Synthesis and bioactivity of novel pyrazole oxime derivatives containing oxazole ring

Article abstract of DOI:10.1016/j.cclet.2015.04.017

Abstract A series of novel pyrazole oxime derivatives containing oxazole ring were designed and synthesized. The title compounds were structurally confirmed by ¹H NMR, ¹³C NMR spectra and elemental analyses. Preliminary bioassay results showed that some of the title compounds displayed promising fungicidal activity besides insecticidal and acaricidal activity. Particularly, compound 8c exhibited potent fungicidal activity against cucumber Pseudoperonospora cubensis beyond good insecticidal activity against Aphis craccivora and Nilaparvata lugens.

Full text of DOI:10.1016/j.cclet.2015.04.017

Accepted Manuscript
Title: Synthesis and bioactivity of novel pyrazole oxime
derivatives containing oxazole ring
Author: Sen-Lin Wang Yu-Jun Shi Hai-Bing He Yu Li Yang
Li Hong Dai
PII:
S1001-8417(15)00150-3
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2015.04.017
CCLET 3284
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
27-2-2015
25-3-2015
30-3-2015
Please cite this article as: S.-L. Wang, Y.-J. Shi, H.-B. He, Y. Li, Y. Li, H. Dai, Synthesis
and bioactivity of novel pyrazole oxime derivatives containing oxazole ring, Chinese
Chemical Letters (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.017
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Graphical Abstract
Synthesis and bioactivity of novel pyrazole oxime derivatives containing oxazole ring
Sen-Lin Wanga, Yu-Jun Shia,b*, Hai-Bing Heb, Yu Lib, Yang Lia, Hong Daib*
a School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, China
b College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, China
A series of novel pyrazole oxime derivatives containing oxazole moiety were designed and prepared. Preliminary bioassay showed that
some title compound, e.g. 8c displayed promising fungicidal activity besides insecticidal activity.
———
* Corresponding authors.
Email address: yjshi2015@163.com (Y. J. Shi), daihong_2001@aliyun.com (H. Dai).
Page 1 of 5

Original article
Synthesis and bioactivity of novel pyrazole oxime derivatives containing oxazole ring
Sen-Lin Wanga, Yu-Jun Shia,b*, Hai-Bing Heb, Yu Lib, Yang Lia, Hong Daib
a School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, China
b College of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, China
ARTICLE INFO
ABSTRACT
A series of novel pyrazole oxime derivatives containing oxazole ring were designed and
Article history:
1
synthesized. The title compounds were structurally confirmed by H NMR, 13C NMR spectra
Received 27 February 2015
Received in revised form 25 March 2015
Accepted 20 March 2015
Available online
and elemental analyses. Preliminary bioassay results showed that some of the title compounds
displayed promising fungicidal activity besides insecticidal and acaricidal activity. Particularly,
compound 8c exhibited potent fungicidal activity against cucumber Pseudoperonospora
cubensis beyond good insecticidal activity against Aphis craccivora and Nilaparvata lugens.
Keywords:
Pyrazole oxime
Substituted oxazole
Insecticidal activity
Acaricidal activity
Fungicidal activity
1. Introduction
In recent years, pyrazole derivatives are an important class of heterocyclic compounds which have attracted much attention for their
good bioactivity, such as fungicidal [1], insecticidal [2,3], acaricidal [4], herbicidal [5], antibacterial [6] and anticancer activity [7]. For
example, Fenpyroximate (in Fig. 1), a potent acaricide with a significant pyrazole ring in the structure, was found to display excellent
acaricidal properties against some phytophagous mites such as Tetranychus urticae Koch and Polyphagotarsonemus latus Banks [8-
10]. This endowed a great impetus to the study of biologically active pyrazole compounds.
In addition, oxazole ring is widely used to design pesticide and medicine for oxazole derivatives displayed versatile biological
activity such as insecticidal [11], herbicidal [12], fungicidal [13,14], and pharmacological activity [15]. More recently, Zhao et al.
reported that some 2-cyanoacrylate compounds bearing oxazole group exhibit a variety of valuable biological effects [16]. Therefore,
oxazole-based compounds became a focus of chemical and pharmaceutical research.
Considering these facts, we speculated that the replacement of the esterified aryl group of Fenpyroximate with a substituted oxazole
moiety (Fig.1) might afford new compounds with wide spectrum of bioactivities. In the present study we describe the synthesis of a
variety of novel pyrazole oximes bearing oxazole ring. Furthermore, all the new compounds have been investigated for their biological
activities including insecticidal, acaricidal and fungicidal activities.
2. Experimental
The synthesis of the title compounds 8a-8r is shown in Scheme 1. Starting from substituted pyrazole aldehyde 1, intermediate 2 was
conveniently obtained by the similar method in the literature [17]. Aldehyde 2 was directly converted to the key intermediate 3 by
treatment with hydroxylamine under basic conditions. Intermediate 4-chloromethyl-2-aryloxazole 7 was successively prepared from
substituted benzoic acid 4. Compound 4 was converted to substituted benzoyl chloride 5 by the reaction with thionyl chloride using
N,N-dimethylformamide as the catalyst. Intermediate 5 was reacted with 25% ammonium hydroxide to give substituted benzamide 6
[18]. The treatment of compound 6 with 1,3-dichloropropanone produced 4-chloromethyl-2-aryloxazole 7. Further reaction of oxime 3
with the key intermediate 7 under Cs2CO3 promoting conditions produced the corresponding pyrazole oximes containing substituted
oxazole moiety. The synthesized compounds 8a-8r were tested for insecticidal activity against Aphis craccivora, and Nilaparvata
lugens and acaricidal activity against Tetranychus cinnabarinus using known procedures [19,20]. Additionally, the fungicidal activity
of compounds 8a-8r against cucumber Pseudoperonospora cubensis in vivo was evaluated according to the literature method [21].
3. Results and discussion
———
* Corresponding authors.
Email addresses: yjshi2015@163.com (Y. J. Shi), daihong_2001@aliyun.com (H. Dai).
Page 2 of 5

The target compounds 8a-8r were separated by column chromatography on silica gel with the solvent system of ethyl acetate and
petroleum ether (60–90 °C). The structures of all the compounds were confirmed by 1H NMR, 13C NMR and elemental analyses. In the
1H NMR spectrum, methyl protons at the 1-position of the pyrazole ring were observed at δ 3.54-3.64, a singlet signal at δ 7.46-7.54
was due to C=CH proton at the 5-position of the oxazole moiety, and a singlet signal at δ 7.79-7.86 was due to C=N proton at the 4-
position of the pyrazole ring. In the 13C NMR spectrum, CH=N group was observed at about δ 147.0, and CH2 group could be seen at
about δ 67.7.
The insecticidal activity against Aphis craccivora and Nilaparvata lugens, and the acaricidal activity against Tetranychus
cinnabarinus of all title compounds were evaluated and the data were listed in Table 1. Imidacloprid and Fenpyroximate were used as
controls, respectively. The results indicated that some of the title compounds exhibited good insecticidal activity against A. craccivora
and N. lugens at the concentration of 500 mg/L. For example, compounds 8b, 8c, 8d, 8f, 8g, 8h, 8i and 8j achieved 100% inhibition
against A. craccivora, which was comparable to that of the control Imidacloprid. The mortalities of compounds 8b, 8c, 8d, 8f, 8g, 8h,
8i, 8j and 8p against N. lugens were around 80%. Moreover, compounds 8b, 8c, 8e, 8f, 8g and 8j showed good to excellent inhibition
against A. craccivora at the dosage of 100 mg/L. Among them, compounds 8d and 8j were still active against A. craccivora when the
dosage was reduced to 20 mg/L with inhibitory values of 70%. Compounds 8b, 8c, and 8f also displayed wonderful inhibition against
N. lugens at the concentration of 100 mg/L. In addition, some of the designed compounds were exhibited moderate insecticidal activity
against T. cinnabarinus at the dosage of 500 mg/L, especially compounds 8i and 8j had 100% inhibition against T. cinnabarinus,
which were comparable to that of the control Fenpyroximate. The data presented in Table 1 also showed that when R2 is the 4-fluoro
atom, compound 8c (R1 is 4-fluoro atom) was more potent against N. lugens than other oxime derivatives. When R2 is the 4-chloro
atom, compound 8j (R1 is 3-fluoro atom) was more active against A. craccivora and T. cinnabarinus than other oxime compounds.
Furthermore, when R2 is the 4-fluoro or 4-chloro atom, pyrazole oximes had more potency against A. craccivora and N. lugens than
did the corresponding 2,4-dichloro analogues, for example, compounds 8c, 8g, and 8m showed 100%, 100%, and 0% against A.
craccivora at the dosage of 500 mg/L, respectively, and compounds 8c, 8g, and 8m displayed 100%, 80%, and 0% against N. lugens at
the dosage of 500 mg/L, respectively.
Fungicidal activity data of compounds 8a-8r against cucumber Pseudoperonospora cubensis were presented in Table 2, and the
commercial fungicide Kresoxim-methyl was used as the standard. As indicated in Table 2, some of the aimed compounds displayed
perfect in vivo fungicidal activity against P. cubensis at the concentration of 200 mg/L. For example, the inhibitory activity of
compounds 8b, 8c, 8d, 8e, 8g, 8h, 8i, and 8m were around 95%, 100%, 100%, 95%, 100%, 100%, 100%, 95%, respectively, which
were similar to that of the control Kresoxim-methyl. Moreover, some of them still exhibited good fungicidal activity against P.
cubensis when the concentration was reduced to 50 mg/L, compounds 8c, and 8g had 80% and 100% inhibition rate, especially,
compound 8g had more potency than the control Kresoxim-methyl (90%). From the data presented in Table 2, we also found that
when R1 is the 4-fluoro atom, R2 is the 4-fluoro or 4-chloro atom, pyrazole oximes 8c and 8g were more active against P. cubensis than
that of the 2,4-dichloro substituted analogue 8m at the concentration of 50 mg/L.
The results of bioassays implied that structural modification of Fenpyroximate by a substituted oxazole ring could give some new
compounds possessing wide spectrum of biological activities. Especially, compound 8c displayed good fungicidal activity besides
insecticidal activity. This study represents a significant basis for the development of novel agrochemicals in future.
4. Conclusion
In summary, a number of novel pyrazole oxime compounds containing oxazole moieties were designed and conveniently prepared.
The preliminary bioassays showed that some title compounds possessed good insecticidal, acaricidal and fungicidal activities.
Particularly, compound 8c exhibited good fungicidal activity against P. cubensis beyond insecticidal activity against A. craccivora and
N. lugens. Further structural optimization and biological activities about these pyrazole oximes are well under way.
Acknowledgment
This study was funded by the National Natural Science Foundation of China (No. 21202089), the Research Foundation of the Six
People Peak of Jiangsu Province (Nos. 2011-SWYY-009, 2013-SWYY-013) and the Technology Project Fund of Nantong City (Nos.
AS2013004, CP12013002).
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O
O
CH3
CH3
CH3
R2
O
N
O
H3C
N
O
H3C
N
N
R1
O
N
N
O
CH3
N
8
CH3
R1=4-F, 4-Cl, 4-Br, 4-CH3 , 2,4-Cl2, etc.
R2=4-F, 4-Cl, 2,4-Cl2
Fenpyroximate
Fig. 1. Designed strategy of the title compounds.
O
OH
O
H3C
H3C
N
H
H3C
H
R1
b
a
R1
N
N
O
Cl
N
O
N
N
N
CH3
CH3
1
CH3
3
2
O
O
O
d
c
R2
R2
R2
NH2
Cl
OH
6
5
4
H
C
CH3
O
O
O
N
f
R2
N
e
R2
N
O
N
N
Cl
CH3
R1
7
8a-8r
Scheme 1. Reagents and conditions: (a) substituted phenols, potassium hydroxide, DMF or DMSO, 45 °C for 2 h, then 110 °C for 6-20 h; (b) hydroxylamine
hydrochloride, potassium hydroxide, methanol or ethanol, reflux for 4-16 h; (c) thionyl chloride, DMF, reflux for 8-12 h; (d) ammonium hydroxide, 0 °C for 4-8
h; (e) 1,3-dichloropropanone, 130 °C for 4-6 h; (f) compound 3, potassium carbonate, Cs2CO3, DMF, 75 °C for 8-28 h.
Page 4 of 5

Table 1
Acaricidal and insecticidal activities of compounds 8a-8r (Mortality, %).
A. craccivora.
N. lugens
500 mg/L
70
T. cinnabarinus
500 mg/L
Compounds
R1
R2
500 mg/L
50
100 mg/L
—
20 mg/L
—
50
60
70
0
100 mg/L
—
80
100
60
—
80
50
0
100 mg/L
—
4-CH3
4-OCH3
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
0
0
0
0
0
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
100
100
100
85
100
100
100
100
100
50
50
0
40
0
80
0
80
100
90
70
80
100
80
0
0
80
—
—
—
—
—
70
—
0
90
100
80
0
80
80
80
80-
100
60
50
0
0
0
80
50
0
100
—
—
—
—
—
—
—
—
0
0
—
—
—
—
—
—
—
4-Cl
2,4-F2
2,4-Cl2
4-F
4-Cl
4-Br
50
60
—
—
70
—
—
—
—
—
0
0
40
50
100
100
0
0
0
0
0
0
0
0
—
100
0
0
3-F
3-CF3
2,4-Cl2
4-F
4-Cl
4-Br
3-CF3
4-OCF3
2,4-F2
—
—
—
—
—
0
—
—
100
—
—
—
100
—
8q
8r
—
Imidacloprid
Fenpyroximate
100
—
100
—
100
“—” refers to “not tested”.
Table 2
Fungicidal activity of compounds 8a-8r (inhibitory ratio, %)
P. cubensis
200 mg/L
Compounds
R1
R2
50 mg/L
4-CH3
4-OCH3
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
2,4-Cl2
75
95
100
100
95
—
45
80
70
0
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
4-Cl
2,4-F2
2,4-Cl2
4-F
4-Cl
4-Br
0
—
100
35
30
—
—
—
30
—
—
—
—
—
90
100
100
100
70
0
30
95
60
60
0
3-F
3-CF3
2,4-Cl2
4-F
4-Cl
4-Br
3-CF3
4-OCF3
2,4-F2
0
0
100
8q
8r
Kresoxim-methyl
“—” refers to “not tested”.
Page 5 of 5