (q, J = 271.2 Hz), 119.18
(dq, J = 33.3, 14.3 Hz) 119.10, 118.22 (d, J = 22.5 Hz),
113.80, 112.57, 60.37 ppm; HR-MS (ESI?): m/z calcd for
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[4-(trifluoromethoxy)phenoxy]methyl]-1,3,4-oxadiazole
(16n, C18H10BrClF3N5O3)
Yield 78.2%; white solid; m.p.: 62–64 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.51 (dd, 3J = 4.6 Hz,
4J = 1.4 Hz, 1H, pyridine-H), 8.27 (dd, 3J = 8.1 Hz,
4J = 1.3 Hz, 1H, pyridine-H), 7.71 (dd, 3J = 8.1 Hz,
4J = 4.8 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H),
7.30 (d, 3J = 9.0 Hz, 2H, benzene-H), 7.08 (d,
3J = 9.1 Hz, 2H, benzene-H), 5.43 (s, 2H) ppm; 19F
NMR (471 MHz, CDCl3): d = -58.18 ppm; 13C NMR
(126 MHz, CDCl3): d = 162.12, 156.57, 155.80, 147.84,
147.30, 143.92, 139.70, 129.94, 129.39, 128.93, 126.69,
122.76, 120.56 (q, J = 256.5 Hz), 115.85, 112.54,
60.00 ppm; HR-MS (ESI?): m/z calcd for C18H10BrClF3-
N5O3 ([M?H]?) 515.96804, found 515.96674.
C18H9BrClF4N5O2
517.96412.
([M?H]?)
517.96371,
found
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(2-chloro-4-fluorophenoxy)methyl]-1,3,4-oxadiazole
(16l, C17H9BrCl2FN5O2)
Yield 78.2%; white solid; m.p.: 110–112 °C; 1H NMR
(500 MHz, CDCl3): d = 8.46 (dd, 3J = 4.7 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.92 (dd, 3J = 8.1 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.46 (dd, 3J = 8.1 Hz,
4J = 4.7 Hz, 1H, pyridine-H), 7.26 (s, 1H, pyrazole-H),
6.97 (d, J = 4.8 Hz, 1H, benzene-H), 6.91 (d, J = 3.0 Hz,
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(3-fluorophenoxy)methyl]-1,3,4-oxadiazole
(16o, C17H10BrClFN5O2)
Yield 78.2%; white solid; m.p.: 78–79 °C; 1H NMR
(500 MHz, CDCl3): d = 8.40 (dd, 3J = 4.7 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.86 (dd, 3J = 8.0 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.40 (dd, 3J = 8.1 Hz,
4J = 4.8 Hz, 1H, pyridine-H), 7.21 (dd, 3J = 8.3 Hz,
4J = 6.8 Hz, 1H, benzene-H), 7.09 (s, 1H, pyrazole-H),
5.18 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3):
d = -110.37 ppm; 13C NMR (126 MHz, CDCl3):
d = 163.52 (d, J = 246.7 Hz), 162.11, 158.56, 156.55,
147.81, 147.31, 139.7, 130.77, 129.96, 129.36, 128.92,
126.72, 112.56, 110.33, 109.37 (d, J = 21.3 Hz), 103.00
(d, J = 25.2 Hz), 59.79 ppm; HR-MS (ESI?): m/z calcd
for C17H10BrClFN5O2 ([M?H]?) 449.97632, found
449.97424.
3
4
1H, benzene-H), 6.85 (dd, J = 9.1 Hz, J = 4.9 Hz, 2H,
benzene-H) ppm; 19F NMR (471 MHz, CDCl3):
d = -119.23 ppm; 13C NMR (126 MHz, CDCl3):
d = 163.04, 159.02 (d, J = 246.1 Hz), 157.68, 157.60,
156.18, 148.29, 147.48, 140.70, 131.42, 130.23, 128.90,
128.72, 128.26, 112.99 (d, J = 14.1 Hz), 112.53, 104.82
(d, J = 24.6 Hz), 60.46 ppm; HR-MS (ESI?): m/z calcd
for C17H9BrCl2FN5O2 ([M?H]?) 483.93735, found
483.93530.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(3,4-difluorophenoxy)methyl]-1,3,4-oxadiazole
(16m, C17H9BrClF2N5O2)
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(3-chlorophenoxy)methyl]-1,3,4-oxadiazole
Yield 78.2%; white solid; m.p.: 85–86 °C; 1H NMR
(500 MHz, CDCl3): d = 8.42 (dd, 3J = 4.7 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.1 Hz,
4J = 1.5 Hz, 1H), 7.43 (dd, 3J = 8.1 Hz, 4J = 4.9 Hz,
1H), 7.09 (s, 1H, pyrazole-H), 7.04 (dd, JF–H = 18.7 Hz,
JF–H = 9.2 Hz, 1H), 6.76 (ddd, JF–H = 11.4 Hz,
JF–H = 6.4 Hz, JF–H = 2.9 Hz, 1H, benzene-H), 6.67-
6.61 (m, 1H, benzene-H), 5.16 (s, 2H, –CH2–) ppm; 19F
NMR (470 MHz, CDCl3): d = -134.08 (d, J = 21.2 Hz),
-145.50 (d, J = 21.1 Hz) ppm; 13C NMR (126 MHz,
CDCl3): d = 161.91, 156.59, 153.53, 150.51 (dd,
(16p, C17H10BrCl2N5O2)
Yield 78.2%; white solid; m.p.: 98–99 °C; 1H NMR
(500 MHz, CDCl3): d = 8.43 (dd, 3J = 4.7 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.1 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.44 (dd, 3J = 8.1 Hz,
3
4J = 4.7 Hz, 1H, pyridine-H), 7.21 (d, J = 8.2 Hz, 1H,
benzene-H), 7.12 (s, 1H, pyrazole-H), 7.01 (dd,
3J = 8.1 Hz, 4J = 1.9 Hz, 1H, benzene-H), 6.94–6.92
3
(m, 1H, benzene-H), 6.82 (dd, J = 8.3 Hz, J = 2.5 Hz,
4
1H, benzene-H), 5.21 (s, 2H, -CH2-) ppm; 13C NMR
123

Y. Wang et al.
(126 MHz, CDCl3): d = 162.05, 157.98, 156.61, 147.84,
147.32, 139.72, 135.28, 130.69, 129.92, 129.41, 129.00,
126.65, 122.74, 115.64, 112.93, 112.61, 59.75 ppm; HR-
MS (ESI?): m/z calcd for C17H10BrCl2N5O2 ([M?H]?)
465.94677, found 465.94492.
125.25, 124.70, 118.92, 117.82 (d, J = 6.5 Hz), 117.59 (d,
J = 7.9 Hz), 112.65, 111.17, 61.49 ppm; HR-MS (ESI?):
m/z calcd for C17H9BrCl2FN5O2 ([M?H]?) 483.93735,
found 483.93515.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(2-fluorophenoxy)methyl]-1,3,4-oxadiazole
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[4-(tert-butyl)phenoxy]methyl]-1,3,4-oxadiazole
(16t, C17H10BrClFN5O2)
(16q, C21H19BrClN5O2)
Yield 78.2%; white solid; m.p.: 74–75 °C; 1H NMR
(500 MHz, CDCl3): d = 8.39 (dd, 3J = 4.6 Hz,
4J = 1.3 Hz, 1H), 7.86 (dd, 3J = 8.1 Hz, 4J = 1.3 Hz,
1H), 7.40 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H), 7.09 (s, 1H,
pyrazole-H), 7.06-6.92 (m, 4H, benzene-H), 5.24 (s, 2H, –
Yield 78.2%; white solid; m.p.: 53–54 °C; 1H NMR
(500 MHz, CDCl3): d = 8.43 (dd, 3J = 4.7 Hz,
4J = 1.6 Hz, 1H), 7.85 (d, 3J = 8.0 Hz, 4J = 1.6 Hz,
1H), 7.39 (dd, 3J = 8.0 Hz, 4J = 4.7 Hz, 1H), 7.30 (d,
3J = 7.2 Hz, 2H, benzene-H), 7.11 (s, 1H, pyrazole-H),
6.86 (d, J = 7.2 Hz, 2H, benzene-H), 5.18 (s, 2H, –CH2–),
1.28 (s, 9H, –CH3) ppm; 13C NMR (126 MHz, CDCl3):
d = 162.78, 156.46, 155.20, 147.86, 147.33, 145.21,
139.72, 130.13, 129.38, 128.91, 126.72, 126.66, 114.39,
112.49, 77.61, 77.36, 77.10, 59.79, 34.29, 31.61 ppm; HR-
MS (ESI?): m/z calcd for C21H19BrClN5O2 ([M?H]?)
488.04835, found 488.04849.
CH2–)
ppm;
19F
NMR
(471 MHz,
CDCl3):
d = -132.95 ppm; 13C NMR (126 MHz, CDCl3):
d = 162.16, 156.60, 152.93 (d, J = 247.0 Hz), 147.78,
147.33, 145.26 (d, J = 10.7 Hz), 139.73, 130.00, 129.32,
128.92, 126.74, 124.72, 123.57, 116.86 (d, J = 18.1 Hz)
116.54, 112.55, 61.19 ppm; HR-MS (ESI?): m/z calcd for
C17H10BrClFN5O2
449.97446.
([M?H]?)
449.97632,
found
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazole
(16r, C17H9BrCl2FN5O2)
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(2,4-difluorophenoxy)methyl]-1,3,4-oxadiazole
(16u, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 124–126 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.58–8.46 (dd, 1H,
3J = 4.7 Hz, 4J = 1.5 Hz, pyridine-H), 8.32 (dd, 1H,
3J = 7.9, 4J = 1.5 Hz, 1H, pyridine-H), 7.70 (dd,
Yield 78.2%; white solid; m.p.: 93–94 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.51 (dd, 3J = 4.5 Hz,
4J = 1.2 Hz, 1H, pyridine-H), 8.26 (dd, 3J = 8.1 Hz,
4J = 1.3 Hz, 1H, pyridine-H), 7.70 (dd, 3J = 8.1 Hz,
4J = 4.7 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H),
7.33–7.20 (m, 2H, benzene-H), 7.01 (t, J = 8.7 Hz, 1H,
benzene-H), 5.45 (s, 2H, –CH2–) ppm; 19F NMR
(471 MHz, DMSO-d6): d = -117.96, -129.00 ppm; 13C
NMR (126 MHz, DMSO-d6): d = 163.15, 157.08 (dd,
J = 240.8, 10.8 Hz), 156.21, 152.22 (dd, J = 247.9,
12.7 Hz),148.30, 147.48, 142.14 (dd, J = 10.7, 3.3 Hz),
140.71, 130.23, 128.91, 128.71, 128.29, 117.78, 117.77,
117.71, 117.69, 112.94, 111.63 (dd, J = 22.6, 3.9 Hz),
105.70 (dd, J = 27.5, 22.4 Hz), 61.56 ppm; HR-MS
(ESI?): m/z calcd for C17H9BrClF2N5O2 ([M?H]?)
467.96690, found 467.96680.
4
3J = 7.9 Hz, J = 4.7 Hz, 1H, pyridine-H), 7.56 (s, 1H,
pyrazole-H), 7.48 (t, J = 8.8 Hz, 1H, benzene-H), 7.17
(dd, J = 11.2, 2.6 Hz, 1H, benzene-H), 6.87 (d,
J = 8.6 Hz, 1H, benzene-H), 5.45 (s, 2H, –CH2–) ppm;
19F NMR (471 MHz, DMSO-d6): d = -113.29 ppm; 13C
NMR (126 MHz, DMSO-d6): d = 163.04, 159.02 (d,
J = 246.1 Hz), 157.68, 157.60, 156.18, 148.29, 147.48,
140.70, 131.42, 130.23, 128.90, 128.72, 128.26, 112.99 (d,
J = 14.1 Hz), 112.53, 104.82 (d, J = 24.6 Hz),
60.46 ppm; HR-MS (ESI?): m/z calcd for C17H9BrCl2-
FN5O2 ([M?H]?) 483.93735, found 483.93729.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(4-chloro-2-fluorophenoxy)methyl]-1,3,4-oxadiazole
(16s, C17H9BrCl2FN5O2)
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[2-(trifluoromethyl)phenoxy]methyl]-1,3,4-oxadiazole
(16v, C18H10BrClF3N5O2)
Yield 78.2%; white solid; m.p.: 76–77 °C; 1H NMR
(500 MHz, DMSO-d6): d = 8.46 (dd, 3J = 4.6 Hz,
3J = 1.5 Hz, 1H, pyridine-H), 8.23 (dd, 3J = 8.1 Hz,
Yield 78.2%; white solid; m.p.: 83–84 °C; 1H NMR
(500 MHz, CDCl3): d = 8.46 (dd, 3J = 4.7 Hz,
4J = 1.5 Hz, 1H), 7.92 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz,
1H), 7.45 (dd, 3J = 7.8 Hz, 4J = 4.9 Hz, 1H), 7.13 (s, 1H,
pyrazole-H), 7.12 (s, 1H, benzene-H), 7.04 (dt, J = 6.2,
2.0 Hz, 2H, benzene-H), 5.26 (s, 2H, –CH2–) ppm; 19F
NMR (471 MHz, CDCl3): d = -129.45 ppm; 13C NMR
(126 MHz, CDCl3): d = 156.73, 153.80, 152.97 (d,
J = 208.9 Hz), 147.32, 139.71, 129.87, 128.17, 126.65,
4J = 1.5 Hz,
1H,
pyridine-H),
7.70–7.64
(dd,
3J = 8.1 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.61 (t,
J = 7.7 Hz, 2H, benzene-H), 7.50 (s, 1H, benzene-H),
3
7.34 (dd, J = 8.6 Hz, J = 3.1 Hz, 1H, benzene-H), 7.19
4
(s, 1H, pyrazole-H), 5.58 (s, 2H, –CH2–) ppm; 19F NMR
123

Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-…
(471 MHz, DMSO-d6): d = -60.62 ppm; 13C NMR
(126 MHz, DMSO-d6): d = 163.12, 156.21, 155.33,
148.24, 147.39, 140.70, 134.84, 130.21, 128.92, 128.60,
128.23, 127.53, 127.49, 123.95 (q, J = 272.6 Hz),122.35,
118.17 (q, J = 30.6 Hz), 114.91, 112.91, 60.64 ppm; HR-
MS (ESI?): m/z calcd for C18H10BrClF3N5O2 ([M?H]?)
499.97313, found 499.97113.
112.62, 61.33 ppm; HR-MS (ESI?): m/z calcd for C18H9-
BrClF4N5O2 ([M?H]?) 517.96371, found 517.96343.
2-[[3,5-Bis(trifluoromethyl)phenoxy]methyl]-5-[3-bromo-
1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-1,3,4-oxadia-
zole (16z, C19H9BrClF6N5O2)
Yield 78.2%; white solid; m.p.: 73–74 °C; 1H NMR
(500 MHz, CDCl3): d = 8.44 (dd, 3J = 4.7 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.90 (dd, 3J = 8.1 Hz,
4J = 1.5 Hz, 1H, pyridine-H), 7.54 (s, 1H, benzene-H),
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(2,4,6-trichlorophenoxy)methyl]-1,3,4-oxadiazole
(16w, C17H8BrCl4N5O2)
3
4
7.44 (dd, J = 8.1 Hz, J = 4.7 Hz, 1H, pyridine-H), 7.39
Yield 78.2%; white solid; m.p.: 123–124 °C; 1H NMR
(s, 2H, benzene-H), 7.10 (s, 1H, pyrazole-H), 5.33 (s, 2H, –
3
(500 MHz, CDCl3): d = 8.48 (d, J = 4.7 Hz, 1H, pyr-
CH2–)
ppm;
19F
NMR
(471 MHz,
CDCl3):
3
idine-H), 7.92 (d, J = 8.0 Hz, 1H, pyridine-H), 7.45 (dd,
d = -62.93 ppm; 13C NMR (126 MHz, CDCl3):
d = 161.16, 157.82, 156.76, 147.84, 147.32, 139.72,
133.33 (q, J = 33.7 Hz), 129.74, 129.42, 128.97, 126.70,
124.01, 121.84, 116.13, 115.28, 112.64, 60.02 ppm; HR-
MS (ESI?): m/z calcd for C19H9BrClF6N5O2 ([M?H]?)
567.96051, found 567.96055.
3J = 8.0 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.29 (d,
4J = 0.9 Hz, 2H, benzene-H), 7.13 (s, 1H, pyrazole-H),
5.18 (s, 2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3):
d = 161.53, 156.76, 148.76, 147.91, 147.38, 139.72,
131.19, 130.03, 129.51, 129.14, 128.98, 126.73, 112.57,
63.50 ppm; HR-MS (ESI?): m/z calcd for C17H8BrCl4N5-
O2 ([M?H]?) 533.86883, found 533.86873.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[4-(2-phenylpropan-2-yl)phenoxy]methyl]-1,3,4-oxadia-
zole (16aa, C26H21BrClN5O2)
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(4-methoxyphenoxy)methyl]-1,3,4-oxadiazole
Yield 78.2%; white solid; m.p.: 191–192 °C; 1H NMR
3
(16x, C18H13BrClN5O3)
(500 MHz, CDCl3): d = 8.42 (d, J = 4.6 Hz, 1H, pyr-
idine-H), 7.87 (d, J = 8.0 Hz, 1H, pyridine-H), 7.40 (dd,
Yield 78.2%; white solid; m.p.: 94–95 °C; 1H NMR
(500 MHz, CDCl3): d = 8.42 (dd, 3J = 4.3 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.88 (dd, 3J = 8.0 Hz,
4J = 1.6 Hz, 1H, pyridine-H), 7.42 (dd, 3J = 8.0 Hz,
4J = 4.3 Hz, 1H, pyridine-H), 7.10 (s, 1H, pyrazole-H),
6.86 (d, J = 9.0 Hz, 2H, benzene-H), 6.81 (d, J = 9.1 Hz,
2H, benzene-H), 5.15 (s, 2H, –CH2–), 3.74 (s, 3H, –CH3–)
ppm; 13C NMR (126 MHz, CDCl3): d = 162.74, 156.46,
155.08, 151.51, 147.90, 147.32, 139.68, 130.09, 129.43,
128.92, 126.64, 116.22, 114.90, 112.47, 60.64, 55.78 ppm;
HR-MS (ESI?): m/z calcd for C18H13BrClN5O3 ([M?H]?)
461.99631, found 461.99411.
3
4
3J = 8.0 Hz, J = 4.6 Hz, 1H, pyridine-H), 7.32–7.22 (m,
5H, benzene-H), 7.17 (d, J = 7.7 Hz, 2H, benzene-H),
7.12 (s, 1H, pyrazole-H), 6.84 (d, J = 7.9 Hz, 2H,
benzene-H), 5.20 (s, 2H, –CH2–), 1.67 (s, 6H, –CH3)
ppm; 13C NMR (126 MHz, CDCl3): d = 162.69, 156.50,
155.32, 150.61, 147.91, 147.35, 144.89, 139.73, 130.10,
129.43, 128.97, 128.20, 128.06, 126.80, 126.67, 125.83,
114.93, 114.30, 112.52, 59.74, 42.51, 30.94 ppm; HR-MS
(ESI?): m/z calcd for C26H21BrClN5O2 ([M?H]?)
550.06400, found 550.06398.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[4-(methylthio)phenoxy]methyl]-1,3,4-oxadiazole
(16ab, C18H13BrClN5O2S)
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[[2-fluoro-5-(trifluoromethyl)phenoxy]methyl]-1,3,4-oxa-
diazole (16y, C18H9BrClF4N5O2)
Yield 78.2%; white solid; m.p.: 78–80 °C; 1H NMR
(500 MHz, CDCl3): d = 8.43 (dd, 3J = 4.7 Hz,
4J = 1.6 Hz, 1H), 7.89 (dd, 3J = 8.1 Hz, 4J = 1.6 Hz,
1H), 7.42 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H), 7.22 (d,
3J = 8.7 Hz, 2H, benzene-H), 7.11 (s, 1H, pyrazole-H),
Yield 78.2%; white solid; m.p.: 64–66 °C; 1H NMR
(500 MHz,
CDCl3):
d = 8.44
(d,
3J = 4.6 Hz,
4J = 1.5 Hz, 1H), 7.89 (dd, 3J = 8.0 Hz, 4J = 1.5 Hz,
1H), 7.43 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H), 7.29 (d,
3J = 5.9 Hz, 2H, benzene-H), 7.20 (t, J = 9.2 Hz, 1H,
6.87 (d, J = 8.8 Hz, 2H, benzene-H), 5.19 (s, 2H, –CH2–
3
3
benzene-H), 7.13 (s, 1H, pyrazole-H), 5.31 (s, 2H, –CH2–)
ppm; 19F NMR (471 MHz, CDCl3): d = -61.90,
), 2.43 (s, 3H, CH3) ppm; 13C NMR (126 MHz, CDCl3):
d = 162.41, 156.53, 155.68, 147.87, 147.30, 139.69,
131.38, 129.99, 129.57, 129.42, 128.95, 126.64, 115.72,
115.60, 112.53, 59.87, 17.45 ppm; HR-MS (ESI?): m/
z calcd for C18H13BrClN5O2S ([M?H]?) 477.97347, found
477.97360.
-126.72 ppm;
13C
NMR
(126 MHz,
CDCl3):
d = 161.43, 156.74, 154.79 (d, J = 253.7 Hz), 147.80,
147.34, 145.53 (d, J = 11.5 Hz), 139.74, 129.85, 129.37,
128.96, 127.25 (d, J = 29.5 Hz), 126.74, 123.37 (q,
J = 272.4 Hz), 120.91, 117.40 (d, J = 19.4 Hz) 113.87,
123

Y. Wang et al.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
(phenoxymethyl)-1,3,4-oxadiazole
lepidoptera) were used as positive controls under the
same conditions.
(16ac, C17H11BrClN5O2)
Yield 78.2%; white solid; m.p.: 72–73 °C; 1H NMR
(500 MHz, CDCl3): d = 8.42 (dd, 3J = 4.6 Hz,
4J = 1.0 Hz, 1H, pyridine-H), 7.87 (dd, 3J = 8.0 Hz,
4J = 1.0 Hz, 1H, pyridine-H), 7.41 (dd, 3J = 8.1 Hz,
4J = 4.7 Hz, 1H, pyridine-H), 7.29 (t, J = 7.6 Hz, 2H,
benzene-H), 7.11 (s, 1H, pyrazole-H), 7.02 (t, J = 7.4 Hz,
1H, benzene-H), 6.92 (d, J = 8.7 Hz, 2H, benzene-H),
5.21 (s, 2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3):
d = 162.58, 157.40, 156.51, 147.87, 147.32, 139.70,
130.05, 129.88, 129.41, 128.94, 126.66, 122.47, 114.82,
112.51, 59.65 ppm; HR-MS (ESI?): m/z calcd for C17H11-
BrClN5O2 ([M?H]?) 431.98574, found 431.98380.
Insecticidal activity against P. xylostella
The insecticidal activities against the P. xylostella were
determined according to previously determined protocols
[29, 30, 33]. Fresh cabbage discs (diameter was 2 cm) were
dipped into the prepared solutions containing compounds
16a–16ad for 10 s, dried in the air, and then placed in a
Petri dish (diameter 9 cm) lined with filter paper. Then, ten
third instar larvae were carefully transferred to the Petri
dish. Each assay was conducted in triplicate. Mortalities
were determined after 72 h. The commercial chlo-
rantraniliprole, chlorpyrifos, and avermectins were tested
under the same condition for positive controls.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-
[(p-tolyloxy)methyl]-1,3,4-oxadiazole
Acknowledgements This work was supported by the National Nat-
ural Science Foundation of China (nos. 21562012, 21132003 and
21162004), the Special Foundation of S&T for Outstanding Young
Talents in Guizhou (no. 2015-15#) and the S&T Foundation of
Guizhou Province (no. J[2014]2056#).
(16ad, C18H13BrClN5O2)
Yield 78.2%; white solid; m.p.: 61–62 °C; 1H NMR
3
(500 MHz, CDCl3): d = 8.41 (d, J = 4.4 Hz, 1H), 7.86
3
3
4
(d, J = 8.0 Hz, 1H), 7.40 (dd, J = 7.9 Hz, J = 4.7 Hz,
1H), 7.10 (s, 1H, pyrazole-H), 7.07 (d, J = 8.1 Hz, 2H,
benzene-H), 6.81 (d, J = 8.4 Hz, 2H, benzene-H), 5.17 (s,
2H, –CH2–), 2.27 (s, 3H, –CH3) ppm; 13C NMR
(101 MHz, CDCl3): d = 162.63, 156.41, 155.28, 147.84,
147.24, 139.60, 131.82, 130.20, 130.03, 130.01, 129.38,
128.86, 126.53, 114.69, 112.41, 77.40, 77.08, 76.76, 59.84,
20.53 ppm; HR-MS (ESI?): m/z calcd for C18H13BrClN5-
O2 ([M?H]?) 446.00139, found 446.00139.
References
1. Oerke EC (2006) J Agric Sci 144:31
2. Hasanshahi G, Abbasipour H, Askarianzadeh A, Karimi J, Jahan
F (2013) Arch Phytopathol Plant Protect 46:1136
3. Furlong MJ, Wright DJ, Dosdall LM (2013) Annu Rev Entomol
58:517
4. Guo Y, Qu L, Wang X, Huang M, Jia L, Zhang Y (2016) RSC
Adv 6:93505
5. Guo Y, Qu L, Wang X, Huang M (2017) 3-(5-Aryl-1,3,4-oxa-
diazole-2-yl)sarisan derivative, its preparation method and
application as pesticide. CN Patent 106,397,420, 15 Feb 2017
6. Guo Y, Qu L, Wang X, Huang M (2017) Chem Abstr 166:283974
7. He D, Li X (2011) Preparation of 1,3,4-oxadiazole containing
stilbene derivatives as insect inhibitors. CN Patent 102,161,646,
24 Aug 2011
8. He D, Li X (2011) Chem Abstr 155:352554
9. He D, Lu H (2013) Preparation of pyridine-containing 1,3,4-
oxadiazole derivatives as insecticides. CN Patent 103,450,170, 18
Dec 2013
Insecticidal activity
The larvicidal activity was conducted on organism reared
in the lab and repeated at 25 1 °C according to statistical
requirements. Mortalities were disposed according to
Abbott’s formula [37]. Evaluations were based on a per-
centage scale (0 = no activity and 100 = complete
eradication).
10. He D, Lu H (2013) Chem Abstr 160:117899
11. Zhou Y, Wang B, Di F, Xiong L, Yang N, Li Y, Li Y, Li Z (2014)
Bioorg Med Chem Lett 24:2295
Insecticidal activity against H. armigera
12. Liu Q, Chen K, Wang Q, Ni J, Li Y, Zhu H, Ding Y (2014) RSC
Adv 4:55445
13. Dai H, Shi Y, He H, Li Y, Jin Z, Xiao Y, Yuan Y, Fang Y (2016)
Preparation of 1,3,4-oxadiazole-containing difluoromethyl pyra-
zole as agrochemical insecticides. CN Patent 105,753,856, 13
July 2016
14. Dai H, Shi Y, He H, Li Y, Jin Z, Xiao Y, Yuan Y, Fang Y (2016)
Chem Abstr 165:223979
15. Cui ZN, Shi YX, Zhang L, Ling Y, Li BJ, Nishida Y, Yang XL
(2012) J Agric Food Chem 60:11649
The insecticidal activity of the synthesized compounds
against H. armigera was tested by the diet-incorporated
method [29]. A quantity of 3 cm3 of solution containing
the synthesized compound was added to the prepared
forage (27 g), subsequently diluted to corresponding
concentrations, and then placed in a 24-pore plate. One
larva of H. armigera was placed in each of the pores on
the plate. Mortalities were calculated after 72–96 h.
16. Liu Y, Liu M, Chen M, Wu C, Hua X, Zhou S, Wang B, Li Z
(2011) Chin J Org Chem 37:403
17. Modh RP, Shah D, Chikhalia KH (2013) Indian J Chem Sect B
Org Chem Incl. Med Chem 52B:1318
Commercial insecticides chlorantraniliprole (with
a
3-chloropyridin-2-yl-1H-pyrazole scaffold) and chlor-
pyrifos (an effective organophosphorus pesticide against
123

Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-…
18. Duan WG, Li XR, Mo QJ, Huang JX, Cen B, Xu XT, Lei FH
(2011) Holzforschung 65:191
29. Wu J, Song BA, Hu DY, Yue M, Yang S (2012) Pest Manag Sci
68:801
19. Kalhor M, Dadras A (2013) J Heterocycl Chem 50:220
20. Mo Q, Duan W, Li X, Huang D, Luo Z (2011) Chin J Org Chem
31:1114
21. Tajik H, Dadras A (2011) J Pestic Sci 36:27
22. Lahm GP, Stevenson TM, Selby TP, Freudenberger JH, Cordova
D, Flexner L, Bellin CA, Dubas CM, Smith BK, Hughes KA,
Hollingshaus JG, Clark CE, Benner EA (2007) Bioorg Med
Chem Lett 17:6274
30. Wu J, Xie DD, Shan WL, Zhao YH, Zhang W, Song BA, Yang S,
Ma J (2015) Chem Pap 69:993
31. Song BA, Luo LJ, Xue W, Wu J, Hu DY, Yang S, Jin LH, Yuan
QK, Lv MM (2014) Pyridinyl-pyrazole heterocyclic diacylhy-
drazine derivative, preparation method and application as
pesticide. CN Patent 103,539,778, 29 Jan 2014
32. Song BA, Luo LJ, Xue W, Wu J, Hu DY, Yang S, Jin LH, Yuan
QK, Lv MM (2014) Chem Abstr 160:295044
23. Hughes KA, Lahm GP, Selby TP, Stevenson TM (2004) Prepa-
ration of cyano anthranilamide insecticides. WO Patent
2,004,067,528, 12 Aug 2004
24. Hughes KA, Lahm GP, Selby TP, Stevenson TM (2004) Chem
Abstr 141:190786
25. Li K, Chang X, Song Y, Li B, Liu J (2011) Agrochemistry 50:761
26. Xu J, Dong WL, Xiong LX, Li Y, Li ZM (2009) Chin J Chem
27:2007
27. Zhao Y, Li YQ, Xiong LX, Xu LP, Peng LN, Li F, Li ZM (2013)
Chem Res Chin Univ 29:51
33. Kang SH, Song BA, Wu J, He M, Hu DY, Jin LH, Zeng S, Xue
W, Yang S (2013) Eur J Med Chem 67:14
34. Li AF, Ruan YB, Jiang QQ, He WB, Jiang YB (2010) Chem Eur
J 16:5794
35. Wang H, Fu YF, Fan ZJ, Song HB, Wu QJ, Zhang YJ, Belskaya
NP, Bakulev VA (2011) Chin J Struct Chem 30:412
36. Wang H, Yang Z, Fan Z, Wu Q, Zhang Y, Mi N, Wang S, Zhang
Z, Song H, Liu F (2011) J Agric Food Chem 59:628
37. Abbott WS (1987) J Am Mosquito Cont 3:302
28. Wu J, Huang CQ, Wang J, Hu DY, Jin LH, Yang S, Song BA
(2013) J Sep Sci 36:602
123