Synthesis and bioactivities of novel pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety

Article abstract of DOI:10.3390/molecules21030276

In this study, in order to find novel biologically active pyrazole oxime compounds, a series of pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety were synthesized. Preliminary bioassays indicated that most title compounds were found to display good to excellent acaricidal activity against Tetranychus cinnabarinus at a concentration of 200 μg/mL, and some designed compounds still showed excellent acaricidal activity against Tetranychus cinnabarinus at the concentration of 10 μg/mL, especially since the inhibition rates of compounds 8e, 8f, 8l, 8m, 8n, 8p, and 8q were all 100.00%. Interestingly, some target compounds exhibited moderate to good insecticidal activities against Plutella xylostella and Aphis craccivora at a concentration of 200 μg/mL; furthermore, compounds 8e and 8l possessed outstanding insecticidal activities against Plutella xylostella under the concentration of 50 μg/mL.

Full text of DOI:10.3390/molecules21030276

molecules
Article
Synthesis and Bioactivities of Novel Pyrazole Oxime
Derivatives Containing a 5-Trifluoromethylpyridyl Moiety
Hong Dai 1, Jia Chen 1, Hong Li 2, Baojiang Dai 3, Haibing He 1,*, Yuan Fang 1 and Yujun Shi 1,
*
1
College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, China;
daihong_2015@aliyun.com (H.D.); 15642891665@163.com (J.C.); fyuan6586@aliyun.com (Y.F.)
Nantong Fengtian Chemical Industry Co. Ltd., Nantong 226005, China; leehomer@sina.com
School of Chemical and Biological Engineering, Nantong Vocational University, Nantong 226007, China;
dbj20110802@163.com
2
3
*
Correspondence: gaohbhe2015@aliyun.com (H.H.); syj@ntu.edu.cn (Y.S.);
Tel./Fax: +86-513-8501-2851 (H.H. & Y.S.)
Academic Editor: Derek J. McPhee
Received: 1 February 2016; Accepted: 23 February 2016; Published: 27 February 2016
Abstract: In this study, in order to find novel biologically active pyrazole oxime compounds, a
series of pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety were synthesized.
Preliminary bioassays indicated that most title compounds were found to display good to excellent
acaricidal activity against Tetranychus cinnabarinus at a concentration of 200
designed compounds still showed excellent acaricidal activity against Tetranychus cinnabarinus
at the concentration of 10 g/mL, especially since the inhibition rates of compounds 8e 8f 8l
8m 8n 8p, and 8q were all 100.00%. Interestingly, some target compounds exhibited moderate
to good insecticidal activities against Plutella xylostella and Aphis craccivora at a concentration of
200 g/mL; furthermore, compounds 8e and 8l possessed outstanding insecticidal activities against
µg/mL, and some
µ
,
,
,
,
,
µ
Plutella xylostella under the concentration of 50 µg/mL.
Keywords: pyrazole oxime; 5-trifluoromethylpyridyl; synthesis; bioactivity
1. Introduction
Agrochemicals, together with genetically modified insect-resistant crops and biological plant
protection methods, prevent severe harvest losses caused by phytophagous insects and mites [1–3].
Over the past decades, a great variety of chemical pesticides have been developed and used in
the protection of crops, among which pyrazole derivatives occupy a considerable proportion in
insecticides, germicides and acaricides [4–7]. As a well-known pyrazole-based pesticide developed by
Nihon Nohyaku Co. in 1991, Fenpyroximate (Figure 1) has been widely used in protecting various
crops due to its high efficiency against agricultural mites such as Polyphagotarsonemus latus Banks and
Tetranychus urticae Koch, and its low toxicity to mammals [
of Fenpyroximate in recent years led to the occurrence of resistance from some field populations
of T. urticae [ ]. Researchers are therefore propelled to search for new compounds that are highly
8]. Unfortunately, continuous application
9
active against phytophagous mites, and the development of novel analogues of Fenpyroximate is
extraordinarily focused on [10–12].
Fenpyroximate is structurally characterized by the unique 4-pyrazole oxime, which is recognized
as an irreplaceable pharmacophore for acaricidal or insecticidal activities. In the process of developing
new Fenpyroximate derivatives, modification of phenyl B (Figure 1) and its substituents was mainly
concentrated on with the 4-pyrazole oxime moiety retained. For example, Dai and coworkers reported
some acaricidal or insecticidal Fenpyroximate mimics that were obtained by replacing the phenyl
B (Figure 1) with thiazole [13], or a pyridyl group [14]. Many of these efforts succeeded in getting
Molecules 2016, 21, 276; doi:10.3390/molecules21030276
www.mdpi.com/journal/molecules

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some heterocycle-based pyrazole oxime compounds that displayed promising biological activities.
Therefore, structural optimization of the phenyl B of Fenpyroximate (Figure 1) to explore novel
bioactive molecules is a reasonable design.
Figure 1. The design of the target molecules.
As we know, due to its special aromaticity, basicity and hydrophilicity, a pyridyl group is a
very commonly used active moiety in pesticidal molecules [15
have indicated that introducing CF3 into heterocyclic molecules mostly results in the improvement of
physical, chemical and biological properties [22 23]. In fact, it has been proved that CF3-substituted
–21]. In addition, many investigations
,
pyridine is a highly efficient functional group in active pesticidal molecules, for instance neonicotinoids
insecticide Sulfoxaflor [24], and dichloropropene insecticide Pyridalyl [25], each of which has a similar
trifluoromethyl pyridyl fragment.
Encouraged by these reports, in this study we integrated the 5-trifluoromethyl pyridyl unit
into the scaffold of Fenpyroximate for the first time, and the substituents on the 5-position of the
pyrazole ring are screened and optimized (Figure 1). Insecticidal and acaricidal activities of the target
compounds were tested accordingly.
2. Results and Discussion
2.1. Chemistry
As shown in Scheme 1, 23 pyrazole oxime derivatives bearing a 5-trifluoromethyl pyridyl
moiety were conveniently synthesized. The synthon
available 2-chloro-5-trifluoromethylpyridine ( ) as shown in Scheme 1. Compound
4-hydroxybenzaldehyde using Cs2CO3 as the base and N,N-dimethylformamide as the solvent to
give intermediate in 75% yield. The next reaction with NaBH4 afforded compound in 90%
yield. Further chlorination of compound obtained intermediate in satisfactory yield. The
addition of a few drops of N,N-dimethylformamide accelerated the chlorination reaction. The
pyrazole oximes 7a 7w were prepared via two steps from pyrazole carbaldehyde . Benefitting
4
was synthesized from commercially
1
1
reacted with
2
3
3
4
–
5
from the activated C-Cl bond by the electron-withdrawing formyl group at the 4-position of the
pyrazole ring, the introduction of either alkyl alcohol or substituted phenol nucleophiles into
5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (
and afforded 5-substituted pyrazole-4-carbaldehydes (6a
and 7a 7w proceeded smoothly with Cs2CO3 as the base and acetonitrile as the solvent to provide the
title compounds 8a 8w in good yields. The structures of all the target compounds were analyzed and
confirmed by 1H-NMR, 13C-NMR and elemental analyses.
5) was performed smoothly and successfully,
–6w). The condensation of intermediates
4
–
–

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Scheme 1. Synthesis of the title compounds 8a
Cs2CO3, N,N-dimethylformamide, 105 ˝C for 10 h, 75% for
for ; ( ) thionyl chloride, N,N-dimethylformamide, dichloromethane, r.t. for 8 h, 82% for
(R = Me, Et and t-Bu), ROH, 30 ˝C for 3 h, 45 ˝C for 2 h, 41%–49% for 6a
6c; NaOR (R = substituted
phenyl), dimethylsulfoxide, 105 ˝C for 4–15 h, 60%–81% for 6d
6w; ( ) hydroxylamine hydrochloride,
–
8w. Reagents and conditions: (
; (
) NaBH4, ethanol, 0 ˝C for 3 h, 90%
; ( ) NaOR
a) 4-hydroxybenzaldehyde,
2
b
3
c
4 d
–
–
e
potassium hydroxide, methanol or ethanol, reflux for 6–16 h, 65%–87% for 7a
Cs2CO3, acetonitrile, reflux for 10–18 h, 44%–63% for 8a–8w.
–7w; (f) compound 4,
2.2. Biological Activities
2.2.1. Acaricidal Activity
The acaricidal activity of all the title compounds against Tetranychus cinnabarinus was evaluated
and the data are listed in Table 1. The results indicated that 5-alkoxy pyrazole derivatives 8a 8b and 8c
possessed no acaricidal activity at a concentration of 200 g/mL. For the other 5-aryloxy-substituted
compounds 8d 8w, an obvious substituent effect was found on the phenyl ring C. When the substituent
at the 2-position of phenyl C (Figure 1) was halogen (8d 8g and 8j) or methoxy (8o), it would reduce
the acaricidal activity, and the mortality obviously declined depending on the concentration and
disappeared at the concentration of 10 g/mL. Moreover, 3-substituted phenyl C (Figure 1) affected
,
µ
–
,
µ
the acaricidal activities in a similar manner. The introduction of halogen atoms (8h and 8k) led to
the loss of acaricidal activity, except for that of 3-fluoro derivative (8e). As well as unsubstituted
compound 8n, compound 8e retained 100.00% mortality, even at 10 µg/mL. The results seem to
show that compared with the inductive effect, steric hindrance of the 2- or 3-position on phenyl C
(Figure 1) plays a more important role in regulating the acaricidal activity. In contrast, it exhibited
a good tolerance of 4-substituents on phenyl C (Figure 1 and Table 1), because the introduction of
halogen atoms (8f
acaricidal activities at concentrations ranging from 200
compound 8r was an exception, whose activity against T. cinnabarinus disappeared completely at a
concentration of 200 g/mL. Additionally, among disubstituted derivatives, compounds 8t and 8w
,
8l and 8m), methoxy (8p), methyl (8q) or trifluoromethoxy (8s) did not affect the
µ
g/mL to 10 g/mL. However, 4-tert butyl
µ
µ
displayed relatively higher acaricidal activity than compounds 8u and 8v from the concentrations of
200 µg/mL to 50 µg/mL.

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Table 1. Acaricidal activities of compounds 8a–8w (mortality, %).
Tetranychus cinnabarinus
Compd.
R
200 µg/mL
100 µg/mL
50 µg/mL
10 µg/mL
b
8a
8b
Me
Et
0
0
—
—
—
—
—
—
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
t-Bu
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-IC6H4
0
—
—
—
0
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
70.28 ˘ 1.33 a
100.00 ˘ 0.00
100.00 ˘ 0.00
80.16 ˘ 0.38
70.33 ˘ 1.22
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
0
100.00 ˘ 0.00
100.00 ˘ 0.00
0
100.00˘ 0.00
100.00 ˘ 0.00
80.17 ˘ 0.82
0
90.32 ˘ 1.38
100.00 ˘ 0.00
100.00 ˘ 0.00
0
30.39 ˘ 0.67
100.00 ˘ 0.00
30.46 ˘ 1.52
0
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
—
100.00 ˘ 0.00
100.00 ˘ 0.00
—
70.43 ˘ 0.82
100.00 ˘ 0.00
100.00 ˘ 0.00
—
100.00 ˘ 0.00
100.00 ˘ 0.00
—
—
—
100.00 ˘ 0.00
50.49 ˘ 1.78
0
—
—
—
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
—
100.00 ˘ 0.00
100.00 ˘ 0.00
—
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
—
100.00 ˘ 0.00
100.00 ˘ 0.00
—
100.00 ˘ 0.00
80.42 ˘ 1.56
0
C6H5
2-OMeC6H4
4-OMeC6H4
4-MeC6H4
4-t-BuC6H4
4-OCF3C6H4
2,3-F2C6H3
2,4-Cl2C6H3
2,3-Me2C6H3
2,4-Me2C6H3
8s
8t
8u
8v
100.00 ˘ 0.00
100.00 ˘ 0.00
50.23 ˘ 1.43
—
95.29 ˘ 1.45
—
—
—
—
—
8w
100.00 ˘ 0.00
100.00 ˘ 0.00
60.35 ˘ 1.45
Fenpyroximate
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
Each value represents the mean ˘ standard error of three replications; b “—” refers to “not tested”.
a
2.2.2. Insecticidal Activities
Besides acaricidal potencies, the insecticidal activities of the new compounds were also explored
on Plutella xylostella and Aphis craccivora. As shown in Table 2, some of the obtained compounds
displayed good insecticidal activities against P. xylostella. For instance, the mortalities of compounds
8e
some of them showed good insecticidal activities against P. xylostella when the concentration was
reduced to 50 g/mL; compounds 8e and 8l possessed relatively higher insecticidal activities against
P. xylostella than other derivatives. Some target compounds also demonstrated moderate to good
insecticidal activities against A. craccivora at 200 g/mL; for example, compounds 8e 8h 8i, and 8r had
, 8f, 8i, 8l, 8m, 8n, 8p, and 8q against P. xylostella were all 100.00% at 200 µg/mL. Moreover,
µ
µ
,
,
100.00%, 85.33%, 95.28%, and 100.00% inhibition rates, respectively. In fact, similar to that of acaricidal
activities, the compounds possessing more potent insecticidal abilities against P. xylostella were
4-substituted derivatives with compound 8e as the only exception. When it comes to A. craccivora, the
structure-activity relationships were not obvious. Overall, they were more potent against P. xylostella
than against A. craccivora.
All the above data implied that structural modification of Fenpyroximate by a 5-trifluoromethyl
pyridyl unit could produce some new compounds with good biological activities. To get more active
derivatives, further analogue synthesis and structural optimization are well under way.

Molecules 2016, 21, 276
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Table 2. Insecticidal activities of compounds 8a–8w (mortality, %).
Plutella xylostella
Aphis craccivora
Compd.
R
200 µg/mL
50 µg/mL
200 µg/mL
100 µg/mL
8a
8b
Me
Et
100.00 ˘ 0.00
0
—
30.26 ˘ 1.56
—
—
b
0
0
8c
8d
t-Bu
2-FC6H4
0
0
—
—
0
0
—
—
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
3-FC6H4
4-FC6H4
100.00 ˘ 0.00
100.00 ˘ 0.00
0
86.42 ˘ 0.88
100.00 ˘ 0.00
60.18 ˘ 1.33
43.36 ˘ 1.07
60.29 ˘ 1.52
30.41 ˘ 0.71
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-IC6H4
—
0
0
—
30.29 ˘ 1.55 a
100.00 ˘ 0.00
0
85.33 ˘ 1.25
50.27 ˘ 1.06
71.23 ˘ 0.95
95.28 ˘ 1.32
60.26 ˘ 1.69
—
20.41
—
57.35 ˘ 0.54
100.00 ˘ 0.00
100.00 ˘ 0.00
100.00 ˘ 0.00
0
100.00 ˘ 0.00
100.00 ˘ 0.00
0
57.27 ˘ 0.83
43.09 ˘ 1.26
43.25 ˘ 1.07
0
43.18 ˘ 0.92
100.00 ˘ 0.00
—
29.16 ˘ 1.86
0
—
0
—
100.00 ˘ 0.00
50.37 ˘ 1.32
71.39 ˘ 1.53
0
C6H5
71.18 ˘ 0.65
70.25 ˘ 1.63
50.43 ˘ 1.38
2-OMeC6H4
4-OMeC6H4
4-MeC6H4
4-t-BuC6H4
4-OCF3C6H4
2,3-F2C6H3
2,4-Cl2C6H3
2,3-Me2C6H3
2,4-Me2C6H3
—
0
—
43.41 ˘ 1.71
70.32 ˘ 1.95
20.17 ˘ 0.71
71.22 ˘ 1.24
0
—
—
100.00 ˘ 0.00
40.09 ˘ 0.36
43.35 ˘ 1.65
—
—
0
0
—
—
—
—
—
—
—
—
—
—
8u
8v
—
8w
Pyridalyl
Imidacloprid
a
0
100.00 ˘ 0.00
—
100.00 ˘ 0.00
100.00 ˘ 0.00
Each value represents the mean ˘ standard error of three replications; b “—” refers to “not tested”.
3. Experimental Section
3.1. Chemistry
3.1.1. General Procedures
All reagents were chemically pure and solvents were dried according to standard methods.
The 1H-NMR and 13C-NMR spectra were obtained on a Bruker AV400 spectrometer (400 MHz, 1H;
100 MHz, 13C, Bruker, Billerica, MA, USA) in CDCl3 with tetramethylsilane as the internal standard.
The melting points were determined on an X-4 binocular microscope melting point apparatus (Beijing
Tech Instrument Co., Beijing, China) and are uncorrected. Elemental analyses were determined on a
Yanaco CHN Corder MT-3 elemental analyzer (Yanaco, Kyoto, Japan). The reactions were monitored
by analytical thin-layer chromatography (TLC) with ultraviolet (UV) light and TLC was carried out on
silica gel GF254. The intermediates 5-chloropyrazole aldehyde
5
and 5-alkoxy pyrazole aldehyde 6a
–
6c
were synthesized according to the reported procedures [26]. The 5-Substituted pyrazole oximes 7a
–
7w
were prepared by the literature method [11].
3.1.2. Synthesis of 4-(5-Trifluoromethylpyridin-2-yloxy)benzaldehyde (2)
To a solution of 4-hydroxybenzaldehyde (6.4 g, 52.5 mmol) in N,N-dimethylformamide (150 mL)
was added Cs2CO3 (16.3 g, 50 mmol), the mixture was then stirred for 20 min at room temperature,
followed by adding compound 1 (9.1 g, 50 mmol). The resulting mixture was then heated slowly to
105 ˝C and stirred for 10 h. After cooled to room temperature, the solvent was evaporated in vacuo.
The slurry was then distributed in water (150 mL) and ethyl acetate (100 mL), and the separated water
phase was then extracted with ethyl acetate (3
water and brine, dried over anhydrous Na2SO4, and concentrated in rotatory evaporator to afford
ˆ
50 mL). The combined organic layer was washed by

Molecules 2016, 21, 276
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compound
2 in 75% yield as a white solid, which was used for the following transformations without
further purification.
3.1.3. Synthesis of 4-(5-Trifluoromethylpyridin-2-yloxy)phenylmethanol (3)
Intermediate
2
(13.4 g, 50 mmol) was dissolved in ethanol (100 mL) and cooled to 0 ˝C. To the
solution was added NaBH4 (3.8 g, 100 mmol) in portions over 30 min. After being stirred at 0 ˝C for
3 h, the reaction mixture was poured into water, followed by adding 5% hydrochloric acid to adjust
pH to 5–6. The resulting solution was extracted by chloroform (3
Na2SO4 and concentrated under reduced pressure to give compound
in the next procedure without further purification.
ˆ
50 mL), dried over anhydrous
3 in 90% yield, which was used
3.1.4. Synthesis of 2-(4-Chloromethylphenoxy)-5-(trifluoromethyl)pyridine (4)
A solution of intermediate (13.5 g, 50 mmol) in dichloromethane (80 mL) was cooled in ice-water
3
bath followed by adding thionyl chloride (8.9 g, 74.8 mmol) dropwise over 20 min. Then a few drops of
N,N-dimethylformamide was added thereto. The resulting solution was stirred at room temperature
for 8 h. The reaction mixture was quenched by trash ice, then the organic phase was separated, washed
by water and saturated NaHCO3, dried over anhydrous Na2SO4, and evaporated in vacuo to produce
compound
4 δ 8.36 (s, 1H, Py-H), 7.84 (dd, J1 = 8.8 Hz,
(yield 82%) as a white solid; 1H-NMR (CDCl3):
J2 = 2.4 Hz, 1H, Py-H), 7.38 (d, J = 8.4 Hz, 2H, Ar-H), 7.07 (d, J = 8.4 Hz, 2H, Ar-H), 6.96 (d, J = 8.8 Hz,
1H, Py-H), 4.54 (s, 2H, CH2). Anal. Calcd for C13H9ClF3NO: C 54.28; H 3.15; N 4.87. Found: C 54.41;
H 3.03; N 4.70.
3.1.5. General Procedure for the Preparation of 6d–6w
To a solution of substituted phenol (26 mmol) in absolute ethanol (50 mL) was added sodium
hydroxide (26 mmol) at room temperature. The mixture was heated to reflux for 3–5 h. After the
removal of the solvent, the residue was dissolved in dimethylsulfoxide (50 mL), to the resulting mixture
was added 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (5) (20 mmol) in portions. Then the
˝
solution was heated to 105 C and maintained at that temperature for 4–15 h and cooled to room
temperature. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate
(3
ˆ
50 mL). The organic layer was washed with water (3
ˆ
25 mL) and dried over anhydrous Na2SO4,
filtered and evaporated to produce the corresponding carbaldehydes 6d–6w, with yields ranging from
60% to 81% [11].
3.1.6. General Procedure for the Preparation of 8a–8w
To a stirred solution of intermediate 4 (7.2 mmol), compound 7 (6 mmol) in anhydrous acetonitrile
(30 mL) was added Cs2CO3 (7.2 mmol) at room temperature, the resulting mixture was heated to reflux
for 10–18 h. After cooled to room temperature, the reaction mixture was filtered. After most of the
solvent had been evaporated under reduced pressure, the residue was admixed with water (100 mL)
and extracted with dichloromethane (3
(3 30 mL), and dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator to
give a residue, which was then separated by silica gel column chromatography using petroleum ether
and ethyl acetate (v/v = 30:1) as eluent to afford the target compounds 8a 8w, with yields ranging
8w were novel and the physical and spectral
ˆ
30 mL). The combined organic layer was washed with water
ˆ
–
from 44% to 63%. All 23 pyrazole oxime derivatives 8a
–
data for these compounds are listed below.
1,3-Dimethyl-5-methyloxy-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]-
1
oxime (8a): White oil, yield 52%. H-NMR (CDCl3):
δ 8.44 (s, 1H, Py-H), 8.08 (s, 1H, CH=N), 7.90 (d,
J = 8.8 Hz, 1H, Py-H), 7.49 (d, J = 7.6 Hz, 2H, Ar-H and Py-H), 7.15 (d, J = 7.2 Hz, 2H, Ar-H), 7.01 (d,
J = 8.8 Hz, 1H, Ar-H), 5.16 (s, 2H, CH2), 3.94 (s, 3H, OCH3), 3.62 (s, 3H, N-CH3), 2.28 (s, 3H, CH3);
13C-NMR (CDCl3):
δ 165.8, 153.0, 152.8, 146.8, 145.5, 145.4, 141.6, 136.7, 136.6, 135.2, 130.0, 121.4, 111.3,

Molecules 2016, 21, 276
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97.4, 75.4, 61.7, 33.6, 14.0. Anal. Calcd for C20H19F3N4O3: C 57.14; H 4.56; N 13.33. Found: C 57.28;
H 4.39; N 13.16.
1,3-Dimethyl-5-ethyloxy-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]-
oxime (8b). White solid, yield 55%, mp 48–50 ˝C. 1H-NMR (CDCl3):
δ 8.42 (s, 1H, Py-H), 8.04 (s, 1H,
CH=N), 7.88 (d, J = 8.8 Hz, 1H, Py-H), 7.47 (d, J = 7.2 Hz, 2H, Ar-H and Py-H), 7.14 (d, J = 6.8 Hz,
2H, Ar-H), 6.99 (d, J = 8.4 Hz, 1H, Ar-H), 5.14 (s, 2H, CH2), 4.16 (q, J = 6.8 Hz, 2H, CH2), 3.60 (s, 3H,
N-CH3), 2.26 (s, 3H, CH3), 1.32 (t, J = 6.0 Hz, 3H, CH3); 13C-NMR (CDCl3):
δ 165.8, 152.8, 152.1, 146.8,
145.4, 145.3, 141.7, 136.7, 136.6, 135.3, 130.0, 121.4, 111.3, 97.8, 75.3, 70.6, 33.6, 15.3, 14.0. Anal. Calcd for
C21H21F3N4O3: C 58.06; H 4.87; N 12.90. Found: C 58.23; H 4.69; N 12.76.
1,3-Dimethyl-5-tert-butyloxy-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]-
oxime (8c). White solid, yield 50%, mp 64–65 ˝C. 1H-NMR (CDCl3):
δ 8.45 (s, 1H, Py-H), 8.01 (s, 1H,
CH=N), 7.90 (d, J = 8.4 Hz, 1H, Py-H), 7.49 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.15 (d, J = 7.2 Hz, 2H,
Ar-H), 7.01 (d, J = 8.8 Hz, 1H, Ar-H), 5.15 (s, 2H, CH2), 3.62 (s, 3H, N-CH3), 2.35 (s, 3H, CH3), 1.38 (s,
9H, t-C4H9); 13C-NMR (CDCl3):
δ 165.8, 152.7, 150.1, 146.6, 145.5, 145.4, 143.0, 136.7, 135.3, 130.0, 125.1,
121.3, 111.3, 101.6, 85.4, 75.3, 34.6, 29.0, 15.2. Anal. Calcd for C23H25F3N4O3: C 59.73; H 5.45; N 12.11.
Found: C 59.62; H 5.58; N 12.30.
1,3-Dimethyl-5-(2-fluorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]-
˝
1
oxime (8d). Yellow solid, yield 48%, mp 56–58 C. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d,
J = 8.4 Hz, 1H, Py-H), 7.84 (s, 1H, CH=N), 7.37 (d, J = 6.8 Hz, 2H, Ar-H and Py-H), 7.01–7.22 (m, 6H,
ArH), 6.78–6.82 (m, 1H, ArH), 5.01 (s, 2H, CH2), 3.68 (s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR
(CDCl3):
δ 165.8, 153.2, 152.8, 150.8, 147.3, 147.0, 145.5, 145.4, 144.3, 144.2, 140.4, 136.7, 135.0, 130.0,
124.6, 124.5, 121.3, 117.2, 117.1, 116.8, 111.3, 99.9, 75.5, 34.2, 14.5. Anal. Calcd for C25H20F4N4O3:
C 60.00; H 4.03; N 11.20. Found: C 60.19; H 3.85; N 11.02.
1,3-Dimethyl-5-(3-fluorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
1
-oxime (8e). White oil, yield 51%. H-NMR (CDCl3):
δ 8.45 (s, 1H, Py-H), 7.91 (d, J = 8.8 Hz, 1H, Py-H),
7.86 (s, 1H, CH=N), 7.37 (d, J = 7.2 Hz, 2H, Ar-H and Py-H), 7.25–7.31 (m, 1H, ArH), 7.11 (d, J = 6.8 Hz,
2H, Ar-H), 7.01 (d, J = 8.4 Hz, 1H, Ar-H), 6.65–6.85 (m, 3H, ArH), 5.03 (s, 2H, CH2), 3.63 (s, 3H, N-CH3),
2.40 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 164.8, 162.3, 157.6, 152.8, 147.0, 145.5, 140.5, 136.7, 134.9,
130.9, 130.8, 130.0, 125.1, 121.3, 111.3, 110.9, 110.8, 110.6, 103.7, 103.4, 100.4, 75.5, 34.2, 14.6. Anal. Calcd
for C25H20F4N4O3: C 60.00; H 4.03; N 11.20. Found: C 59.85; H 4.21; N 11.39.
1,3-Dimethyl-5-(4-fluorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8f). White solid, yield 56%, mp 46–48 C. H-NMR (CDCl3):
δ 8.44 (s, 1H, Py-H), 7.90 (d,
J = 8.4 Hz, 1H, Py-H), 7.83 (s, 1H, CH=N), 7.36 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.11 (d, J = 8.4 Hz,
2H, Ar-H), 6.98–7.02 (m, 3H, ArH), 6.86–6,88 (m, 2H, ArH), 5.02 (s, 2H, CH2), 3.62 (s, 3H, N-CH3),
2.38 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 160.0, 157.5, 152.8, 152.7, 147.7, 147.0, 145.5, 145.4, 140.6,
136.7, 135.0, 130.0, 125.1, 121.3, 120.0, 116.6, 116.5, 116.4, 111.4, 100.1, 75.4, 34.2, 14.6. Anal. Calcd for
C25H20F4N4O3: C 60.00; H 4.03; N 11.20. Found: C 60.17; H 3.89; N 11.08.
1,3-Dimethyl-5-(2-chlorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8g). White solid, yield 53%, mp 46–48 C. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d,
J = 8.8 Hz, 1H, Py-H), 7.82 (s, 1H, CH=N), 7.46 (d, J = 7.6 Hz, 1H, Ar-H), 7.36 (d, J = 7.6 Hz, 2H, Ar-H
and Py-H), 7.05–7.19 (m, 4H, ArH), 7.01 (d, J = 8.8 Hz, 1H, Ar-H), 6.71 (d, J = 8.0 Hz, 1H, Ar-H), 5.01 (s,
2H, CH2), 3.66 (s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 152.8, 152.2, 147.1, 147.0,
145.6, 145.5, 145.4, 140.3, 136.7, 134.9, 131.0, 130.1, 128.0, 124.6, 122.8, 121.3, 115.6, 111.3, 100.2, 75.5, 34.2,
14.5. Anal. Calcd for C25H20ClF3N4O3: C 58.09; H 3.90; N 10.84. Found: C 58.22; H 3.78; N 10.65.
1,3-Dimethyl-5-(3-chlorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
1
-oxime (8h). White oil, yield 55%. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d, J = 8.4 Hz, 1H, Py-H),
7.85 (s, 1H, CH=N), 7.36 (d, J = 7.6 Hz, 2H, Ar-H and Py-H), 7.23–7.27 (m, 1H, ArH), 7.01–7.13 (m,

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4H, ArH), 6.93 (s, 1H, Ar-H), 6.80 (d, J = 8.4 Hz, 1H, Ar-H), 5.02 (s, 2H, CH2), 3.63 (s, 3H, N-CH3),
2.39 (s, 3H, CH3). 13C-NMR (CDCl3):
165.8, 157.2, 152.8, 147.1, 146.9, 145.5, 145.4, 140.4, 136.7,
δ
135.5, 134.9, 130.8, 130.1, 125.1, 124.0, 121.3, 116.0, 113.6, 111.3, 100.4, 75.5, 34.3, 14.5. Anal. Calcd for
C25H20ClF3N4O3: C 58.09; H 3.90; N 10.84. Found: C 58.18; H 3.81; N 10.72.
1,3-Dimethyl-5-(4-chlorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8i). White solid, yield 58%, mp 67–69 C. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d,
J = 8.4 Hz, 1H, Py-H), 7.83 (s, 1H, CH=N), 7.35 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.29 (d, J = 8.4 Hz,
2H, Ar-H), 7.12 (d, J = 7.6 Hz, 2H, Ar-H), 7.03 (d, J = 8.4 Hz, 1H, Ar-H), 6.85 (d, J = 8.4 Hz, 2H, Ar-H),
5.02 (s, 2H, CH2), 3.62 (s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 155.2, 152.8, 147.2,
147.0, 145.5, 145.4, 140.5, 136.7, 134.9, 130.0, 129.9, 128.7, 121.3, 119.2, 116.6, 111.4, 100.3, 75.5, 34.2, 14.5.
Anal. Calcd for C25H20ClF3N4O3: C 58.09; H 3.90; N 10.84. Found: C 57.93; H 4.06; N 10.98.
1,3-Dimethyl-5-(2-bromophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
-oxime (8j). White oil, yield 47%. 1H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d, J = 8.4 Hz, 1H,
Py-H), 7.82 (s, 1H, CH=N), 7.64 (d, J = 8.0 Hz, 1H, Ar-H), 7.36 (d, J = 7.6 Hz, 2H, Ar-H and Py-H),
7.10–7.24 (m, 3H, ArH), 7.02 (d, J = 8.0 Hz, 2H, Ar-H), 6.68 (d, J = 8.0 Hz, 1H, Ar-H), 5.01 (s, 2H, CH2),
3.66 (s, 3H, N-CH3), 2.39 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 153.1, 152.8, 147.2, 147.0, 145.5,
140.3, 136.7, 134.0, 130.1, 128.8, 125.0, 121.3, 115.4, 111.4, 111.3, 100.2, 75.5, 34.3, 14.5. Anal. Calcd for
C25H20BrF3N4O3: C 53.49; H 3.59; N 9.98. Found: C 53.62; H 3.40; N 9.80.
1,3-Dimethyl-5-(3-bromophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
1
-oxime (8k). White oil, yield 50%. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d, J = 8.4 Hz, 1H, Py-H),
7.85 (s, 1H, CH=N), 7.36 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.26 (d, J = 7.6 Hz, 1H, Ar-H), 7.09–7.21
(m, 4H, ArH), 7.02 (d, J = 8.4 Hz, 1H, Ar-H), 6.85 (d, J = 8.0 Hz, 1H, Ar-H), 5.02 (s, 2H, CH2), 3.63 (s,
3H, N-CH3), 2.39 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 157.2, 152.8, 147.1, 146.8, 145.5, 145.4, 140.4,
136.7, 134.9, 131.1, 130.0, 126.9, 125.0, 123.2, 121.3, 118.9, 114.0, 111.3, 100.4, 75.5, 34.3, 14.5. Anal. Calcd
for C25H20BrF3N4O3: C 53.49; H 3.59; N 9.98. Found: C 53.38; H 3.72; N 10.13.
1,3-Dimethyl-5-(4-bromophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8l). White solid, yield 53%, mp, 68–70 C. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.92 (d,
J = 8.8 Hz, 1H, Py-H), 7.84 (s, 1H, CH=N), 7.43 (d, J = 7.2 Hz, 2H, Ar-H), 7.35 (d, J = 7.2 Hz, 2H, Ar-H
and Py-H), 7.12 (d, J = 7.2 Hz, 2H, Ar-H), 7.03 (d, J = 8.8 Hz, 1H, Ar-H), 6.80 (d, J = 7.2 Hz, 2H, Ar-H),
5.02 (s, 2H, CH2), 3.63 (s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 155.8, 152.8, 147.1,
145.5, 145.4, 140.4, 136.7, 136.6, 134.9, 132.9, 130.1, 121.3, 117.1, 116.1, 111.4, 109.2, 100.3, 75.5, 34.2, 14.5.
Anal. Calcd for C25H20BrF3N4O3: C 53.49; H 3.59; N 9.98. Found: C 53.32; H 3.76; N 10.09.
1,3-Dimethyl-5-(4-iodophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
-oxime (8m). White solid, yield 55%, mp 59–60 ˝C. 1H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d,
J = 8.8 Hz, 1H, Py-H), 7.83 (s, 1H, CH=N), 7.61 (d, J = 7.2 Hz, 2H, Ar-H), 7.35 (d, J = 7.6 Hz, 2H, Ar-H
and Py-H), 7.12 (d, J = 6.8 Hz, 2H, Ar-H), 7.03 (d, J = 8.4 Hz, 1H, Ar-H), 6.69 (d, J = 7.2 Hz, 2H, Ar-H),
5.01 (s, 2H, CH2), 3.61 (s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 156.6, 152.8, 147.0,
146.9, 145.5, 145.4, 140.4, 138.8, 136.7, 134.9, 130.1, 125.1, 121.3, 117.6, 111.4, 100.3, 86.4, 75.5, 34.2, 14.5.
Anal. Calcd for C25H20F3IN4O3: C 49.36; H 3.31; N 9.21. Found: C 49.51; H 3.16; N 9.03.
1,3-Dimethyl-5-phenoxy-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]-
˝
1
oxime (8n). White solid, yield 56%, mp 45–46 C. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d,
J = 8.4 Hz, 1H, Py-H), 7.84 (s, 1H, CH=N), 7.34–7.39 (m, 4H, ArH and Py-H), 7.01–7.12 (m, 4H, ArH),
6.92 (d, J = 7.6 Hz, 2H, Ar-H), 5.03 (s, 2H, CH2), 3.63 (s, 3H, N-CH3), 2.40 (s, 3H, CH3). 13C-NMR
(CDCl3):
δ 165.8, 156.8, 152.8, 147.8, 146.9, 145.5, 145.4, 140.8, 136.7, 135.0, 130.1, 130.0, 125.1, 123.7,
121.3, 115.3, 111.3, 100.3, 75.5, 34.2, 14.8. Anal. Calcd for C25H21F3N4O3: C 62.24; H 4.39; N 11.61.
Found: C 62.41; H 4.23; N 11.42.

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1,3-Dimethyl-5-(2-methoxyphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8o). White solid, yield 52%, mp 55–57 C. H-NMR (CDCl3):
δ 8.45 (s, 1H, Py-H), 7.90 (d,
J = 8.8 Hz, 1H, Py-H), 7.80 (s, 1H, CH=N), 7.38 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.00–7.12 (m, 5H,
ArH), 6.71–6.88 (m, 2H, ArH), 5.03 (s, 2H, CH2), 3.91 (s, 3H, OCH3), 3.65 (s, 3H, N-CH3), 2.38 (s, 3H,
CH3). 13C-NMR (CDCl3):
δ 165.8, 152.7, 149.0, 148.5, 146.8, 145.8, 145.5, 145.4, 140.9, 136.7, 136.6, 135.1,
130.1, 124.6, 121.3, 121.0, 115.9, 112.8, 111.3, 99.6, 75.4, 56.1, 34.2, 14.9. Anal. Calcd for C26H23F3N4O4:
C 60.93; H 4.52; N 10.93. Found: C 60.78; H 4.71; N 11.06.
1,3-Dimethyl-5-(4-methoxyphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8p). White solid, yield 63%, mp 76–78 C. H-NMR (CDCl3):
δ 8.45 (s, 1H, Py-H), 7.90 (d,
J = 8.8 Hz, 1H, Py-H), 7.82 (s, 1H, CH=N), 7.39 (d, J = 8.4 Hz, 2H, Ar-H and Py-H), 7.11 (d, J = 8.4 Hz,
2H, Ar-H), 7.01 (d, J = 8.4 Hz, 1H, Ar-H), 6.85 (s, 4H, Ar-H), 5.04 (s, 2H, CH2), 3.77 (s, 3H, OCH3), 3.62
(s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 155.8, 152.8, 150.7, 148.5, 146.9, 145.5,
145.4, 140.9, 136.7, 136.6, 135.0, 130.1, 121.3, 116.4, 114.9, 111.3, 99.9, 75.4, 55.7, 34.2, 14.8. Anal. Calcd
for C26H23F3N4O4: C 60.93; H 4.52; N 10.93. Found: C 61.04; H 4.35; N 10.78.
1,3-Dimethyl-5-(4-methylphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
˝
1
-oxime (8q). White solid, yield 61%, mp 52–53 C. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.90 (d,
J = 8.4 Hz, 1H, Py-H), 7.84 (s, 1H, CH=N), 7.39 (d, J = 7.6 Hz, 2H, Ar-H and Py-H), 7.12 (d, J = 7.2 Hz,
4H, Ar-H), 7.01 (d, J = 8.4 Hz, 1H, Ar-H), 6.81 (d, J = 7.6 Hz, 2H, Ar-H), 5.05 (s, 2H, CH2), 3.61 (s, 3H,
N-CH3), 2.40 (s, 3H, CH3), 2.32 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 154.8, 152.8, 148.1, 146.8,
145.5, 145.4, 140.9, 136.7, 136.6, 135.1, 133.1, 130.4, 130.1, 121.3, 115.1, 111.3, 100.1, 75.4, 34.2, 20.5, 14.9.
Anal. Calcd for C26H23F3N4O3: C 62.90; H 4.67; N 11.28. Found: C 62.73; H 4.81; N 11.42.
1,3-Dimethyl-5-(4-tert-butylphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
1
-oxime (8r). White oil, yield 57%. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d, J = 8.8 Hz, 1H, Py-H),
7.85 (s, 1H, CH=N), 7.41 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.12 (d, J = 8.4 Hz, 2H, Ar-H), 7.02 (d,
J = 8.8 Hz, 1H, Ar-H), 6.84 (d, J = 8.4 Hz, 2H, Ar-H), 5.05 (s, 2H, CH2), 3.62 (s, 3H, N-CH3), 2.41 (s, 3H,
CH3), 1.32 (s, 9H, t-C4H9). 13C-NMR (CDCl3):
δ 165.8, 154.6, 152.8, 148.1, 146.8, 145.5, 145.4, 141.0,
136.7, 136.6, 135.0, 130.1, 126.8, 121.3, 100.2, 75.4, 34.3, 34.2, 31.4, 14.9. Anal. Calcd for C29H29F3N4O3:
C 64.67; H 5.43; N 10.40. Found: C 64.52; H 5.61; N 10.58.
1,3-Dimethyl-5-(4-trifluoromethoxyphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-
yloxy)phenylmethyl]-oxime (8s). White solid, yield 52%, mp 75–77 ˝C. 1H-NMR (CDCl3):
δ 8.45 (s, 1H,
Py-H), 7.91 (d, J = 8.4 Hz, 1H, Py-H), 7.85 (s, 1H, CH=N), 7.36 (d, J = 8.0 Hz, 2H, Ar-H and Py-H),
7.19 (d, J = 8.4 Hz, 2H, Ar-H), 7.11 (d, J = 8.0 Hz, 2H, Ar-H), 7.02 (d, J = 8.4 Hz, 1H, Ar-H), 6.92 (d,
J = 8.8 Hz, 2H, Ar-H), 5.00 (s, 2H, CH2), 3.64 (s, 3H, N-CH3), 2.39 (s, 3H, CH3). 13C-NMR (CDCl3):
δ
154.9, 152.8, 147.1, 145.5, 140.4, 136.7, 134.8, 130.0, 122.8, 121.3, 116.4, 111.4, 100.3, 75.5, 34.2, 14.5.
Anal. Calcd for C26H20F6N4O4: C 55.13; H 3.56; N 9.89. Found: C 55.01; H 3.71; N 10.03.
1,3-Dimethyl-5-(2,3-difluorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)
˝
phenylmethyl]-oxime (8t). White solid, yield 44%, mp 61–62 C. 1H-NMR (CDCl3):
δ 8.45 (s, 1H, Py-H),
7.91 (d, J = 8.8 Hz, 1H, Py-H), 7.85 (s, 1H, CH=N), 7.36 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.11 (d,
J = 8.0 Hz, 2H, Ar-H), 7.02 (d, J = 8.4 Hz, 1H, Ar-H), 6.93–6.97 (m, 2H, ArH), 6.54 (d, J = 8.4 Hz, 1H,
Ar-H), 5.00 (s, 2H, CH2), 3.68 (s, 3H, N-CH3), 2.36 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 152.8, 147.1,
146.7, 145.5, 145.4, 140.1, 136.7, 136.6, 134.9, 129.9, 123.5, 123.4, 121.3, 112.3, 112.1, 111.6, 111.5, 111.3,
100.0, 75.5, 34.2, 14.3. Anal. Calcd for C25H19F5N4O3: C 57.92; H 3.69; N 10.81. Found: C 57.76; H 3.83;
N 10.96.
1,3-Dimethyl-5-(2,4-dichlorophenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)
˝
1
phenylmethyl]-oxime (8u). White solid, yield 52%, mp 109–111 C. H-NMR (CDCl3):
δ 8.45 (s, 1H,
Py-H), 7.90 (d, J = 8.4 Hz, 1H, Py-H), 7.82 (s, 1H, CH=N), 7.46 (s, 1H, Ar-H), 7.33 (d, J = 8.4 Hz, 2H,
Ar-H and Py-H), 7.00–7.12 (m, 4H, ArH), 6.63 (d, J = 8.8 Hz, 2H, Ar-H), 4.98 (s, 2H, CH2), 3.65 (s, 3H,
N-CH3), 2.36 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 152.8, 150.9, 147.1, 146.5, 145.5, 145.4, 140.1,

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136.7, 134.9, 130.5, 130.0, 129.0, 127.9, 125.1, 123.6, 122.4, 121.3, 116.3, 111.4, 100.1, 75.5, 34.2, 14.2. Anal.
Calcd for C25H19Cl2F3N4O3: C 54.46; H 3.47; N 10.16. Found: C 54.62; H 3.29; N 10.02.
1,3-Dimethyl-5-(2,3-dimethylphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)
phenylmethyl]-oxime (8v). White oil, yield 49%. 1H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d,
J = 8.0 Hz, 1H, Py-H), 7.77 (s, 1H, CH=N), 7.38 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.12 (d, J = 8.0 Hz,
2H, Ar-H), 6.93–7.03 (m, 3H, ArH), 6.42 (d, J = 8.0 Hz, 1H, Ar-H), 5.04 (s, 2H, CH2), 3.62 (s, 3H, N-CH3),
2.41 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.32 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 154.9, 152.8, 148.6,
146.9, 145.5, 141.0, 139.0, 136.7, 136.6, 135.1, 130.1, 126.2, 125.2, 121.3, 111.3, 111.2, 99.8, 75.4, 34.1, 20.0,
14.9, 11.8. Anal. Calcd for C27H25F3N4O3: C 63.52; H 4.94; N 10.97. Found: C 63.36; H 5.09; N 11.05.
1,3-Dimethyl-5-(2,4-dimethylphenoxy)-1H-pyrazole-4-carbaldehyde-O-[4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl]
1
-oxime (8w). White oil, yield 53%. H-NMR (CDCl3):
δ 8.46 (s, 1H, Py-H), 7.91 (d, J = 8.4 Hz, 1H, Py-H),
7.76 (s, 1H, CH=N), 7.38 (d, J = 8.0 Hz, 2H, Ar-H and Py-H), 7.11 (d, J = 7.6 Hz, 2H, Ar-H), 6.88–7.05 (m,
3H, ArH), 6.45 (d, J = 8.4 Hz, 1H, Ar-H), 5.04 (s, 2H, CH2), 3.62 (s, 3H, N-CH3), 2.40 (s, 3H, CH3), 2.36 (s,
3H, CH3), 2.29 (s, 3H, CH3). 13C-NMR (CDCl3):
δ 165.8, 152.9, 152.7, 148.6, 146.9, 145.5, 141.0, 136.7, 135.1,
133.0, 132.2, 130.1, 127.5, 126.2, 125.1, 122.4, 121.7, 121.3, 113.4, 99.7, 75.4, 34.1, 20.5, 16.0, 14.9. Anal. Calcd
for C27H25F3N4O3: C 63.52; H 4.94; N 10.97. Found: C 63.69; H 4.78; N 10.82.
3.2. Biological Tests
3.2.1. Bioassay Methods
All bioassays were performed on representative test organisms reared in the laboratory. The
˝
bioassay was repeated in triplicate at 25
˘
1 C. Assessments were made on a dead/alive basis,
and mortality rates were corrected using Abbott’s formula. For comparative purposes, the controls
Fenpyroximate, Pyridalyl and Imidacloprid were evaluated under the same conditions.
3.2.2. Acaricidal Activity against Tetranychus cinnabarinus
The acaricidal activities against Tetranychus cinnabarinus of the designed compounds were
evaluated using the reported procedure [27]. Sieva bean plants with primary leaves expanded to 10 cm
were selected and cut back to one plant per pot. A small piece was cut from a leaf taken from the main
colony and placed on each leaf of the test plants. This was done about 2 h before treatment to allow
the mites to move over to the test plant and to lay eggs. The size of the piece was varied to obtain
about 60–100 mites per leaf. At the time of the treatment, the piece of leaf used to transfer the mites
was removed and discarded. The mite-infested plants were dipped in the test formulation for 3 s with
agitation and set in the hood to dry. Plants were kept for 48 h before the numbers of live and dead
adults were counted. Each experiment for one compound was triplicated.
3.2.3. Insecticidal Activity against Plutella xylostella
The insecticidal activities of the title compounds against Plutella xylostella were evaluated using the
leaf disk assay [28]. First, a solution of each test sample in N,N-dimethylformamide at a concentration
of 200 µg/mL was prepared and then diluted to the required concentration with water. Cabbage leaves
were dipped into the obtained solutions for 2–3 s. After air-drying, the soaked leaves were put into a
10-cm-long tube, inoculated with second Plutella xylostella larva. Covered with gauze and then kept in
a room for normal cultivation. Mortality was assessed 48 h after treatment. Each experiment for one
compound was triplicated.
3.2.4. Insecticidal Activity against Aphis craccivora
Insecticidal activities of the target compounds were tested against Aphis craccivora by foliar
application [29]. About 60 aphids were transferred to the shoot with 3–5 fresh leaves of horsebean.
The shoot with aphids was cut and dipped into a required solution from 200 µg/mL to 100 µg/mL of

Molecules 2016, 21, 276
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the tested compound for 2 s. After removing extra solutions on the leaf, the aphids were raised in the
˝
shoot at 25 C and 85% relative humidity for 48 h. Each experiment for one compound was triplicated.
4. Conclusions
In summary, 23 pyrazole oxime compounds bearing a 5-trifluoromethyl pyridyl subunit were
synthesized. A preliminary evaluation of the acaricidal and insecticidal activities of the designed
compounds was conducted. Most of them exhibited obvious acaricidal activity against T. cinnabarinus
at a concentration of 200
and 8q still possessed excellent acaricidal activity against T. cinnabarinus under the concentration of
10 g/mL. Additionally, some compounds showed potent insecticidal activities against P. xylostella
and A. craccivora at a concentration of 200 g/mL. Notably, compounds 8e and 8l were more active
against P. xylostella than other compounds, even when the concentration was decreased to 50 g/mL.
Among these compounds, compounds 8e 8i, and 8n showed broad spectrum biological activities; they
µg/mL, and some derivatives such as compounds 8e, 8f, 8l, 8m, 8n, 8p,
µ
µ
µ
,
displayed potential insecticidal activity against P. xylostella and A. craccivora and beyond satisfactory
acaricidal activity against T. cinnabarinus. Further investigations on the structural optimization and
bioactivities of these pyrazole oximes are currently in progress.
Acknowledgments: This work was funded by the National Natural Science Foundation of China (Nos. 21202089,
21372135), the Research Foundation of the Six People Peak of Jiangsu Province (No. 2013-SWYY-013), the
Natural Science Foundation of Jiangsu Province (No. BK20140425), the Technology Project Fund of Nantong City
(Nos. CP12013002, AS2014011, MS22015020).
Author Contributions: H.H. designed the research; H.D., J.C., H.L., B.D., Y.F. performed the research and analyzed
the data; Y.S. wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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