Design, synthesis and bioactivities of novel isoxazole-containing pyrazole oxime derivatives

Article abstract of DOI:10.3390/molecules22122000

In this study, in order to find novel biologically active pyrazole oxime derivatives, twenty-eight new pyrazole oxime compounds containing a substituted isoxazole ring were synthesized and evaluated for their acaricidaland insecticidal activities. Bioassays exhibited that some target compounds indicated good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis, Mythimna separata, and Nilaparvata lugens. Especially, compounds 9c, 9h, 9u, and 9v showed 100.00%, 90.56%, 90.78%, and 90.62% insecticidal activities against A. medicaginis at the concentration of 20 μg/mL, respectively, compounds 9k and 9u had 70.86% and 100.00% insecticidal activities against M. separata at 20 μg/mL, respectively.

Full text of DOI:10.3390/molecules22122000

molecules
Article
Design, Synthesis and Bioactivities of Novel
Isoxazole-Containing Pyrazole Oxime Derivatives
Hong Dai 1 ID , Wei Yao 1, Yuan Fang 2, Siyu Sun 1, Yujun Shi 1,2,*, Jia Chen 1, Guoqing Jiang 1,
*
and Jian Shi 3,
*
1
College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, China;
daihong_2015@aliyun.com (H.D.); yaowei265688@126.com (W.Y.); sunsiyu95@163.com (S.S.);
15642891665@163.com (J.C.)
School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology,
Zhenjiang 212003, China; fyuan6586@aliyun.com
Analysis and Testing Center, Nantong University, Nantong 226019, China
Correspondence: syj@ntu.edu.cn (Y.S.); jguoj2016@163.com (G.J.); shi.j1@ntu.edu.cn (J.S.);
Tel./Fax: +86-513-8501-2851 (Y.S.); +86-513-8501-2851 (G.J.); +86-513-8501-2965 (J.S.)
2
3
*
Received: 9 November 2017; Accepted: 24 November 2017; Published: 27 November 2017
Abstract: In this study, in order to find novel biologically active pyrazole oxime derivatives,
twenty-eight new pyrazole oxime compounds containing a substituted isoxazole ring were
synthesized and evaluated for their acaricidaland insecticidal activities. Bioassays exhibited that some
target compounds indicated good acaricidal and insecticidal activities against Tetranychus cinnabarinus,
Aphis medicaginis, Mythimna separata, and Nilaparvata lugens. Especially, compounds 9c
9v showed 100.00%, 90.56%, 90.78%, and 90.62% insecticidal activities against A. medicaginis at the
concentration of 20 g/mL, respectively, compounds 9k and 9u had 70.86% and 100.00% insecticidal
, 9h, 9u, and
µ
activities against M. separata at 20 µg/mL, respectively.
Keywords: isoxazole; pyrazole oxime; synthesis; bioactivity
1. Introduction
In the past few decades, heterocycles play a significant role in the research of agricultural and
medicinal chemistry. The isoxazole skeleton, a crucial type of nitrogen-containing heterocycle, has been
used in pesticide and drug design because of their various biological activities, such as insecticidal [
1–3],
herbicidal [ ], fungicidal [ ], antiviral [ 10], and anticancer activities [11]. Recently, Yu et al.
4
–
6
7
8–
obtained a series of 3,4,5-trisubstituted isoxazoles that were showing good insecticidal activities [12].
More recently, Sun et al. reported several series of isoxazole compounds carrying benzoylurea moiety
displaying perfect insecticidal activities [13]. The widespread use of isoxazole-based compounds as a
scaffold in the field of agriculture and medicine research endows the isoxazole ring as an important
structural class.
On the other hand, pyrazole oxime derivatives are one of the hotspots in the design of new
drugs due to their broad spectrum of insecticidal [14,15], acaricidal [16], fungicidal [17], anti-TMV [18],
and antitumor activities [19]. In particular, the insecticidal and acaricidal activities have been widely
investigated for their potential applications in agricultural production. For instance, Fenpyroximate
(Figure 1), an excellent acaricide containing a pyrazole oxime moiety, is used to control some
phytophagous mites, such as Tetranychus urticae Koch and Polyphagotarsonemus latus Banks [20,21].
Recently, Dai et al. reported that some pyrazole oximes possessed interesting insecticidal and acaricidal
activity through modification of the esterified group of Fenpyroximate with thiazolylmethoxy or
thiadiazolylmethoxy unit [22,23]. Wang and co-workers synthesized and evaluated the insecticidal
activity of a series of pyrazole oxime ethers containing oxazole ring and found that some compounds
Molecules 2017, 22, 2000; doi:10.3390/molecules22122000
www.mdpi.com/journal/molecules

Molecules 2017, 22, 2000
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showed good insecticidal properties against Aphis craccivora and Nilaparvata lugens [24]. Very recently,
Dai and co-workers also obtained some pyrazole oximes owning wonderful acaricidal and insecticidal
activities against Tetranychus cinnabarinus, Aphis medicaginis and Nilaparvata lugens by substituting the
esterified aryl group of Fenpyroximate with oxadiazole ring [25]. This gave a great impetus to the
search for biologically active molecules carrying the pyrazole oxime subunit.
Encouraged by the aforementioned facts, we envisioned that the introduction of a substituted
isoxazole pharmacophore into the parent pyrazole oxime scaffold might produce some new compounds
with multiple biological activities. In this study, we describe the design and synthesis of a number
of novel pyrazole oxime derivatives bearing isoxazole ring (Figure 1). Moreover, all of the new
compounds were tested for their acaricidal and insecticidal activities.
R2
O
N
N
O
N
N
O
R1
R1 =Me, F, Cl, Br, I, etc.
R2 =4-F, 4-Cl, 2,4-F2
O
N
N
O
O
N
R2
O
O
N
O
O
N
N
N
Fenpyroximate
O
R1
R1=Me, F, Br, I
R2 =4-F, 4-Cl
Target Compounds
Figure 1. The design of the target molecules.
2. Results and Discussion
2.1. Chemistry
The general synthetic route of the title compounds 9a–9v was depicted in Scheme 1. The key
intermediates
pyrazole-4-carbaldehyde (
under basic conditions gave compounds
treatment with hydroxylamine hydrochloride using potassium hydroxide as the base. Intermediate
3-chloromethyl-5-substituted phenyl isoxazole ( ) was prepared from compound . Compound was
easily reacted with dimethyl oxalate under basic conditions to obtain compound . Further reaction
with hydroxylamine hydrochloride afforded compound successfully. Next, a reaction with LiAlH4
was undertaken to form compound in good yields. Further chlorination of compound provided
intermediate smoothly by the addition of some drops of N,N-dimethylformamide. Finally, pyrazole
oximes were admixed with 3-chloromethyl-5-substituted phenyl isoxazole ( ) in acetonitrile using
potassium carbonate as alkali and cesium carbonate as catalyst to afford corresponding compounds
9a 9v in satisfactory yields (Scheme 1). The synthetic route for the target compounds 13a 13f is
shown in Scheme 2. The important intermediates 12 were smoothly prepared in three steps from
compound . The condensation of compound with 4-hydroxybenzaldehyde under basic condition
afforded compounds 10, which were transformed to intermediates 11 by treatment with LiAlH4. Then,
3
were conveniently synthesized by two steps from 1,3-dimethyl-5-chloro-1H-
). The condensation of compound with various substituted phenols
, which were easily transformed into intermediates by
1
1
2
3
8
4
4
5
6
7
7
8
3
8
–
–
8
8

Molecules 2017, 22, 2000
3 of 14
compounds 11 reacted with SOCl2 to give intermediates 12 conveniently. At last, intermediates 12 were
treated with compound in acetonitrile using potassium carbonate as alkali to obtain corresponding
pyrazole oximes derivatives 13a 13f in good yields (Scheme 2). The target compounds 9a 9v and
13a–13f were effectively characterized by 1H-NMR, 13C-NMR, and elemental analyses.
8
–
–
O
O
OH
H3C
H3C
H3C
H
H
N
b
a
N
R1
N
R1
N
Cl
O
N
N
O
N
CH3
CH3
CH3
3
2
1
N
O
O
O
O
O
O
d
O
c
R2
R2
R2
N
O
6
5
4
O
N
O
f
Cl
R2
e
OH
R2
R2 =4-F, 4-Cl, 2,4-F2
8
7
R2
CH3
g
O
N
N
O
N
N
H3C
O
R1
9a-9v
9m: R1 =2-F, R2 =4-Cl
9n: R1 =4-F, R2 =4-Cl
9o: R1 =3-Br, R2 =4-Cl
9p: R1 =4-I, R2 =4-Cl
9r: R1 =4-OMe, R2 =2,4-F2
9s: R1 =4-F, R2 =2,4-F2
9t: R1 =4-Cl, R2 =2,4-F2
9u: R1 =4-Br, R2 =2,4-F2
9a: R1 =2-Me, R2 =4-F
9b: R1 =4-Me, R2 =4-F
9c: R1 =4-OMe, R2 =4-F
9d R1 =2-Cl, R2 =4-F
9e: R1 =4-F, R2 =4-F
9g: R1 =4-Br, R2 =4-F
9h: R1 =4-I, R2 =4-F
9i: R1 =2,4-F2, R2 =4-F
9j: R1 =2,4-Cl2, R2 =4-F
9k: R1 =4-OMe, R2 =4-Cl
9l: R1 =4-OCF3, R2 =4-Cl
9v: R1 =4-I, R2 =2,4-F2
9q: R1 =2,4-F2, R2 =4-Cl
9f: R1 =4-Cl, R2 =4-F
Scheme 1. Synthesis of the title compounds 9a
–
9v. Reagents and conditions: (a) substituted phenol,
; (b) NH2OH HCl, KOH, CH3OH,
KOH, DMF or DMSO, 40 ◦C, 2–4 h, 105 ◦C, 8–24 h, 52–76% for
2
·
reflux, 7–22 h, 61–73% for
3
; (◦c) dimethyl oxalate, CH3ONa, CH3OH, 60 ◦C, 6–8 h, 53–65% for
5
7
;
;
◦
(d) NH2OH
·
HCl, CH3OH, 60 C, 7–10 h, 55–60% for
6
; (e) LiAlH4, THF, 0 C, 3–6 h, 70–76% for
◦
(f) SOCl2, DMF, CH2Cl2, 0 C, 4–7 h, 73–80% for
8
; (g) compound
3, K2CO3, Cs2CO3, CH3CN, reflux,
8–19 h, 47–63% for 9.
O
N
N
O
O
O
O
N
Cl
O
b
OH
H
a
R2
R2
R2
11
10
8
R2
O
N
O
N
O
O
CH3
O
N
d
Cl
N
N
c
R2
H3C
O
R1
12
13a-13f
13a: R1 =4-Me, R2 =4-F 13d R1 =4-I, R2 =4-F
13b: R1 =4-F, R2 =4-F
13c: R1 =4-Br, R2 =4-F
13e: R1 =4-Br, R2 =4-Cl
13f: R1 =4-I, R2 =4-Cl
Scheme 2. Synthesis of the title compounds 13a–13f. Reagents and conditions: (a) 4-hydroxybenzaldehyde,
Cs2CO3, CH3CN, reflux, 5 h, 71–77% for 10; (b) LiAlH4, THF, 0 ◦C, 30 min, 68–72% for 11; (c) SOCl2,
◦
DMF, CH2Cl2, 0 C, 6–8 h, 62–65% for 12; and, (d) compound
46–56% for 13.
3, K2CO3, CH3CN, reflux, 10–15 h,

Molecules 2017, 22, 2000
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2.2. Biological Activities
The synthesized compounds 9a
–
9v and 13a
–
13f were evaluated for insecticidal activities
against Aphis medicaginis, Mythimna separata and Nilaparvata lugens, and acaricidal activity against
Tetranychus cinnabarinus using known procedures, and Chlorantraniliprole, Pyridalyl, Abamectin and
Fenpyroximate were used as the positive controls, respectively. As indicated in Table 1, some title
compounds showed moderate to good acaricidal activity against T. cinnabarinus at a concentration
of 500
Besides acaricidal potencies, most title compounds displayed wonderful insecticidal activities against
A. medicaginis at a dosgae of 500 g/mL, for example, compounds 9b 9c 9d 9e 9g 9h 9i 9j
9k 9q 9r 9s 9t 9u, and 9v all possessed 100.00% inhibition rates, respectively, which were equal
to that of the control Chlorantraniliprole. Furthermore, some aimed compounds exhibited potent
insecticidal activities against A. medicaginis when the dosage was lowered to 100 g/mL. For instance,
compounds 9b 9c 9d 9g 9h 9i 9j 9u, and 9v all owned 100.00% insecticidal activity against
A. medicaginis, respectively, which were comparable to that of the control Chlorantraniliprole. Even
when the dosage was reduced to 20 g/mL, some compounds still had satisfactory insecticidal activity
against A. medicaginis, and the mortalities of compounds 9c 9h 9u, and 9v were 100.00%, 90.56%,
µg/mL. The mortalities of compounds 9e and 9q were 80.46% and 50.38%, respectively.
µ
,
,
,
,
,
,
,
,
,
,
,
,
,
µ
,
,
,
,
,
,
,
µ
,
,
90.78%, and 90.62%, respectively. From the above insecticidal activity data, we can find that the
substituents (R1) on the phenyl ring may have an impact on the activities. When R2 is 4-fluoro or
2,4-difluoro, the substituent (R1) at 4-position of phenyl ring was methoxy (9c), halogen (9g
,
9h
and 9v), or 2,4-position of phenyl ring was fluoro or chloro (9i and 9j), it was more favorable to
the insecticidal activity against A. medicaginis at the dosage of 20 g/mL. Table 2 demonstrated that
most target compounds showed excellent larvicidal activity against M. separata at a concentration
of 500 g/mL. Moreover, some of them had moderate to good larvicidal activity against M. separata
when the concentration came to 100 g/mL, among these derivatives, compounds 9c 9k, and 9u all
exhibited 100.00% inhibition rates, respectively, which were comparable to that of the control Pyridalyl.
, 9u,
µ
µ
µ
,
When the concentration arrived at 20 µg/mL, compounds 9k and 9u still indicated potential inhibitory
activities against M. separata, with the inhibition rates being 70.86% and 100.00%, respectively. When R2
is 4-fluoro or 2,4-difluoro, the substituent (R1) at 4-position of phenyl ring was methoxy (9k) or bromo
(
9u), it was more favorable to the insecticidal activity against M. separata at 20
some designed compounds possessed wonderful inhibitory activities against N. lugens besides good
insecticidal activities against A. medicaginis and M. separata. Among them, compounds 9c 9d 9i
9k 9r 9s, and 9t all had 100.00% inhibition rates against N. lugens at 500 g/mL. When the dosage
was reduced to 100 g/mL, some title compounds were still active against N. lugens, especially, the
µg/mL. Interestingly,
,
,
,
,
,
µ
µ
inhibition rates of compounds 9e and 9g were 75.23% and 75.76%. From the data shown in Tables 1
and 2, we found that the structure-insecticidal activity relationship of some obtained compounds
against N. lugens is similar to structure-insecticidal activity relationship of some compounds against
A. medicaginis. When R2 is 4-fluoro, the substituent (R1) was 4-fluoro (9e) or 4-bromo (9g), it was
more advantageous to increase the insecticidal activity against N. lugens at 100
substituents. The data presented in Tables 1 and 2 also displayed that compounds 9c
9j 9k 9r 9s, and 9t exhibited exciting insecticidal effects against N. lugens and M. separata beyond
wonderful insecticidal activities against A. medicaginis at the dosage of 500 g/mL. At the same time,
compound 9e had good acaricidal activity against T. cinnabarinus besides potent insecticidal activities
against A. medicaginis, M. separata, and N. lugens at 500 g/mL. From the data listed in Tables 1
and 2, we can find that some benzyloxy-linked isoxazole derivatives also possessed good insecticidal
activities against A. medicaginis, M. separata, and N. lugens at the dosage of 500 g/mL. For example,
compounds 13c and 13f both had 100.00% insecticidal activities against A. medicaginis, which were
similar to that of the control Chlorantraniliprole. Compounds 13a 13b 13c 13e, and 13f all displayed
µg/mL than other
,
9g 9h 9i,
,
,
,
,
,
µ
µ
µ
,
,
,
100.00% insecticidal activities against M. separata, respectively, which were equal to that of the control
Pyridalyl. In addition, compound 13d indicated 100.00% inhibitory activity against N. lugens, which
was near to that of the control Abamectin. All of the above data implied that the bioactivity spectrum

Molecules 2017, 22, 2000
5 of 14
of pyrazole oxime derivatives was significantly improved by introducing the important isoxazole ring.
This research indicated that these target compounds may function as potential lead structures for the
discovery of novel pesticides in future.
Table 1. Acaricidal and insecticidal activities of target compounds 9a–9v and 13a–13f (mortality, %).
Tetranychus cinnabarinus
Aphis medicaginis
Compd.
500 µg/mL
100 µg/mL
500 µg/mL
100 µg/mL
20 µg/mL
b
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
0
0
0
0
90.52 ± 0.72
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
50.33 ± 1.59
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
0
40.54 ± 1.22
0
—
—
—
—
100.00 ± 0.00
40.89 ± 0.57
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
60.36 ± 1.08
80.46 ± 0.65 a
50.49 ± 1.78
90.66 ± 0.53
50.67 ± 1.36
0
0
0
0
0
0
0
—
0
—
—
—
—
—
—
—
100.00 ± 0.00
80.73 ± 0.71
100.00 ± 0.00
90.56 ± 0.82
100.00 ± 0.00
85.83 ± 0.69
100.00 ± 0.00
80.28 ± 1.21
0
—
—
—
9m
9n
0
0
—
—
50.72 ± 1.37
0
—
—
—
0
9o
9p
0
0
—
—
0
0
—
—
—
—
9q
9r
9s
9t
9u
9v
13a
50.38 ± 1.23
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
0
0
—
0
—
—
0
70.89 ± 1.25
0
0
0
0
40.57 ± 0.68
0
100.00 ± 0.00
90.78 ± 1.35
100.00 ± 0.00
90.62 ± 0.96
0
—
—
13b
13c
13d
0
—
—
—
0
—
—
—
—
20.26 ± 1.61
100.00 ± 0.00
20.92 ± 0.52
0
0
—
13e
0
—
0
—
—
—
—
13f
Fenpyroximate
Chlorantraniliprole
a
0
100.00 ± 0.00
—
—
100.00 ± 0.00
—
100.00 ± 0.00
30.81 ± 1.47
—
—
100.00 ± 0.00
b
100.00 ± 0.00
100.00 ± 0.00
Each value represents the mean ± standard error of three replications. “—” refers to “not tested”.
Table 2. Insecticidal activities of title compounds 9a–9v and 13a–13f (mortality, %).
Mythimna separata
Nilaparvata lugens
Compd.
500 µg/mL
100 µg/mL
20 µg/mL
500 µg/mL
100 µg/mL
20 µg/mL
b
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
0
—
—
85.54 ± 1.32
0
—
0
0
—
—
—
—
—
0
100.00
90.37 ± 0.85 a
100.00 ± 0.00
60.29 ± 1.03
50.55 ± 0.92
80.76 ± 0.65
80.32 ± 0.82
100.00 ± 0.00
100.00 ± 0.00
90.74 ± 0.57
100.00 ± 0.00
0
0
±
0.00
40.57 ± 0.76
100.00
100.00
±
0.00
0.00
0
0
0
—
±
—
—
0
—
—
—
90.26 ± 1.45
50.32 ± 1.21
80.79 ± 0.87
95.23 ± 0.65
75.23 ± 0.69
30.87 ± 1.43
0
—
0
50.43 ± 0.73
40.56 ± 0.47
30.19 ± 1.58
0
75.76 ± 0.75
50.43 ± 1.58
0
100.00
±
0.00
0
0
0
0
0
—
—
—
—
—
—
90.86 ± 0.71
100.00
±
0.00
70.86 ± 0.63
100.00 0.00
±
—
—
—
—
50.43 ± 0.54
80.31 ± 1.29
0
0
0
—
—
—

Molecules 2017, 22, 2000
6 of 14
Table 2. Cont.
Mythimna separata
Nilaparvata lugens
Compd.
500 µg/mL
100 µg/mL
20 µg/mL
500 µg/mL
100 µg/mL
20 µg/mL
9o
9p
9q
9r
9s
9t
9u
9v
13a
13b
13c
13d
13e
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
70.91 ± 0.89
100.00 ± 0.00
100.00 ± 0.00
100.00 ± 0.00
—
0
—
0
—
—
—
0
0
—
—
0
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
60.58 ± 1.21
0
70.32 ± 0.86
30.48 ± 0.65
100.00
100.00
100.00
±
±
±
0.00
0.00
0.00
40.87 ± 0.73
0
0
70.18 ± 1.43
30.27 ± 1.22
30.75 ± 0.82
100.00
±
0.00 100.00
±
0.00
0
—
50.21 ± 1.56
0
0
0
0
—
—
—
—
40.43 ± 1.81
—
—
—
—
—
—
30.61 ± 0.63
0
0
0
0
20.68 ± 1.21
100.00 0.00
±
20.65 ± 0.53
30.21 ± 1.12
20.57 ± 0.43
—
—
—
—
13f
Pyridalyl
Abamectin
a
100.00
±
0.00 100.00
±
0.00
—
—
100.00
±
0.00 100.00
±
0.00 100.00
±
0.00
b
Each value represents the mean ± standard error of three replications. “—” refers to “not tested”.
3. Experimental Section
3.1. Chemistry
3.1.1. General Procedures
All of the reagents were chemically pure and solvents were dried according to standard methods.
1
1H-NMR and 13C-NMR spectra were obtained on a Bruker AV400 spectrometer (400 MHz, H;
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 elmental 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 intermediate 5-chloropyrazole aldehyde 1 was synthesized according to the
reported procedure [26]. The intermediates 5 and 6 were prepared by the literature method [27].
3.1.2. General Procedure for the Preparation of 2
To a well stirred solution of substituted phenol (30 mmol) in DMF or DMSO (30 mL), KOH was
added (40 mmol) at room temperature. The resulting mixture was heated to 40 ◦C for 2–4 h, and then
compound
After being cooled to room temperature, the mixture was poured into water and extracted with ethyl
acetate (3 50 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered,
1
(20 mmol) was added thereto. The reaction solution was heated to 105 ◦C for 8–24 h.
×
and evaporated to afford intermediate 2, with yields ranging from 52% to 76% [25].
3.1.3. General Procedure for the Preparation of 3
To a solution of hydroxylamine hydrochloride (30 mmol) in anhydrous methanol (60 mL) at room
temperature, was added KOH (40 mmol) in portions, and the mixture was stirred at room temperature
for 20 min. To the above solution was added intermediate 2, the reaction mixture was heated to reflux
for 7–22 h. After being cooled to room temperature, the mixture was poured into water (100 mL), and
the solid precipitate was filtered, washed with water, and dried to give corresponding 5-substituted
phenoxy pyrazole oximes 3, with yields ranging from 61% to 73% [25].

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3.1.4. General Procedure for the Preparation of 7
To a well stirred cold (0 ◦C) solution of intermediate
LiAlH4 (10 mmol) in three portions and the reaction mixture was stirred at 0 C for 3–6 h. To the above
solution, was added ice water (40 mL). After the solid precipitate was filtered, the filtrate was extracted
6
(4 mmol) and THF (60 mL), was added
◦
with ethyl acetate (3
×
50 mL). The combined extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated to produce compound 7, with yields ranging from 70% to 76% [28].
3.1.5. General Procedure for the Preparation of 8
To a well stirred cold (0 ◦C) solution of compound
7 (20 mmol) in CH2Cl2 (50 mL), was added
dropwise a mixture of thionyl chloride (40 mmol) in CH2Cl2 (15 mL). Then, several drops of DMF was
◦
added thereto. The resulting mixture was stirred at 0 C for 4–7 h. To the above solution, was added ice
water (50 mL), and pH value of the mixture was adjusted to 6 by saturated sodium bicarbonate solution.
The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to
afford the corresponding compound 8, with yields ranging from 73% to 80% [28].
3.1.6. General Procedure for the Preparation of 9a–9v
To a mixture of intermediate
8 (4 mmol), compound 3 (5 mmol), and potassium carbonate
(12 mmol) in acetonitrile (30 mL) at room temperature, was added cesium carbonate (1 mmol).
The resulting mixture was heated to reflux for 8–19 h. The reaction mixture was allowed to cool
at room temperature and filtered. The solvent was evaporated under reduced pressure, and the
residue was admixed with water (50 mL) and extracted with ethyl acetate (3
organic layer was washed with water (3 20 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated. The residue was purified by silica gel column chromatography using a mixture of
petroleum ether and ethyl acetate as an eluent to produce the target compounds 9a 9v, with yields
9v were novel, and the physical and spectral
×
50 mL). The combined
×
–
ranging from 47% to 63%. Pyrazole oxime derivatives 9a
–
data for these compounds are listed below. 1H-NMR and 13C-NMR spectra are provided in the
Supplementary Materials.
◦
Data for 9a. Yellow solid, yield 51%, m.p.: 93–94 C. 1H-NMR (400 MHz, DMSO-d6):
δ 7.87–7.91 (m, 2H,
Ar-H), 7.75 (s, 1H, CH=N), 6.98–7.40 (m, 5H, Ar-H), 6.80 (s, 1H, Isoxazole-H), 6.56 (d, J = 8.0 Hz, 1H,
Ar-H), 5.00 (s, 2H, CH2), 3.55 (s, 3H, N-CH3), 2.32 (s, 3H, CH3), 2.24 (s, 3H, CH3). 13C-NMR (100 MHz,
CDCl3):
δ 168.9, 165.0, 162.5, 162.1, 154.9, 148.4, 147.0, 141.7, 131.6, 127.9, 127.1, 126.7, 123.8, 123.6, 116.3,
116.0, 113.3, 99.5, 98.9, 67.0, 34.1, 16.1, 14.7. Anal. Calcd for C23H21FN4O3: C, 65.70; H, 5.03; N, 13.33.
Found: C, 65.56; H, 5.16; N, 13.18.
◦
Data for 9b. White solid, yield 53%, m.p.: 96–97 C. 1H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H, CH=N),
7.68 (d, J = 8.8 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 7.09 (d, J = 8.0 Hz, 2H, Ar-H), 6.79 (d,
J = 8.8 Hz, 2H, Ar-H), 6.47 (s, 1H, Isoxazole-H), 5.10 (s, 2H, CH2), 3.60 (s, 3H, N-CH3), 2.38 (s, 3H,
CH3), 2.27 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 168.8, 162.1, 154.7, 148.3, 146.9, 141.8, 136.2,
133.3, 130.6, 130.4, 129.3, 127.1, 125.9, 118.0, 115.2, 99.8, 99.6, 67.0, 34.3, 20.6, 14.9. Anal. Calcd for
C23H21FN4O3: C, 65.70; H, 5.03; N, 13.33. Found: C, 65.85; H, 4.90; N, 13.21.
◦
1
Data for 9c. Yellow solid, yield 55%, m.p.: 104–105 C. H-NMR (400 MHz, CDCl3):
δ 7.82 (s, 1H,
CH=N), 7.66 (d, J = 8.8 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 6.80–6.85 (m, 4H, Ar-H), 6.46
(s, 1H, Isoxazole-H), 5.11 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 3.61 (s, 3H, N-CH3), 2.37 (s, 3H, CH3).
13C-NMR (100 MHz, CDCl3):
δ 168.8, 162.1, 155.8, 150.6, 148.6, 146.9, 141.8, 136.2, 129.3, 127.1, 125.8,
119.8, 116.4, 115.0, 114.9, 99.5, 99.4, 67.0, 55.6, 34.2, 14.8. Anal. Calcd for C23H21FN4O4: C, 63.30; H,
4.85; N, 12.84. Found: C, 63.45; H, 4.71; N, 12.96.
◦
Data for 9d. Yellow solid, yield 47%, m.p.: 76–78 C. 1H-NMR (400 MHz, CDCl3):
δ 7.82 (s, 1H, CH=N),
7.68 (d, J = 8.4 Hz, 2H, Ar-H), 7.41–7.44 (m, 3H, Ar-H), 7.00–7.15 (m, 2H, Ar-H), 6.70 (d, J = 8.4 Hz,
1H, Ar-H), 6.44 (s, 1H, Isoxazole-H), 5.05 (s, 2H, CH2), 3.65 (s, 3H, CH3), 2.37 (s, 3H, CH3). 13C-NMR

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(100 MHz, CDCl3):
δ
168.7, 162.0, 152.1, 147.3, 147.1, 141.3, 136.2, 131.0, 129.3, 128.0, 127.1, 125.9, 124.6,
122.8, 115.5, 99.7, 99.6, 67.0, 34.3, 14.5. Anal. Calcd for C22H18ClFN4O3: C, 59.94; H, 4.12; N, 12.71.
Found: C, 59.78; H, 4.25; N, 12.85.
1
Data for 9e. Yellow oil, yield 50%. H-NMR (400 MHz, DMSO-d6):
δ 7.89–7.92 (m, 2H, Ar-H), 7.85 (s,
1H, CH=N), 7.14–7.41 (m, 4H, Ar-H), 6.98–7.01 (m, 2H, Ar-H), 6.86 (s, 1H, Isoxazole-H), 5.02 (s, 2H,
CH2), 3.56 (s, 3H, N-CH3), 2.24 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ 169.1, 165.0, 162.5, 161.9,
160.0, 157.6, 152.5, 148.8, 148.0, 147.1, 141.3, 127.9, 123.8, 116.7, 116.3, 116.1, 99.8, 98.9, 67.1, 34.4, 14.6.
Anal. Calcd for C22H18F2N4O3: C, 62.26; H, 4.27; N, 13.20. Found: C, 62.10; H, 4.41; N, 13.33.
Data for 9f. White solid, yield 49%, m.p.: 116–118 ◦C. 1H-NMR (400 MHz, DMSO-d6):
3H, CH=N and Ar-H), 7.36–7.41 (m, 4H, Ar-H), 6.98 (d, J = 8.0 Hz, 2H, Ar-H), 6.85 (s, 1H, Isoxazole-H),
5.02 (s, 2H, CH2), 3.56 (s, 3H, N-CH3), 2.24 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
169.0, 165.0,
δ 7.88–7.92 (m,
δ
162.5, 161.9, 155.2, 147.4, 147.1, 141.3, 129.9, 128.9, 127.9, 127.8, 123.7, 116.7, 116.3, 98.9, 98.6, 67.1, 34.3,
14.5. Anal. Calcd for C22H18ClFN4O3: C, 59.94; H, 4.12; N, 12.71. Found: C, 60.07; H, 4.02; N, 12.57.
Data for 9g. White solid, yield 52%, 114–115 ◦C. 1H-NMR (400 MHz, CDCl3):
δ 7.84 (s, 1H, CH=N),
7.72–7.75 (m, 2H, Ar-H), 7.40 (d, J = 9.2 Hz, 2H, Ar-H), 7.16 (t, J = 8.8 Hz, 2H, Ar-H), 6.78 (d, J = 8.8 Hz,
2H, Ar-H), 6.40 (s, 1H, Isoxazole-H), 5.08 (s, 2H, CH2), 3.60 (s, 3H, CH3), 2.37 (s, 3H, CH3). 13C-NMR
(100 MHz, CDCl3):
δ 169.0, 165.0, 162.5, 161.9, 155.7, 147.1, 141.3, 132.9, 127.9, 127.8, 123.8, 117.1, 116.3,
116.2, 116.1, 99.9, 98.9, 67.1, 34.3, 14.6. Anal. Calcd for C22H18BrFN4O3: C, 54.45; H, 3.74; N, 11.54.
Found: C, 54.30; H, 3.88; N, 11.63.
◦
1
Data for 9h. White solid, yield 55%, m.p.: 100–101 C. H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H,
CH=N), 7.72–7.76 (m, 2H, Ar-H), 7.59 (d, J = 8.8 Hz, 2H, Ar-H), 7.16 (t, J = 8.8 Hz, 2H, Ar-H), 6.67 (d,
J = 8.8 Hz, 2H, Ar-H), 6.41 (s, 1H, Isoxazole-H), 5.09 (s, 2H, CH2), 3.60 (s, 3H, N-CH3), 2.37 (s, 3H, CH3).
13C-NMR (100 MHz, CDCl3):
δ 169.1, 165.0, 162.5, 161.9, 156.6, 147.1, 141.3, 138.8, 127.9, 123.8, 123.7,
117.5, 116.3, 99.9, 98.9, 86.5, 67.1, 34.3, 14.6. Anal. Calcd for C22H18FIN4O3: C, 49.64; H, 3.41; N, 10.53.
Found: C, 49.52; H, 3.27; N, 10.66.
1
Data for 9i. Yellow oil, yield 48%. H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H, CH=N), 7.68 (d, J = 8.4 Hz,
2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 6.73–6.94 (m, 3H, Ar-H), 6.46 (s, 1H, Isoxazole-H), 5.05 (s, 2H,
CH2), 3.67 (s, 3H, N-CH3), 2.34 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ 168.9, 162.0, 147.4, 147.2,
141.1, 136.2, 129.3, 127.1, 125.8, 123.9, 117.5, 117.4, 111.2, 110.9, 105.9, 105.4, 99.4, 99.2, 67.0, 34.3, 14.3.
Anal. Calcd for C22H17F3N4O3: C, 59.73; H, 3.87; N, 12.66. Found: C, 59.85; H, 3.76; N, 12.51.
1
Data for 9j. Yellow oil, yield 51%. H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H, CH=N), 7.68 (d, J = 8.4 Hz,
2H, Ar-H), 7.41–7.44 (m, 3H, Ar-H), 7.08–7.11 (m, 1H, Ar-H), 6.63 (d, J = 8.8 Hz, 1H, Ar-H), 6.44 (s, 1H,
Isoxazole-H), 5.05 (s, 2H, CH2), 3.64 (s, 3H, CH3), 2.35 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ
168.9, 161.9, 150.8, 147.3, 146.8, 141.0, 136.2, 130.7, 129.3, 127.9, 127.1, 125.9, 123.7, 121.9, 116.3, 99.8, 99.4,
67.1, 34.3, 14.2. Anal. Calcd for C22H17Cl2FN4O3: C, 55.59; H, 3.61; N, 11.79. Found: C, 55.45; H, 3.72;
N, 11.94.
◦
1
Data for 9k. Yellow solid, yield 63%, m.p.: 113–115 C. H-NMR (400 MHz, CDCl3):
δ 7.82 (s, 1H,
CH=N), 7.67 (d, J = 8.8 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 6.80–6.85 (m, 4H, Ar-H), 6.46
(s, 1H, Isoxazole-H), 5.11 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 3.61 (s, 3H, N-CH3), 2.37 (s, 3H, CH3).
13C-NMR (100 MHz, CDCl3):
δ 168.8, 162.1, 155.9, 150.6, 148.7, 147.0, 141.8, 136.2, 129.3, 127.1, 125.9,
116.4, 115.0, 99.6, 99.5, 67.0, 55.7, 34.2, 14.8. Anal. Calcd for C23H21ClN4O4: C, 61.00; H, 4.67; N, 12.37.
Found: C, 60.84; H, 4.81; N, 12.49.
◦
1
Data for 9l. Yellow solid, yield 61%, m.p.: 152–154 C. H-NMR (400 MHz, CDCl3):
δ 7.85 (s, 1H,
CH=N), 7.68 (d, J = 8.8 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 7.16 (d, J = 8.8 Hz, 2H, Ar-H), 6.91
(d, J = 9.2 Hz, 2H, Ar-H), 6.46 (s, 1H, Isoxazole-H), 5.07 (s, 2H, CH2), 3.62 (s, 3H, N-CH3), 2.37 (s, 3H,
CH3). 13C-NMR (100 MHz, CDCl3):
δ 168.9, 161.9, 154.9, 147.4, 147.2, 144.8, 141.3, 136.3, 129.3, 127.1,

Molecules 2017, 22, 2000
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125.8, 122.8, 116.4, 99.9, 99.4, 67.1, 34.3, 14.6. Anal. Calcd for C23H18ClF3N4O4: C, 54.50; H, 3.58; N,
11.05. Found: C, 54.63; H, 3.46; N, 11.16.
◦
Data for 9m. Yellow solid, yield 56%, m.p.: 96–98 C. 1H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H, CH=N),
7.68 (d, J = 8.4 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H), 7.00–7.18 (m, 3H, Ar-H), 6.76–6.80 (m, 1H,
Ar-H), 6.45 (s, 1H, Isoxazole-H), 5.05 (s, 2H, CH2), 3.67 (s, 3H, N-CH3), 2.36 (s, 3H, CH3). 13C-NMR
(100 MHz, CDCl3):
δ 168.8, 162.0, 153.2, 150.7, 147.4, 147.1, 144.1, 141.3, 136.2, 129.3, 127.1, 125.8, 124.5,
117.3, 117.1, 116.7, 99.5, 99.4, 67.0, 34.3, 14.4. Anal. Calcd for C22H18ClFN4O3: C, 59.94; H, 4.12; N,
12.71. Found: C, 59.80; H, 3.99; N, 12.79.
◦
1
Data for 9n. White solid, yield 52%, m.p.: 146–147 C. H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H,
CH=N), 7.67 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.8 Hz, 2H, Ar-H), 6.83–7.00 (m, 4H, Ar-H), 6.44
(d, 1H, Isoxazole-H), 5.09 (s, 2H, CH2), 3.61 (s, 3H, N-CH3), 2.36 (s, 3H, CH3). 13C-NMR (100 MHz,
CDCl3):
δ 168.8, 162.0, 159.9, 157.5, 152.6, 147.9, 147.1, 141.5, 136.2, 129.3, 127.1, 125.8, 116.6, 116.4, 99.7,
99.4, 67.0, 34.2, 14.6. Anal. Calcd for C22H18ClFN4O3: C, 59.94; H, 4.12; N, 12.71. Found: C, 60.04; H,
4.23; N, 12.57.
◦
1
Data for 9o. White solid, yield 50%, m.p.: 116–118 C. H-NMR (400 MHz, CDCl3):
δ 7.85 (s, 1H,
CH=N), 7.68 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.8 Hz, 2H, Ar-H), 6.82–7.20 (m, 4H, Ar-H), 6.42
(s, 1H, Isoxazole-H), 5.09 (s, 2H, CH2), 3.61 (s, 3H, N-CH3), 2.37 (s, 3H, CH3). 13C-NMR (100 MHz,
CDCl3):
δ 168.8, 162.0, 157.1, 147.2, 141.3, 136.2, 131.1, 129.3, 127.1, 126.9, 125.8, 123.1, 118.7, 114.1, 100.0,
99.4, 67.1, 34.3, 14.5. Anal. Calcd for C22H18BrClN4O3: C, 52.66; H, 3.62; N, 11.17. Found: C, 52.79; H,
3.48; N, 11.30.
◦
1
Data for 9p. White solid, yield 58%, m.p.: 147–149 C. H-NMR (400 MHz, CDCl3):
δ 7.83 (s, 1H,
CH=N), 7.68 (d, J = 8.4 Hz, 2H, Ar-H), 7.59 (d, J = 8.8 Hz, 2H, Ar-H), 7.45 (d, J = 8.4 Hz, 2H, Ar-H),
6.67 (d, J = 8.8 Hz, 2H, Ar-H), 6.45 (s, 1H, Isoxazole-H), 5.09 (s, 2H, CH2), 3.59 (s, 3H, CH3), 2.36 (s, 3H,
CH3). 13C-NMR (100 MHz, CDCl3):
δ 168.9, 161.9, 156.6, 147.2, 147.1, 141.3, 138.8, 136.2, 129.3, 127.1,
125.8, 117.5, 99.9, 99.4, 86.5, 67.1, 34.3, 14.6. Anal. Calcd for C22H18ClIN4O3: C, 48.15; H, 3.31; N, 10.21.
Found: C, 48.01; H, 3.25; N, 10.33.
◦
Data for 9q. Yellow solid, yield 49%, m.p.: 80–81 C. 1H-NMR (400 MHz, CDCl3):
7.68 (d, J = 8.4 Hz, 2H, Ar-H), 7.44 (d, J = 8.4 Hz, 2H, Ar-H), 6.70–6.95 (m, 3H, Ar-H), 6.46 (s, 1H,
Isoxazole-H), 5.06 (s, 2H, CH2), 3.68 (s, 3H, CH3), 2.34 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 7.83 (s, 1H, CH=N),
δ
167.8, 160.9, 158.5, 156.0, 152.1, 149.6, 146.4, 146.2, 140.1, 139.6, 135.2, 128.3, 126.0, 124.8, 116.5, 110.1,
104.8, 98.3, 98.2, 66.0, 33.2, 13.2. Anal. Calcd for C22H17ClF2N4O3: C, 57.59; H, 3.73; N, 12.21. Found: C,
57.75; H, 3.58; N, 12.08.
Data for 9r. White solid, yield 61%, m.p.: 86–88 ◦C. 1H-NMR (400 MHz, CDCl3):
Ar-H), 7.81 (s, 1H, CH=N), 6.67–7.04 (m, 7H, Ar-H and Isoxazole-H), 5.12 (s, 2H, CH2), 3.75 (s, 3H,
OCH3), 3.61 (s, 3H, N-CH3), 2.38 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
165.1, 162.9, 162.2, 160.7,
δ 7.91–7.97 (m, 1H,
δ
158.3, 155.9, 150.6, 148.8, 147.0, 141.8, 128.9, 119.8, 116.4, 115.0, 112.4, 104.8, 102.9, 99.5, 66.9, 55.7, 34.2,
14.8. Anal. Calcd for C23H20F2N4O4: C, 60.79; H, 4.44; N, 12.33. Found: C, 60.65; H, 4.59; N, 12.45.
◦
Data for 9s. Yellow solid, yield 52%, m.p.: 106–108 C. 1H-NMR (400 MHz, CDCl3):
Ar-H), 7.83 (s, 1H, CH=N), 7.10 (d, J = 6.0 Hz, 2H, Ar-H), 6.63–7.03 (m, 5H, Ar-H and Isoxazole-H), 5.10
(s, 2H, CH2), 3.61 (s, 3H, CH3), 2.37 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
165.0, 162.9, 162.1,
δ 7.91–7.97 (m, 1H,
δ
160.8, 160.0, 158.2, 157.5, 152.6, 147.9, 147.1, 141.5, 128.9, 116.6, 116.4, 112.4, 104.8, 102.8, 99.7, 67.0, 34.2,
14.6. Anal. Calcd for C22H17F3N4O3: C, 59.73; H, 3.87; N, 12.66. Found: C, 59.58; H, 4.01; N, 12.78.
◦
Data for 9t. Yellow solid, yield 56%, m.p.: 108–109 C. 1H-NMR (400 MHz, CDCl3):
Ar-H), 7.84 (s, 1H, CH=N), 6.63–7.26 (m, 7H, Ar-H and Isoxazole-H), 5.10 (s, 2H, CH2), 3.61 (s, 3H,
N-CH3), 2.37 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
165.0, 163.0, 162.6, 162.1, 160.7, 158.2, 155.1,
δ 7.92–7.97 (m, 1H,
δ
147.4, 147.2, 141.4, 129.9, 128.8, 116.6, 112.4, 112.2, 104.8, 102.8, 99.9, 67.0, 34.3, 14.5. Anal. Calcd for
C22H17ClF2N4O3: C, 57.59; H, 3.73; N, 12.21. Found: C, 57.49; H, 3.86; N, 12.35.

Molecules 2017, 22, 2000
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◦
Data for 9u. Yellow solid, yield 60%, m.p.: 101–103 C. 1H-NMR (400 MHz, CDCl3):
δ
7.89 (d, J = 8.4 Hz,
1H, Ar-H), 7.84 (s, 1H, CH=N), 7.53 (d, J = 2.0 Hz, 1H, Ar-H), 6.76–7.40 (m, 6H, Ar-H and Isoxazole-H),
5.11 (s, 2H, CH2), 3.60 (s, 3H, N-CH3), 2.37 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ
165.2, 161.8,
155.7, 147.3, 147.1, 141.4, 136.2, 132.9, 132.2, 130.6, 130.1, 127.7, 124.7, 117.0, 116.2, 104.3, 99.8, 67.0, 34.3,
14.6. Anal. Calcd for C22H17BrF2N4O3: C, 52.50; H, 3.40; N, 11.13. Found: C, 52.66; H, 3.27; N, 11.27.
◦
Data for 9v. Yellow solid, yield 58%, m.p.: 104–106 C. 1H-NMR (400 MHz, CDCl3):
1H, Ar-H), 7.83 (s, 1H, CH=N), 7.58 (d, J = 8.4 Hz, 2H, Ar-H), 6.65–7.54 (m, 5H, Ar-H and Isoxazole-H),
5.11 (s, 2H, CH2), 3.60 (s, 3H, CH3), 2.38 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
165.2, 161.8,
δ 7.89 (d, J = 8.8 Hz,
δ
156.5, 147.3, 147.1, 141.4, 138.8, 136.3, 132.3, 130.7, 130.1, 127.7, 124.7, 117.5, 104.3, 99.9, 86.6, 67.0, 34.3,
14.6. Anal. Calcd for C22H17F2IN4O3: C, 48.02; H, 3.11; N, 10.18. Found: C, 48.13; H, 3.01; N, 10.33.
3.1.7. General Procedure for the Preparation of 10
To a mixture of intermediate
8 (10 mmol), 4-hydroxybenzaldehyde (12 mmol) in acetonitrile
(60 mL) at room temperature, was added cesium carbonate (13 mmol). The resulting mixture was
heated to reflux for 5 h. After being cooled to room temperature, the mixture was poured into water
(100 mL), and the solid precipitate was filtered, washed with water, and dried to afford corresponding
compound 10, with yields ranging from 71% to 77%, which could be used for the next reaction without
further purification.
3.1.8. General Procedure for the Preparation of 11
To a well stirred cold (0 ◦C) solution of intermediate 10 (4 mmol) and TH◦F (60 mL), was added
LiAlH4 (6 mmol) in three portions and the reaction mixture was stirred at 0 C for 30 min. To the
above solution, was added ice water (40 mL). After the solid precipitate was filtered, the filtrate was
extracted with ethyl acetate (3
sulfate, filtered, and concentrated to give compound 11 with yields ranging from 68% to 72%, which
×
30 mL). The combined extracts were dried over anhydrous sodium
could be used for the next reaction without further purification.
3.1.9. General Procedure for the Preparation of 12
To a well stirred cold (0 ◦C) solution of compound 11 (4 mmol) in CH2Cl2 (50 mL), was added
dropwise a mixture of thionyl chloride (8 mmol) in CH2Cl2 (10 mL). Then, several drops of DMF was
added thereto. The resulting mixture was stirred at 0 ◦C for 6–8 h. To the above solution, was added
ice water (50 mL), and the pH value of the mixture was adjusted to 6 by saturated sodium bicarbonate
solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to
afford the corresponding compound 12, with yields ranging from 62% to 65%, which could be used for
the following transformations without further purification.
3.1.10. General Procedure for the Preparation of 13a–13f
To a mixture of intermediate 12 (4 mmol), compound
3 (5 mmol), and potassium carbonate
(10 mmol) in acetonitrile (30 mL) at room temperature. The resulting mixture was heated to reflux for
10–15 h. The reaction mixture was allowed to cool at room temperature and filtered. The solvent was
evaporated under reduced pressure, and the residue was admixed with water (40 mL) and extracted
with ethyl acetate (3
×
30 mL). The combined organic layer was washed with water (3
×
20 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel
column chromatography using a mixture of petroleum ether and ethyl acetate as an eluent to produce
the title compounds 13a
–
13f, with yields ranging from 46% to 56%. Pyrazole oxime derivatives 13a
–
13f
1
were novel and the physical and spectral data for these compounds are listed below. H-NMR and
13C-NMR spectra are provided in the Supplementary Materials.

Molecules 2017, 22, 2000
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Data for 13a. White solid, yield 50%, m.p.: 77–79 ◦C. 1H-NMR (400 MHz, CDCl3):
δ
7.75–7.78 (m, 3H,
Ar-H and CH=N), 7.07–7.26 (m, 6H, Ar-H), 6.94 (d, J = 8.0 Hz, 2H, Ar-H), 6.76 (d, J = 8.0 Hz, 2H, Ar-H),
6.58 (s, 1H, Isoxazole-H), 5.18 (s, 2H, CH2), 4.94 (s, 2H, CH2), 3.58 (s, 3H, N-CH3), 2.37 (s, 3H, CH3),
2.30 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 169.6, 165.1, 162.6, 161.5, 157.8, 154.7, 148.1, 146.8,
140.7, 133.1, 130.8, 130.4, 128.0, 127.9, 123.6, 116.4, 116.1, 115.1, 114.6, 100.2, 98.6, 75.6, 61.8, 34.2, 20.6,
14.9. Anal. Calcd for C30H27FN4O4: C, 68.43; H, 5.17; N, 10.64. Found: C, 68.59; H, 5.05; N, 10.77.
Data for 13b. White solid, yield 48%, m.p.: 99–101 ◦C. 1H-NMR (400 MHz, CDCl3):
Ar-H and CH=N), 7.13–7.24 (m, 4H, Ar-H), 6.82–7.00 (m, 6H, Ar-H), 6.59 (s, 1H, Isoxazole-H), 5.18 (s,
2H, CH2), 4.92 (s, 2H, CH2), 3.60 (s, 3H, N-CH3), 2.35 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 7.75–7.78 (m, 3H,
δ
169.6, 165.1, 162.6, 161.5, 160.0, 157.8, 157.5, 152.7, 152.6, 147.7, 147.0, 140.4, 130.7, 130.3, 128.0, 127.9,
123.6, 116.6, 116.5, 116.4, 116.1, 114.6, 100.2, 98.6, 75.7, 61.8, 34.2, 14.6. Anal. Calcd for C29H24F2N4O4:
C, 65.65; H, 4.56; N, 10.56. Found: C, 65.78; H, 4.42; N, 10.65.
Data for 13c. White solid, yield 46%, m.p.: 91–93 ◦C. 1H-NMR (400 MHz, CDCl3):
δ 7.75–7.78 (m, 3H,
Ar-H and CH=N), 7.40 (d, J = 8.0 Hz, 2H, Ar-H), 7.13–7.22 (m, 4H, Ar-H), 6.94 (d, J = 8.0 Hz, 2H, Ar-H),
6.76 (d, J = 8.0 Hz, 2H, Ar-H), 6.59 (s, 1H, Isoxazole-H), 5.18 (s, 2H, CH2), 4.91 (s, 2H, CH2), 3.59 (s, 3H,
N-CH3), 2.34 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 169.6, 165.1, 162.6, 161.5, 157.8, 155.8, 147.0,
140.3, 132.9, 130.7, 130.3, 128.0, 127.9, 123.6, 117.1, 116.4, 116.1, 114.6, 100.3, 98.6, 75.7, 61.8, 34.2, 14.5.
Anal. Calcd for C29H24BrFN4O4: C, 58.89; H, 4.09; N, 9.47. Found: C, 58.74; H, 4.20; N, 9.61.
Data for 13d. White solid, yield 53%, m.p.: 97–99 ◦C. 1H-NMR (400 MHz, CDCl3):
δ 7.75–7.78 (m, 3H,
Ar-H and CH=N), 7.59 (d, J = 8.0 Hz, 2H, Ar-H), 7.13–7.22 (m, 4H, Ar-H), 6.95 (d, J = 8.0 Hz, 2H, Ar-H),
6.65 (d, J = 8.0 Hz, 2H, Ar-H), 6.59 (s, 1H, Isoxazole-H), 5.19 (s, 2H, CH2), 4.91 (s, 2H, CH2), 3.58 (s, 3H,
N-CH3), 2.34 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 169.5, 165.1, 162.6, 161.5, 157.8, 156.6, 147.0,
146.9, 140.2, 138.8, 130.7, 130.3, 128.0, 127.9, 123.6, 117.5, 116.4, 116.1, 114.6, 100.3, 98.6, 86.4, 75.7, 61.8,
34.2, 14.5. Anal. Calcd for C29H24FIN4O4: C, 54.56; H, 3.79; N, 8.78. Found: C, 54.69; H, 3.90; N, 8.64.
◦
Data for 13e. White solid, yield 51%, m.p.: 88–90 C. 1H-NMR (400 MHz, CDCl3):
δ 7.77 (s, 1H, CH=N),
7.70 (d, J = 8.0 Hz, 2H, Ar-H), 7.39–7.44 (m, 4H, Ar-H), 7.21 (d, J = 8.0 Hz, 2H, Ar-H), 6.94 (d, J = 8.0 Hz,
2H, Ar-H), 6.76 (d, J = 8.0 Hz, 2H, Ar-H), 6.63 (s, 1H, Isoxazole-H), 5.19 (s, 2H, CH2), 4.91 (s, 2H, CH2),
3.59 (s, 3H, N-CH3), 2.34 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 169.4, 161.6, 157.8, 155.8, 147.0,
140.2, 136.4, 133.3, 132.9, 130.7, 130.3, 129.3, 127.1, 125.7, 119.4, 117.1, 116.1, 114.6, 100.3, 99.1, 75.7, 61.7,
34.2, 14.5. Anal. Calcd for C29H24BrClN4O4: C, 57.30; H, 3.98; N, 9.22. Found: C, 57.14; H, 3.85; N, 9.36.
◦
Data for 13f. White solid, yield 56%, m.p.: 83–85 C. 1H-NMR (400 MHz, CDCl3):
δ 7.76 (s, 1H, CH=N),
7.71 (d, J = 8.0 Hz, 2H, Ar-H), 7.59 (d, J = 8.0 Hz, 2H, Ar-H), 7.44 (d, J = 8.0 Hz, 2H, Ar-H), 7.21 (d,
J = 8.0 Hz, 2H, Ar-H), 6.63–6.96 (m, 5H, Ar-H and Isoxazole-H), 5.19 (s, 2H, CH2), 4.91 (s, 2H, CH2),
3.59 (s, 3H, N-CH3), 2.34 (s, 3H, CH3). 13C-NMR (100 MHz, CDCl3):
δ 169.4, 161.6, 157.8, 156.6, 147.0,
146.9, 140.2, 139.2, 138.8, 136.4, 130.7, 130.4, 129.3, 127.1, 119.6, 117.6, 114.6, 100.4, 99.2, 86.4, 75.7, 61.8,
34.2, 14.5. Anal. Calcd for C29H24ClIN4O4: C, 53.19; H, 3.69; N, 8.56. Found: C, 53.33; H, 3.54; N, 8.47.
3.2. Biological Tests
3.2.1. Bioassay Methods
All of the bioassays were performed on representative test organisms reared in the laboratory.
The bioassay was repeated in triplicate. Acaricidal and insecticidal assessments were made on a
dead/alive basis, and mortality rates were corrected using Abbott’s formula.
3.2.2. Insecticidal Activities against Mythimna separata
The larvicidal activities of the title compounds against Mythimna separata were tested by foliar
application [29]. Corn leaves were dipped into the obtained solutions for 2–3 s. After air-drying,
the soaked leaves were put into a culture dish with a piece of filter paper, followed by inoculation

Molecules 2017, 22, 2000
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of 10 third-instar M. separata larvae per dish. Covered with gauze and kept in observation room
for normal cultivation at 24 ◦C–27 ◦C. Mortality was assessed 48 h after treatment. The individuals
who did not respond to the touch of writing brush were recognized as dead. Each test was run
three times and the results were averaged. Pyridalyl, as the control compound, was tested under the
same conditions.
3.2.3. Acaricidal Activities against Tetranychus cinnabarinus, and Insecticidal Activities against
Aphis medicaginis and Nilaparvata lugens
The acaricidal activities against Tetranychus cinnabarinus, and insecticidal activities against
Aphis medicaginis and Nilaparvata lugens of the title compounds were tested by the spray method [30].
Under the Potter spray tower, horsebean leaves, inoculated with T. cinnabarinus were separately
treated with solutions of tested compounds. After th◦at, the◦resultant horsebean leaves were kept
in an observation room for normal cultivation at 24 C–27 C. Mortality was assessed 48 h after
treatment. Each test was run three times and results were averaged. Fenpyroximate was used as
the control. Activities against A. medicaginis were evaluated by the similar procedure except that
the culture temperature was reduced to 20 ◦C–22 ◦C. Inhibitions of N. lugens were tested on the rice
seedlings, which was inoculated with N. lugens first. After that, the resultant rice seedlings were kept in
◦
◦
an observation room for normal cultivation at 24 C–27 C. Mortality was assessed 48 h after treatment.
All of the tests were run with three duplicates and the results were averaged. Chlorantraniliprole and
Abamectin were used as the positive controls, respectively.
4. Conclusions
In summary, a series of novel pyrazole oxime compounds containing isoxazole moiety were
prepared and evaluated for their acaricidal activity against T. cinnabarinus, and insecticidal activities
against A. medicaginis, M. separata and N. lugens. Bioassays results revealed that some title compounds
exhibited potent acaricidal and insecticidal activities. Among these compounds, compound 9e showed
80.46% acaricidal activity against T. cinnabarinus at 500
100.00%, 90.56%, 90.78%, and 90.62% insecticidal activity against A. medicaginis at the concentration
of 20 g/mL, respectively, compounds 9k and 9u possessed 70.86% and 100.00% insecticidal activity
against M. separata at the dosage of 20 g/mL, respectively, and insecticidal activity against N. lugens
µg/mL, compounds 9c, 9h, 9u, and 9v had
µ
µ
of compounds 9e and 9g were 75.23% and 75.76% at 100 µg/mL. Further analogue synthesis and
structural optimization are well under way.
Supplementary Materials: The following are available online.
Acknowledgments: This work was funded by the National Natural Science Foundation of China (No. 21372135),
the Research Foundation of the Six People Peak of Jiangsu Province (No. 2013-SWYY-013), the Technology Project
Fund of Nantong City (Nos. CP12013002, MS22015020), and Postgraduate Research and Practice Innovation
Program of Jiangsu Province (SJCX17_0640).
Author Contributions: Y.S. designed the research; H.D., W.Y., Y.F., S.S., J.C., J.S. performed the research and
analyzed the data; G.J. 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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Sample Availability: Samples of the compounds 9a–9v and 13a–13f are available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).