Synthesis of Novel Pyrazole Derivatives Containing Phenylpyridine Moieties with Herbicidal Activity

To discover new compounds with favorable herbicidal activity, a range of phenylpyridine moiety-containing pyrazole derivatives were designed, synthesized, and identified via NMR and HRMS. Their herbicidal activities against six species of weeds were evaluated in a greenhouse via both pre- and post-emergence treatments at 150 g a.i./hm2. The bioassay revealed that a few compounds exhibited moderate herbicidal activities against Digitaria sanguinalis, Abutilon theophrasti, and Setaria viridis in post-emergence treatment. For instance, compounds 6a and 6c demonstrated 50% inhibition activity against Setaria viridis, which was slightly superior to pyroxasulfone. Thus, compounds 6a and 6c may serve as the new possible leading compounds for the discovery of post-emergence herbicides.

Herein, 10 novel pyrazole derivatives containing phenylpyridine moieties w tained via the principle of active substructure splicing, and the structures of thes compounds were confirmed by NMR and HRMS. In addition, the inhibitory activ the resultant compounds against broadleaf and grass weeds were determined.

Chemistry
As can be seen from Schemes 1 and 2, all target compounds were obtained b step reactions using substituted pyridines and ethyl 4,4,4-trifluoroacetoacetate as materials. Intermediates A (4a-4e) were prepared from substituted pyridine an droxyphenylboronic acid via multi-step reactions, such as the Suzuki cross-coup action, nucleophilic substitution reaction, Newman-Kwart rearrangement reacti hydrolysis reaction [27,28]. Intermediate B was obtained via a simple three-step r as per the previously disclosed method, using ethyl 4,4,4-trifluoroacetoacetate as th ing material [29]. The target compounds 6a-6e were prepared via a nucleophilic s tion reaction from intermediates A and B; compounds 6a-6e were oxidized to yie pounds 7a-7e using 3-chloroperbenzoic acid as the oxidant, according to previou closed methods [30]. After synthesis, all target compounds were characterized via and NMR. The NMR and HRMS spectra of all the target compounds are show Supplementary Materials. Substituted phenylpyridines discovered by Schaefer et al. exhibited good inhibition activity against weeds [20,21]. Substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives disclosed by Liu et al. showed excellent inhibitory activity against a variety of weeds [22][23][24]. Du et al. also reported that a range of kresoxim-methyl derivatives containing phenylpyridine moieties exhibited higher inhibitory activities against broadleaf weeds than mesotrione [25,26].
Herein, 10 novel pyrazole derivatives containing phenylpyridine moieties were obtained via the principle of active substructure splicing, and the structures of these target compounds were confirmed by NMR and HRMS. In addition, the inhibitory activities of the resultant compounds against broadleaf and grass weeds were determined.

Chemistry
As can be seen from Schemes 1 and 2, all target compounds were obtained by multistep reactions using substituted pyridines and ethyl 4,4,4-trifluoroacetoacetate as starting materials. Intermediates A (4a-4e) were prepared from substituted pyridine and p-hydroxyphenylboronic acid via multi-step reactions, such as the Suzuki cross-coupling reaction, nucleophilic substitution reaction, Newman-Kwart rearrangement reaction, and hydrolysis reaction [27,28]. Intermediate B was obtained via a simple three-step reaction as per the previously disclosed method, using ethyl 4,4,4-trifluoroacetoacetate as the starting material [29]. The target compounds 6a-6e were prepared via a nucleophilic substitution reaction from intermediates A and B; compounds 6a-6e were oxidized to yield compounds 7a-7e using 3-chloroperbenzoic acid as the oxidant, according to previously disclosed methods [30]. After synthesis, all target compounds were characterized via HRMS and NMR. The NMR and HRMS spectra of all the target compounds are shown in the Supplementary Materials.

Greenhouse Herbicidal Activity Assays
According to the herbicidal activity test results, none of the target compounds exhibited herbicidal activities for pre-emergence. As can be seen from Table 1, a few target compounds exhibited moderate herbicidal activities. Of these, at 150 g a.i./hm 2 , compounds 6a and 6c exhibited 50-60% inhibitory activities when used for the post-emergence treatment of the weeds Digitaria sanguinalis (DS), Abutilon theophrasti (AT), and Eclipta prostrate (EP). Furthermore, the inhibitory activities of compounds 6a and 6c against EP were superior to pyroxasulfone.

Greenhouse Herbicidal Activity Assays
According to the herbicidal activity test results, none of the target compounds exhibited herbicidal activities for pre-emergence. As can be seen from Table 1, a few target compounds exhibited moderate herbicidal activities. Of these, at 150 g a.i./hm 2 , compounds 6a and 6c exhibited 50-60% inhibitory activities when used for the post-emergence treatment of the weeds Digitaria sanguinalis (DS), Abutilon theophrasti (AT), and Eclipta prostrate (EP). Furthermore, the inhibitory activities of compounds 6a and 6c against EP were superior to pyroxasulfone.
From previous studies on the herbicidal activity of pyrazole derivatives, it can be seen that some reported pyrazole derivatives showed good herbicidal activity. According to the study of Zhou et al. [31], the herbicidal activity of some substituted phenylpyrazole derivatives against Abutilon theophrasti, at 150 g a.i./hm 2 , was above 90%. Although compounds 6a and 6c of this work exhibited moderate herbicidal activities, they could also be further optimized as lead compounds to obtain compounds with higher activity.
From Table 1, we can see that the herbicidal activities of compound 6 were obviously better than those of compound 7, indicating that the structure containing 4-(pyridin-2yl)phenylene sulfide was beneficial to the improvement of the activity. According to the SAR of compound 6 in the field of herbicidal activity, when the 3-position of pyridine was a chlorine atom and the 5-position was a fluorine atom or a trifluoromethyl group, compound 6 exhibited the best herbicidal activity for post-emergence.

Greenhouse Herbicidal Activity Assays
According to the herbicidal activity test results, none of the target compounds exhibited herbicidal activities for pre-emergence. As can be seen from Table 1, a few target compounds exhibited moderate herbicidal activities. Of these, at 150 g a.i./hm 2 , compounds 6a and 6c exhibited 50-60% inhibitory activities when used for the post-emergence treatment of the weeds Digitaria sanguinalis (DS), Abutilon theophrasti (AT), and Eclipta prostrate (EP). Furthermore, the inhibitory activities of compounds 6a and 6c against EP were superior to pyroxasulfone.
From previous studies on the herbicidal activity of pyrazole derivatives, it can be seen that some reported pyrazole derivatives showed good herbicidal activity. According to the study of Zhou et al. [31], the herbicidal activity of some substituted phenylpyrazole derivatives against Abutilon theophrasti, at 150 g a.i./hm 2 , was above 90%. Although compounds 6a and 6c of this work exhibited moderate herbicidal activities, they could also be further optimized as lead compounds to obtain compounds with higher activity.
From Table 1, we can see that the herbicidal activities of compound 6 were obviously better than those of compound 7, indicating that the structure containing 4-(pyridin-2yl)phenylene sulfide was beneficial to the improvement of the activity. According to the SAR of compound 6 in the field of herbicidal activity, when the 3-position of pyridine was a chlorine atom and the 5-position was a fluorine atom or a trifluoromethyl group, compound 6 exhibited the best herbicidal activity for post-emergence.   From previous studies on the herbicidal activity of pyrazole derivatives, it can be seen that some reported pyrazole derivatives showed good herbicidal activity. According to the study of Zhou et al. [31], the herbicidal activity of some substituted phenylpyrazole derivatives against Abutilon theophrasti, at 150 g a.i./hm 2 , was above 90%. Although compounds 6a and 6c of this work exhibited moderate herbicidal activities, they could also be further optimized as lead compounds to obtain compounds with higher activity.
From Table 1, we can see that the herbicidal activities of compound 6 were obviously better than those of compound 7, indicating that the structure containing 4-(pyridin-2yl)phenylene sulfide was beneficial to the improvement of the activity. According to the SAR of compound 6 in the field of herbicidal activity, when the 3-position of pyridine was a chlorine atom and the 5-position was a fluorine atom or a trifluoromethyl group, compound 6 exhibited the best herbicidal activity for post-emergence.

Instrumentation
All reagents and other materials were purchased from commercial sources and used without additional purification unless otherwise noted. A B-545 melting point instrument (Buchi, Hangzhou, China) was used to determine the melting point without calibration. A Bruker AV-400 spectrometer (Billerica, MA, USA) was used to generate NMR spectra with DMSO-d 6 serving as the solvents. An Agilent 6545 Q-TOF LCMS spectrometer (Santa Clara, CA, USA) was used for mass spectrometry.

Synthesis
The synthesis approach for pyrazole derivatives containing substituted 4-(pyridin-2yl)benzene moieties in this work is outlined in Scheme 1.
The yellow solid 2a synthesized in the previous step and N-methyl pyrrolidone (100 mL) were stirred under reflux for 7 h under N 2 . Thereafter, the mixture was extracted using ethyl acetate (100 mL × 3), rinsed using brine, and concentrated to give a yellow solid 3a, which was used in the next reaction without further purification.

General Approach to the Synthesis of Compounds 6a-6e and 7a-7e
The target compounds 6a and 7a are taken as examples.

Conclusions
In conclusion, 10 novel pyrazole derivatives containing phenylpyridine moieties were prepared using pyroxasulfone as the lead compound. Among these, compounds 6a and 6c possessed moderate activity (50%) against EP for post-emergence at 150 g a.i./hm 2 , which was slightly superior to pyroxasulfone. This study suggested that it may be the introduction of the phenylpyridine structure that allowed the target compounds to exhibit herbicidal activity at post-emergence only. Thus, compounds 6a and 6c may be lead compounds for further structural optimization.
Author Contributions: Z.C. and W.Z., carried out experimental work; Z.C. prepared the manuscript; X.D. designed the material and supervised the project; and Z.Y. and X.D. revised the paper. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.