Chinese Chemical Letters  2015, Vol.26 Issue (06):672-674   PDF    
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
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.
Key words: 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, 9, 10]. This endowed a great impetus to the study of biologically active pyrazole compounds.

Fig. 1.Designed strategy of the title 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. [16] reported that some 2-cyanoacrylate compounds bearing oxazole group exhibit a variety of valuable biological effects. 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].

Scheme 1.Reagents and conditions: (a) substituted phenols,potassium hydroxide, DMF or DMSO,45 ℃ for 2 h,then 110 ℃ 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 ℃ for 4-8 h; (e) 1,3-dichloropropanone,130 ℃ for 4-6 h; (f) compound 3,potassium carbonate, Cs2CO3,DMF,75 ℃ for 8-28 h.
3. Results and discussion

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 ℃). 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 A. craccivora and N. lugens,and the acaricidal activity against T. 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[1TD$DIF],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.

Table 1
Acaricidal and insecticidal activities of compounds 8a-8r (mortality,%).

Fungicidal activity data of compounds 8a-8r against cucumber P. 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.

Table 2
Fungicidal activity of compounds 8a-8r (inhibitory ratio,%).

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.


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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