Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic acid derivatives containing fluorine moiety

Article abstract of DOI:10.1016/j.cclet.2019.07.064

A series of novel phenylpyrazole carboxylic acid derivatives containing fluorine moiety, i.e., diamides 11, simple aryl-bearing amides 12 and acylthioureas 14 were successfully synthesized based on the key fluoro-containing phenylpyrazole acid intermediate. The new compounds were identified and confirmed by melting point, ¹H NMR, ¹³C NMR and elemental analysis or HRMS. The bioassay results indicated that some of the compounds possessed excellent insecticidal activities towards oriental armyworm, diamondback moth and corn borer at low concentrations. For examples, compounds 11a, 11e?g and 14b exhibited remarkable larvicidal activities with LC₅₀ values of 0.13 ? 0.39 mg/L and 0.0002 ? 0.0014 mg/L against oriental armyworm and diamondback moth, respectively, were comparable with those of the control chlorantraniliprole. Particularly, 11e were found superior to chlorantraniliprole in oriental armyworm tests (LC₅₀: 0.23 mg/L vs. 0.26 mg/L); 11a, 11e, 11f and 14c in diamondback moth tests with LC₅₀ values of 0.0002 mg/L, 0.0002 mg/L, 0.0008 mg/L and 0.0005 mg/L, respectively, were more effective than that of chlorantraniliprole. In addition, 12a also showed a promising insecticidal potential and development/optimization advantage. Compounds 11a, 11e–g, 12a, 14b and 14c could be considered as possible new leading structures for further study. The SAR investigation indicated that the compounds with fluorine motif (e.g., -F, -CF₂H, -CF₃) held apparently favorable insecticidal potentials, which provided useful guidance for further design/development of new phenylpyrazole-containing agrochemicals.

Full text of DOI:10.1016/j.cclet.2019.07.064

G Model
CCLET 5147 No. of Pages 7
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Synthesis and structure-insecticidal activity relationship of novel
phenylpyrazole carboxylic acid derivatives containing fluorine moiety
*
Baolei Wang , Hongxue Wang, Hang Liu, Lixia Xiong, Na Yang, Yan Zhang,
*
Zhengming Li
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, 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 phenylpyrazole carboxylic acid derivatives containing fluorine moiety, i.e., diamides 11,
simple aryl-bearing amides 12 and acylthioureas 14 were successfully synthesized based on the key
fluoro-containing phenylpyrazole acid intermediate. The new compounds were identified and confirmed
by melting point, 1H NMR, 13C NMR and elemental analysis or HRMS. The bioassay results indicated that
some of the compounds possessed excellent insecticidal activities towards oriental armyworm,
diamondback moth and corn borer at low concentrations. For examples, compounds 11a, 11eꢀg and 14b
exhibited remarkable larvicidal activities with LC50 values of 0.13 ꢀ 0.39 mg/L and 0.0002 ꢀ 0.0014 mg/L
against oriental armyworm and diamondback moth, respectively, were comparable with those of the
control chlorantraniliprole. Particularly, 11e were found superior to chlorantraniliprole in oriental
armyworm tests (LC50: 0.23 mg/L vs. 0.26 mg/L); 11a, 11e, 11f and 14c in diamondback moth tests with
LC50 values of 0.0002 mg/L, 0.0002 mg/L, 0.0008 mg/L and 0.0005 mg/L, respectively, were more effective
than that of chlorantraniliprole. In addition, 12a also showed a promising insecticidal potential and
development/optimization advantage. Compounds 11a, 11e–g, 12a, 14b and 14c could be considered as
possible new leading structures for further study. The SAR investigation indicated that the compounds
with fluorine motif (e.g., -F, -CF2H, -CF3) held apparently favorable insecticidal potentials, which provided
useful guidance for further design/development of new phenylpyrazole-containing agrochemicals.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 28 June 2019
Received in revised form 29 July 2019
Accepted 31 July 2019
Available online xxx
Keywords:
Phenylpyrazole carboxylic acid derivatives
Fluorochemicals
Synthesis
Insecticidal activity
Structure-activity relationship
With the increase of the world population as well as the food,
feed and water consumption, and the decrease of the average
cultivatable land resources all over the world, how to high
efficiently improve the crop production based on the limited
farmlands available is becoming an urgent problem. The agro-
chemicals that are used to control various crop pests, weeds and
diseases undoubtedly exert very important roles in solving this
increasingly prominent issue. However, there always accompanies
negative effects more or less during the use of agrochemicals such
as pollution to the eco-environment, long term residue period and
the resistance problem. Therefore the innovation for new agro-
chemicals with novel structures and excellent bioactivities is a
permanent subject for the pesticide researchers [1,2].
noticeable agrochemicals of this kind of compounds are the
DuPont’s famous insecticides chlorantraniliprole and cyantranili-
prole (targeting at insect RyR) which both contain the anthranilic
diamide and N-pyridylpyrazole structural characteristics [3–5].
Moreover, cyclaniliprole that recently has been developed by
Ishihara Sangyo Kaisha is another insecticide of such kind [6,7].
Because of their potential insecticidal activities towards a variety of
Lepidopera, Coleoptera and Diptera pests, and some other good
properties as well (high efficiency, ecologically safe, less resistance,
etc.), their structural modifications and the bioactivity evaluation
of the synthesized compounds have become a research hot topic in
recent years [8–16].
Based on the structures of pyridylpyrazole-containing anthra-
nilic diamides, our previous research work have shown that the
substitution of Br-containing pyridylpyrazole group with CF3-
containing (chloronitro)phenylpyrazole group [17] (Fig. 1,A), or
replacing amide bridge by acylthiourea bridge (giving rise to the
CF3CH2O-containing pyridylpyrazole acylthiourea derivative) [18]
(Fig. 1,B) could retain or increase the insecticidal activities of the
parent structure towards the test larvae of Mythimna separata
N-Pyridylpyrazole derivatives have received continuous con-
cerns since the early of this century owing to their significant
biological activities in agriculture applications. The most
* Corresponding authors.
E-mail addresses: nkwbl@nankai.edu.cn (B. Wang), nkzml@vip.163.com (Z. Li).
https://doi.org/10.1016/j.cclet.2019.07.064
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: B. Wang, et al., Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic
acid derivatives containing fluorine moiety, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.064

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Fig. 1. The design strategy for the title new phenylpyrazole carboxylic acid derivatives containing fluorine moiety.
Walker and Plutella xylostella L. at low dose concentrations.
Encouraged by these information and with the aim of further
looking for new insecticidal agrochemicals, a series of novel
phenylpyrazole carboxylic acid derivatives containing fluorine
moiety, i.e., diamides 11, simple aryl-bearing amides 12 and
acylthioureas 14 were synthesized in this paper based on the key
intermediate (chlorofluoro)phenyl(CF3)pyrazole acid (a F effect
strategy), which is displayed in Fig. 1. It should be noted that some
similar anthranilic diamide analogues have been involved in
previous patents by Lahm et al. [19–21], however the new pyrazole
carboxylic acid derivatives ((di)amides and acylthioureas) with 2-
chloro-4-fluorophenyl motif were first reported in this article. It is
also worth noting that several fluorine-containing groups
(CH2CF2H, CH2CF3) were introduced into the aliphatic amide part
of the structures of these diamide and acylthiourea derivatives (11
and 14), which is an obvious innovation towards the situations in
previous literatures [17,19–22]. The insecticidal activities of all the
new synthesized title derivatives were systematically investigated
against Mythimna separata Walker, Plutella xylostella L. and O.
nubilalis at different dose concentrations in this research. In
addition, to further study the structure-activity relationship for the
simple aryl-containing amide derivatives 12, chloropyridyl(Br)
pyrazole amides 17 as contrasts were also synthesized and
bioassayed.
As shown the synthetic procedure in Scheme 1, the key
intermediate
1-(2-chloro-4-fluorophenyl)-3-(trifluoromethyl)-
1H-pyrazole-5-carboxylic acid (4) was prepared. A mixture of
(2-chloro-4-fluorophenyl) hydrazine (1, 140 mmol) and 4,4,4-
trifluoro-1-(furan-2-yl)butane-1,3-dione (2, 153 mmol) in glacial
acetic acid (150 mL) was refluxed for 5 h with TLC monitoring. After
cooling down, the mixture was concentrated under reduced
pressure. The residue was added saturated Na2CO3 aq. (50 mL), and
Scheme 1. Synthetic route of the intermediate 4 and the intermediates 7aꢀf.
Please cite this article in press as: B. Wang, et al., Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic
acid derivatives containing fluorine moiety, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.064

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3
then extracted with ethyl acetate (3 ꢁ 20 mL). The organic phase
was combined, washed with brine and dried over anhydrous Na
2SO4, successively. After solvent removal, the residue was
conducted to column chromatography with petroleum ether and
ethyl acetate (6:1, v/v) as solvents to afford the furylpyrazole
intermediate 3 as a yellow sticky oil, yield 84%, 1H NMR (400 MHz,
A solution of 2,4,6-trisubstitutedphenylamine (10, 0.8 mmol) in
pyridine (10 mL) was added to the flask containing the crude acyl
chloride 8 (0.8 mmol) which was prepared from the procedure
described above, and the mixture was refluxed for 3 ꢀ 5 h. After
cooling down, the mixture was poured into water (50 mL) and
extracted with ethyl acetate (3 ꢁ 15 mL). The extracts were
combined and washed with hydrochloric acid (2 ꢁ 10 mL) and
brine, successively. The organic phase was dried over anhydrous
Na2SO4. After solvent removal, the residue was further purified by
recrystallization from ethanol to afford the title compounds 12aꢀc
(Scheme 2) as a solid.
CDCl3):
d 7.51 (dd, 1H, J = 8.8, 5.6 Hz, Ph-H), 7.41 (d, 1H, J =1.2 Hz,
furyl-H), 7.32 (dd, 1H, J = 8.0, 2.8 Hz, Ph-H), 7.14–7.19 (m, 1H, Ph-H),
6.93 (s, 1H, pyrazole-H), 6.34 (dd, 1H, J = 3.2, 1.6 Hz, Ph-H), 5.85 (d,
1H, J =3.6 Hz, furyl-H).
To
a
three-necked flask furylpyrazole intermediate
3
(52.8 mmol), potassium dihydrogen phosphate (68.4 mmol), ace-
tone (100 mL) and water (200 mL) were added. Potassium
permanganate (285 mmol) was then added to the above mixture
in small portions under stirring. After completion of addition, the
reaction system was refluxed for 1 h and cooled down. The mixture
was filtered. The filtrate was acidized with concentrated hydro-
chloric acid, then extracted with ethyl acetate (3 ꢁ 30 mL). The
organic phase was combined and dried over anhydrous Na2SO4.
After solvent removal, the residue was conducted to column
chromatography using petroleum ether and ethyl acetate (3:1, v/v)
as solvents to afford the (chlorofluoro)phenyl(CF3)pyrazole acid
intermediate 4 as a white solid, yield 56%, mp 149 ꢀ 150 ꢂC.1H NMR
The crude acyl chloride 8 (0.85 mmol) prepared from the above
procedure was dissolved in dry aectonitrile (8 mL) and the solution
was added dropwise to a stirred mixture of KSCN (2.13 mmol) and
PEG-400 (2 drops) in dry acetonitrile (15 mL). The mixture was
stirred for 1 h at room temperature and filtered. To the filtrate (i.e.,
acyl isothiocyanate 13 in CH3CN), aminobenzamide intermediate 9
or 7d or 7e (0.8 mmol) was added in small portions. The system
was reacted for further 4 h at room temperature (TLC monitoring)
and concentrated under reduced pressure. The residue was then
made purification via column chromatography using petroleum
ether and ethyl acetate (4:1, v/v) as solvents to afford the title
compounds 14aꢀc (Scheme 2) as a white solid.
(400 MHz, CDCl3):
d
8.71 (br,1H, COOH), 7.45 (dd,1H, J = 8.8, 5.2 Hz,
Using the similar synthetic procedure of compounds 12a and b,
3-bromo-N-(2,4,6-trisubstitutedphenyl)-1-(3-chloropyridin-2-
yl)-1H-pyrazole-5-carboxamide (17a and b) with chloropyridyl(Br)
pyrazole acid 15 as acid material (Scheme 3).
Ph-H), 7.35 (s, 1H, pyrazole-H), 7.28 (dd, 1H, J = 8.0, 2.4 Hz, Ph-H),
7.12–7.17 (m, 1H, Ph-H).
6,8-Disubstituted-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
(6aꢀd) (Scheme 1) was prepared from 2-amino-3,5-disubstituted-
benzoic acid (5aꢀd) and triphosgene following the procedure of
Hanusek et al. [23]. 2-Amino-5-chloro-N,3-dimethylbenzamide (9)
was prepared by literature method via SOCl2 acylation and
aminolysis successively, based on the starting material 2-amino-
3-methyl-5-chlorobenzoic acid [14]. The intermediate 3-bromo-1-
(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (15) was
prepared via multi steps according to the procedure in literature
[18,24].
2-Amino-3,5-disubstituted-N-(2,2-difluoroethyl)/(2,2,2-tri-
fluoroethyl)benzamide (7aꢀf) (Scheme 1) were prepared referring
to a similar procedure in literature [14,23]. A mixture of the
benzooxazinedione intermediate 6 (5 mmol), 2,2-difluoroethan-1-
amine or 2,2,2-trifluoroethan-1-amine (15 mmol) and 1,4-dioxane
or tetrahydrofuran (30 mL) was reacted for 6 ꢀ 8 h with TLC
monitoring. After solvent removal under reduced pressure, the
residue was purified by recrystallization or column chromatogra-
phy using petroleum ether/ethyl acetate (5:1, v/v) as solvents to
afford the new intermediate 7.
As shown in Scheme 1, the key intermediate (chlorofluoro)
phenyl(CF3)pyrazole acid 4 was first prepared via a nucleophilic
addition-elimination-based cyclization of (2-chloro-4-fluoro-
phenyl)hydrazine 1 and trifluoromethyl- and furyl-containing
1,3-dione 2 in boiling acetic acid and KMnO4-oxidation of the
generated new furylpyrazole intermediate 3 with good yield. The
nucleophilic substitution reaction of benzooxazinedione interme-
diate
6 and difluoroethylamine or trifluoroethylamine high
effectively gave rise to the new intermediate 7 (76%ꢀ95%)
(Scheme 1). It is worth noting that the synthesis and the structural
characterization of the intermediates 4 and 7 were first reported in
this article (Supporting information).
Based on the key acid intermediate 4, the diamide derivatives
11aꢀg and the amide derivatives 12aꢀc were smoothly synthe-
sized via (COCl)2-acylation and aminolysis using corresponding
aminobenzamide or amine intermediates, respectively (Scheme 2);
the acyl chloride intermediate 8 reacted with KSCN under PEG-400
catalyzing in CH3CN gave the acyl isothiocyanate intermediate 13,
which further reacted with aminobenzamide intermediate 9 or 7d
or 7e leading to the desired acylthiourea compounds 14aꢀc
(Scheme 2).
Moreover, the amide derivatives 17a and b also could be
obtained in satisfactory yield via similar reaction conditions as
those of 12aꢀc, that is, the acyl chloride 16 which derived from the
chloropyridyl(Br)pyrazole acid 15 reacted with 2,4,6-trisubstitu-
tedphenylamine 10a or 10b in pyridine under reflux for 3 ꢀ 5 h
(Scheme 3).
(Chlorofluoro)phenyl(CF3)pyrazole acid 4 (0.8 mmol), oxalyl
chloride (3.2 mmol) and dry DCM (15 mL) were mixed and stirred
for 2 min at room temperature. Two drops of DMF were added to
the above solution. The reaction system was stirred for further
3.5 h at room temperature, and then concentrated under reduced
pressure to give crude intermediate pyrazole carbonyl chloride 8 as
a yellow solid, which was directly used to do the next step reaction
without purification.
The crude acyl chloride 8 (0.8 mmol) was dissolved in dry DCM
(8 mL) and was added dropwise to a stirred solution of 2-amino-5-
chloro-N,3-dimethylbenzamide 9 or 2-amino-3,5-disubstituted-
The synthesized title compounds were identified and con-
firmed by melting point, 1H NMR and 13C NMR spectra (Supporting
information). The measured elemental analysis or high-resolution
mass spectroscopy data were also consistent with the correspond-
ing calculated values (Supporting information). In the 1H NMR of
these synthesized new compounds, (di)amide or acylthiourea
derivatives, the active proton (NH) signals mainly showed up one
or two or three groups of peaks at very downfield with the
chemical shift of 6.36–12.12 ppm. As bearing fluoro-containing
group, some proton or carbon resonance absorption peaks in most
of the compounds obviously appeared characteristic spin coupling
and splitting of fluorine atom. For examples, the proton signals of
N-(2,2-difluoroethyl)/(2,2,2-trifluoroethyl)benzamide
(7aꢀf)
(0.76 mmol) and Et3N (0.96 mmol) in DCM (20 mL). The system
was reacted for 10 h at room temperature, and washed with
hydrochloric acid, saturated NaHCO3 aq. and brine, successively.
The organic phase was combined and dried over anhydrous
Na2SO4. After solvent removal, the residue was conducted to
column chromatography using petroleum ether and ethyl acetate
(10:1, v/v) as solvents to afford the title compounds 11aꢀg
(Scheme 2) as a white solid.
Please cite this article in press as: B. Wang, et al., Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic
acid derivatives containing fluorine moiety, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.064

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B. Wang et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Scheme 2. Synthetic route of the title compounds 11aꢀg, 12aꢀc and 14aꢀc.
CF2H and CH2 in CH2CF2H-containing compounds 11c and 11e
showed up “tt” peaks (2JFH =56.0 Hz, 3JHH =4.0 Hz) at
14aꢀc, the carbon signals of C
observed at
ꢃ180 ppm, ꢃ166 ppm and ꢃ157 ppm, respectively;
around this region, it also appeared doublet peaks at
ꢃ162.5 ppm,
¼
S and two C O groups were
¼
d
ꢃ5.90 ppm,
d
and multiplet peaks at 3.36 ꢀ 3.75 ppm, respectively; the proton
signalsofCH2 inCH2CF3-containingcompounds11f and14c showed
up multiplet peaks at 3.60 ꢀ 4.40 ppm; the carbon signals of the
CF2H and CH2 groups in CH2CF2H-containing compounds 11e, 11 g
d
ascribing to the benzene carbon that connects to the fluorine atom.
The insecticidal activities of compounds 11,12,14 and 17 against
oriental armyworm (Mythimna separata Walker), corn borer (O.
nubilalis) and diamondback moth (Plutella xylostella L.) were tested
in a greenhouse according to the reported methods [17,18,25–27],
and the detailed procedures are presented in the Supporting
information.
and 14b appeared at
d
ꢃ114 ppm and ꢃ42 ppm as triplet peaks (1JFC
ꢄ 241 Hz) and triplet peaks (2JFC ꢄ 26 Hz), respectively; the carbon
signals of the CF3 and CH2 groups in CH2CF3-containing compounds
11d, 11f and 14c appeared at
d
ꢃ123 ppm and ꢃ40 ppm as quartet
peaks (1JFC ꢄ 279 Hz) and quartet or multiplet peaks (2JFC ꢄ 34 Hz),
As shown in Table 1, initially all the tested compounds exhibited
100% lethality rate against oriental armyworm at a concentration
respectively. In addition, in the 13C NMR of acylthiourea derivatives
Scheme 3. Synthetic route of the compounds 17a and b.
Please cite this article in press as: B. Wang, et al., Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic
acid derivatives containing fluorine moiety, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.064

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Table 1
Larvicidal activity of the title compounds and chlorantraniliprole against oriental armyworm (Mythimna separata Walker) and corn borer (O. nubilalis).
Compd.
Activity (%) against Mythimna separata Walker at conc. (mg/L)
Activity (%) against O. nubilalis at conc. (mg/L)
100
5
2.5
0.5
0.25
100
50
25
5
11a
11b
11c
11d
11e
11f
11 g
12a
12b
12c
14a
14b
14c
17a
17b
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50.0 (10 mg/L)
100
40.0 (10 mg/L)
100
100
100
66.8
60.0 (50 mg/L)
100
70.0 (10 mg/L)
100
100
n.t.*
15.0
n.t.
100
100
100
33.3
n.t.
30.0
n.t.
100
n.t.
100
n.t.
n.t.
20.0
n.t.
n.t.
100
100
100
100
100
100
100
100
100
25.0
100
10.0
100
100
100
100
n.t.
100
20.0
100
10.0
n.t.
100
n.t.
35.0
n.t.
100
100
100
40.0
n.t.
20.0
n.t.
100
n.t.
n.t.
n.t.
65.0
n.t.
n.t.
n.t.
n.t.
n.t.
80.0
60.0
100
n.t.
n.t.
n.t.
n.t.
100
n.t.
n.t.
n.t.
60.0
33.3
96.7
n.t.
n.t.
n.t.
n.t.
96.7
n.t.
n.t.
n.t.
70.0
65.0
100
n.t.
n.t.
n.t.
n.t.
100
n.t.
n.t.
n.t.
60.0 (200 mg/L)
100
100
100
100
70.0
60.0 (200 mg/L)
100
30.0 (10 mg/L)
80.0 (25 mg/L)
40.0 (50 mg/L)
100
n.t.
n.t.
100
n.t.
100
Chlorantraniliprole
70.0
50.0
100
50.0
*
n.t.: not test.
of 100 mg/L. By further determination at lower concentrations,
most of the diamide derivatives 11aꢀg and the acylthiourea
derivatives 14aꢀc could still display remarkable insecticidal
activities, e.g., compounds 11a, 11c, 11eꢀg and 14b possessed
100% larvicidal activities against oriental armyworm at 5 mg/L;
compounds 11a, 11eꢀg and 14b pleasingly showed 20.0%ꢀ96.7%
activity at 0.25 mg/L. In particular, compounds 11e, 11g and 14b
whose lethality rate are 60.0%, 96.7% and 96.7%, respectively, were
more effective than the control chlorantraniliprole (50.0%). The
(chlorofluoro)phenyl(CF3)pyrazole amide derivatives (with simple
phenyl motif) 12aꢀc and chloropyridyl(Br)pyrazole amide deriv-
atives 17a and b also exhibited favorable insecticidal activities
against oriental armyworm. Especially, 12a and 12c at 2.5 mg/L
held lethality rate of 33.3% and 30.0%, respectively. From Table 1, it
also can be seen that compounds 11aꢀg, 12a, 12c and 14aꢀc can
totally kill the test larvae of corn borer at 100 mg/L concentration
(100%). Remarkably, compounds 11a, 11eꢀg and 14b whose
lethality rates at 5 mg/L are 65.0%, 70.0%, 65.0%, 100% and 100%,
respectively were more effective than the control chlorantranili-
prole (50.0%).
200 mg/L and 100 mg/L concentrations. At lower dosage, com-
pounds 11a, 11eꢀg, 14b and 14c had 100% insecticidal activities at
the concentration of 0.1 mg/L; particularly, these six compounds
also possessed 20.0%ꢀ75.0% lethality rate at 0.0005 mg/L, near to
even higher than that of chlorantraniliprole (40.0%).
By analyzing the insecticidal activities of the synthesized title
compounds corresponding to their structures, the following
relationships could be found: (i) When R2 and R3 of compounds
11bꢀg are fixed as H or Cl and H, respectively, the R1 group in
corresponding compounds against oriental armyworm and corn
borer shows an activity trend: Cl > CH3 (e.g., in Table 1, 11c > 11b;
11g > 11e). Interestingly, such situation is somewhat different from
that against diamondback moth, that is, CH3 > Cl (e.g., in Table 2,
11b > 11c; 11e > 11g). (ii) When R1=Cl and R2=H, R3 group in the
corresponding compounds against oriental armyworm and corn
borer shows the activity sequence of H > F (11c > 11d); when
R1=CH3 and R2=Cl, the activity trend for R3 group is H > F (11e > 11f;
14b > 14c), that is, CH2CF2H group is better than CH2CF3 group in
aliphatic amide motif. (iii) Against diamondback moth, it shows a
reverse trend for R3 group, that is F > H (CH2CF3 is better than
CH2CF2H). (iv) Comparing the diamide derivatives 11a, 11e and 11f,
it was found that CH2CF2H group in the respective types of
structures is better than CH3 group for the increase of the
insecticidal activities. Such situation is particularly obvious in the
cases of 14a and 14b against all the three kinds of test larvae, which
indicates the introduction of F atom to the alkyl chain of aliphatic
amide motif could greatly increase the insecticidal activity of the
parent structures. (v) When bearing the same substituents R1, R2
and R3 in the phenylamine motif, (chlorofluoro)phenyl(CF3)
pyrazole group displayed apparent superiority relative to the
chloropyridyl(Br)pyrazole group for the contribution to the
insecticidal activities (e.g., 12a > 17a; 12b > 17b). Whereas, when
R1=Cl, R3=CN both in 12a and b and 17a and b, the R2 group
indicates an activity sequence of Cl > NO2.
As shown in Table 2, all the synthesized compounds displayed
excellent insecticidal activities against diamondback moth at
Table 2
Larvicidal activity of the title compounds and chlorantraniliprole against
diamondback moth (Plutella xylostella L.).
Compd.
Larvicidal activity (%) at conc. (mg/L)
200
100 10
1
0.1
0.001
0.0005
11a
11b
11c
11d
11e
11f
100
100
100
100
100
100
100
100
100 100 100 100 90.0
100 90.0 80.0 60.0 n.t.*
100 90.0 60.0 n.t. n.t.
100 100 90.0 60.0 n.t.
100 100 100 100 90.0
100 100 100 100 70.0
100 100 100 100 65.0
100 100 100 50.0 20.0 (0.01 mg/
L)
55.0
n.t.
n.t.
n.t.
75.0
45.0
30.0
n.t.
11 g
12a
On the whole, compounds with CH3/Cl, Cl and CONHCH2CF2H
groups at benzene ring’s 2-, 4- and 6- positions of phenylamine
part both in diamide derivatives 11 and acylthiourea derivatives 14
showed the excellent insecticidal activities. In addition, (chloro-
fluoro)phenyl(CF3)pyrazole amide derivatives 12a and 12c that
contain simple groups, i.e., 2,4-Cl2-6-CN-phenyl and 2,6-Cl2-4-F-
phenyl, respectively, exhibited a favorable and promising insecti-
cidal potentials. Such substituents favorability corresponding to
the insecticidal activity or SAR contrast could be well reflected and
illustrated as shown in Figs. 2 and 3. An insecticidal activity
enhancement of fluorine-containing groups that linked with the
12b
12c
14a
100
100
100
80.0 50.0 n.t. n.t. n.t.
80.0 50.0 n.t. n.t. n.t.
100 100 100 90.0 60.0 (0.01 mg/
L)
n.t.
n.t.
n.t.
14b
14c
17a
17b
100
100
100
100
100 100 100 100 50.0
100 100 100 100 80.0
100 100 80.0 n.t. n.t.
85.0 60.0 n.t. n.t. n.t.
100 100 100 100 70.0
20.0
40.0
n.t.
n.t.
40.0
Chlorantraniliprole 100
*
n.t.: not test.
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B. Wang et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
also had favorable activities with LC50 values of 0.0008 mg/L and
0.0014 mg/L, respectively. In addition, compound 12a possessed
LC50 values of 3.41 mg/L and 0.12 mg/L against oriental armyworm
and diamondback moth, respectively, showing
a promising
insecticidal potential and development/optimization advantage
considering its comparatively simple structural characteristics.
In summary, a series of novel phenylpyrazole carboxylic acid
derivatives containing fluorine moiety, i.e., diamides 11, simple
aryl-bearing amides 12 and acylthioureas 14 were successfully
synthesized based on the key fluorine-containing phenylpyrazole
acid intermediate. The new compounds were identified and
confirmed by melting point, 1H NMR, 13C NMR and elemental
analysis or HRMS. The bioassay results showed that some of the
title compounds possessed excellent insecticidal activities towards
oriental armyworm, diamondback moth and corn borer at low
concentrations and could be considered as possible new leading
insecticides for further study. For examples, compounds 11a,
11eꢀg and 14b exhibited remarkable larvicidal activities with LC50
value of 0.13 ꢀ 0.39 mg/L against oriental armyworm and
0.0002 ꢀ 0.0014 mg/L against diamondback moth, respectively,
and were comparable with those of the control insecticide
chlorantraniliprole. Particularly, 11e held LC50 value of 0.23 mg/
L, were superior to chlorantraniliprole in oriental armyworm tests;
11a,11e,11f and 14c in diamondback moth tests with LC50 values of
0.0002 mg/L, 0.0002 mg/L, 0.0008 mg/L and 0.0005 mg/L, respec-
tively, were more effective than that of chlorantraniliprole. In
addition, simple aryl-bearing amide derivative 12a of the title
compounds also showed a promising insecticidal potential and
development/optimization advantage. The investigation on struc-
ture-insecticidal activity relationship of these novel compounds
indicated that the compounds with fluorine motif (e.g., -F, -CF2H,
-CF3) held apparently favorable insecticidal potentials, which
provided useful guidance for further design/development of new
phenylpyrazole-containing agrochemicals.
Fig. 2. The larvicidal activity contrast diagram of compounds 11a, 11e, 11 g, 14a, 14b
and chlorantraniliprole (M) against oriental armyworm (Mythimna separata
Walker) at different test concentrations.
Fig. 3. The larvicidal activity contrast diagram of compounds 12a, 12b, 17a and 17b
against oriental armyworm (Mythimna separata Walker) at different test
concentrations.
Acknowledgments
This work was financially supported by the National Key
Research and Development Program of China (No.
2017YFD0200505), the National Natural Science Foundation of
China (No. 21772103), and Tianjin Natural Science Foundation (No.
17JCYBJC19900).This article is dedicated to the 100th anniversary
of Nankai University.
aliphatic amide part of both diamide and acylthiourea derivatives
was apparently found in Fig. 2 [e.g., 11 g (CH2CF3), 11e (CH2CF2H) >
11a (CH3); 14b (CH2CF2H) >> 14a (CH3)]. Also in Fig. 3, when other
part of the compounds was fixed as the same, (chlorofluoro)phenyl
(CF3)pyrazole has greater contribution than chloropyridyl(Br)
pyrazole group for the activity (i.e., 17a > 12a; 17b > 12b).
Obviously, the introduction of fluorine moiety both in pyrazole and
phenyl rings promoted the insecticidal activity, which is possibly
due to the effect of F atom or polyfluoro group by means of
improving lipophilicity, metabolic stability and subsequent
insecticidal activity of the corresponding compounds [28].
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.07.064.
References
Based on the preliminary bioassay results, some compounds
with good insecticidal activities were made further investigation
on LC50 values. From Table S1 (Supporting information) we can see
that compounds 11a, 11eꢀg and 14b exhibited remarkable
larvicidal activities against oriental armyworm with LC50 value
of 0.13 ꢀ 0.39 mg/L, comparable with that of chlorantraniliprole
(0.26 mg/L and 0.11 mg/L at respective batch). Particularly,11e held
LC50 value of 0.23 mg/L (LC95 = 0.88 mg/L), superior to chloran-
traniliprole which had a LC50 value of 0.26 mg/L (LC95 = 1.79 mg/L)
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respectively, were more effective than that of chlorantraniliprole
(0.0014 mg/L and 0.0006 mg/L at respective batch). 11 g and 14b
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Please cite this article in press as: B. Wang, et al., Synthesis and structure-insecticidal activity relationship of novel phenylpyrazole carboxylic
acid derivatives containing fluorine moiety, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.07.064