Synthesis of Novel α-Trifluorothioanisole Derivatives Containing Phenylpyridine Moieties with Herbicidal Activity

To discover novel herbicidal compounds with favorable activity, a range of phenylpyridine-moiety-containing α-trifluorothioanisole derivatives were designed, synthesized, and identified via NMR and HRMS. Preliminary screening of greenhouse-based herbicidal activity revealed that compound 5a exhibited >85% inhibitory activity against broadleaf weeds Amaranthus retroflexus, Abutilon theophrasti, and Eclipta prostrate at 37.5 g a.i./hm2, which was slightly superior to that of fomesafen. The current study suggests that compound 5a could be further optimized as an herbicide candidate to control various broadleaf weeds.


Introduction
Organosulfur compounds are widely present in animals and plants due to their physiological activities, such as diallyl disulfide compounds in garlic, isothiocyanate compounds in cruciferous vegetables and some fruits, and sulfur-containing amino acids and vitamins. These molecules play a vital role in maintaining the metabolism of organisms and various life activities. Therefore, many researchers have conducted in-depth research on these compounds and found that some molecules containing thioheterocycles, thioureas, sulfonamides, thioethers, sulfoxides, sulfones, and other structures show biological activity [1][2][3][4][5][6][7][8]. For instance, Wang et al. [9] reported a class of sulfonylurea compounds with high herbicidal activities against Echinochloa crusgalli and Digitaria sanguinalis for pre-and post-emergence treatment and noted that they were safe for peanut as post-emergence treatment. A range of 5-substituted sulfonylurea derivatives discovered by Li et al. [10] showed good herbicidal activities against Amaranthus retroflexus and Brassica campestris for pre-emergence treatment. It is worth noting that compounds containing sulfide, sulfoxide, and sulfone structures have been widely used in materials [11,12], medicine [13][14][15], and pesticides [16][17][18][19][20][21][22] in the past few decades (Figure 1). The pre-emergence herbicide pyroxasulfone, discovered by Todoroki et al. [23], exhibited excellent herbicidal activity and crop safety, and it is currently used in the field. Substituted 2-phenylpyridines discovered by Schaefer et al. exhibited good inhibition activity against weeds [24,25]. Substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives disclosed by Liu et al. showed excellent inhibitory activity against a variety of weeds [26][27][28]. Du et al. also reported that a range of kresoxim-methyl derivatives containing phenylpyridine moieties exhibited higher inhibitory activities against broadleaf weeds than mesotrione [29,30].
Herein, 18 novel α-trifluorothioanisole derivatives were synthesized through introducing phenylpyridine moieties into α-trifluorothioanisole. The inhibitory activities of the resultant compounds against broadleaf and grass weeds were determined.

Chemistry
The synthesis procedures for the target compounds used in this work are outlined in Scheme 1. Intermediates 3a-3f were obtained according to the literature [31]. The target compounds 5a-5f were prepared via nucleophilic substitution reaction from intermediates 3a-3f and compound 4. In addition, compounds 5a-5f were oxidized to yield compounds 6a-6f and 7a-7f using 3-chloroperbenzoic acid or hydrogen peroxide as oxidants according to previously disclosed methods [32,33]. After synthesis, all target compounds were characterized via HRMS and NMR. X-ray diffraction crystallography was further used to confirm the structure of compound 5a ( Figure 2). The crystal data of compound 5a and the NMR spectrum of all target compounds are shown in the Supplementary Materials.

Chemistry
The synthesis procedures for the target compounds used in this work are outlined in Scheme 1. Intermediates 3a-3f were obtained according to the literature [31]. The target compounds 5a-5f were prepared via nucleophilic substitution reaction from intermediates 3a-3f and compound 4. In addition, compounds 5a-5f were oxidized to yield compounds 6a-6f and 7a-7f using 3-chloroperbenzoic acid or hydrogen peroxide as oxidants according to previously disclosed methods [32,33]. After synthesis, all target compounds were characterized via HRMS and NMR. X-ray diffraction crystallography was further used to confirm the structure of compound 5a ( Figure 2). The crystal data of compound 5a and the NMR spectrum of all target compounds are shown in the Supplementary Materials.

Greenhouse Herbicidal Activity Assays
As can be seen from Table 1, some target compounds exhibited excellent inhibitory activity against the tested dicotyledonous weeds but proved ineffective against monocotyledonous weeds. Of these, at 150 g a.i./hm 2 , compounds 5a, 5f, 6b, and 7a exhibited >80% inhibitory activity when used for the post-emergence treatment of the broadleaf weeds AT, AR, and EP, while compounds 6f and 7f exhibited >80% activity against AT and AR. Furthermore, compound 5a also effectively suppressed the growth of DS and SV, which was slightly better than the positive control fomesafen. Other compounds exhibited varying levels of general herbicidal activity. Further analysis revealed that compound 5a exhibited >85% inhibition against AT, AR, and EP for post-emergence treatment at 37.5 g a.i./hm 2 , which was slightly superior to the inhibition ability of fomesafen, whereas compound 5f also exhibited >70% inhibition against these three weeds. Table 1. The structures and herbicidal activities of α-trifluoroanisole derivatives for post-emergence treatment in a greenhouse assay setting.

Greenhouse Herbicidal Activity Assays
As can be seen from Table 1, some target compounds exhibited excellent inhibitory activity against the tested dicotyledonous weeds but proved ineffective against monocotyledonous weeds. Of these, at 150 g a.i./hm 2 , compounds 5a, 5f, 6b, and 7a exhibited >80% inhibitory activity when used for the post-emergence treatment of the broadleaf weeds AT, AR, and EP, while compounds 6f and 7f exhibited >80% activity against AT and AR. Furthermore, compound 5a also effectively suppressed the growth of DS and SV, which was slightly better than the positive control fomesafen. Other compounds exhibited varying levels of general herbicidal activity. Further analysis revealed that compound 5a exhibited >85% inhibition against AT, AR, and EP for post-emergence treatment at 37.5 g a.i./hm 2 , which was slightly superior to the inhibition ability of fomesafen, whereas compound 5f also exhibited >70% inhibition against these three weeds.  From Table 1, we can see that the herbicidal activities of compound 5 were slightly better than those of compounds 6 and 7. According to the SAR of compound 5 in the field of herbicidal activity, when R 1 and R 2 were both substituted by hydrogen atoms (5a), the activities of compound 5 against three broadleaf weeds were better than those of other compounds. For compound 6, when R 1 was substituted by a hydrogen atom and R 2 was substituted by a fluorine atom (6b), the herbicidal activities of compound 6 were optimal. For compound 7, the optimal herbicidal activities were observed when R 1 and R 2 were substituted by either hydrogen atoms or fluorine atoms (7a, 7f).

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 was used to determine melting point without calibration. A Bruker AV-400 or AV-500 MHz spectrometer was used to generate NMR spectra with DMSO-d 6 or CDCl 3 serving as solvents. An Agilent 6545 Q-TOF LCMS spectrometer was used for mass spectrometry. A Bruker D8 Venture diffractometer was utilized to collect crystallographic data.

Synthesis
The synthesis methods of the title compounds are outlined in Scheme 1.
All target compounds were dissolved in N,N-dimethylformamide, diluted to an appropriate dose with distilled water containing 0.1% Tween-80 emulsifier, and used for seedlings at the three-leaf stage with three replicates. Seedlings treated with N,N-dimethylformamide and distilled water containing 0.1% Tween-80 emulsifier served as blank controls, with fomesafen-treated seedlings serving as positive controls. The application rates were 150, 75, and 37.5 g a.i./ha. Herbicidal activity was assessed visually after a 20-day period, with the results being listed in Table 1.

Conclusions
In conclusion, 18 novel α-trifluorothioanisole derivatives containing phenylpyridine moieties were prepared as candidate herbicides. The preliminary herbicidal activity assay results show that some target compounds exhibited good herbicidal activities against broadleaf weeds at 150 g a.i./hm 2 . Among these, compound 5a possessed excellent activity (>85%) against AT, AR, and EP at 37.5 g a.i./hm 2 , which was slightly superior to fomesafen. Furthermore, compound 5f possessed good activity (>70%) against AT, AR, and EP at 37.5 g a.i./hm 2 , which was equivalent to that of fomesafen. Thus, compound 5a may be a lead compound 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.