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Article

Synthesis and Herbicidal Activity of 5-Heterocycloxy-3-methyl-1-substituted-1H-pyrazoles

by
Jing Kang
1,
Xia Li Yue
1,
Chang Shui Chen
1,
Jian Hong Li
2 and
Hong Ju Ma
2,*
1
Department of Applied Chemistry, College of Science, Huazhong Agricultural University, Wuhan 430070, China
2
Department of Plant Protection, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
*
Author to whom correspondence should be addressed.
Molecules 2016, 21(1), 39; https://doi.org/10.3390/molecules21010039
Submission received: 17 August 2015 / Revised: 9 December 2015 / Accepted: 11 December 2015 / Published: 25 December 2015
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
With the objective of finding valuable herbicidal candidates, a series of new 5-heterocycloxy-3-methyl-1-substituted-1H-pyrazoles were synthesized and their herbicidal activities were evaluated. The bioassay results showed that some compounds exhibited excellent herbicidal activities at the concentration of 100 mg/L, and compound 5-chloro-2-((3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)oxy)pyrimidine showed bleaching activity to green weeds. In greenhouse conditions, this compound also showed excellent post-emergence herbicidal effect against Digitaria sanguinalis L. at the dosage of 750 g a. i. ha−1.

1. Introduction

Pyrazole derivatives not only occupy an important position in medicinal chemistry due to their wide range of bioactivities such as anticancer [1], analgesic [2], anti-convulsant [3], anti-depressant [4], anti-inflammatory [5], antibacterial [6] antimalarial [6], and antituberculosis activity [6], but also has been drawn great attention in agrochemicals because of their excellent bioactivity such as the commercialized herbicides pyrazolate, pyrazoxyfen, benzofenap, pyraflufen-ethyl, fluazolate, and pyrazosulfuron-ethyl [7,8,9,10,11,12,13,14,15]. Owing to the interesting applications of pyrazoles in the field of agricultural research, the combination of such pyrazole molecule with the additional heterocycles to form polycyclic systems to add functional diversity, is increasingly becoming a fruitful area of the study for their biological activity [16]. Compounds with fused heterocycles showed excellent bioactivity, such as metamifop, fenoxaprop, and pyriftalid [17,18]. Plants treated with herbicides inhibiting carotenoid biosynthesis show characteristic white foliage. Carotenoids protect chlorophyll from photooxidation and chlorophyll is destroyed as it is formed in tissues being devoid of carotenoids. One of the well-studied sites of carotenoid biosynthesis inhibition is that of phytoene desaturase (PDS) and many reviews have been published [19,20,21,22,23,24,25,26]. Despite the great number of structurally diverse inhibitors of phytoene desaturase have been known, the enzyme is still a good target site for new herbicides owing to their good selective toxicity. This has led to the discovery of 2-((5-methyl-3’-(trifluoromethyl)-[1,1’-biphenyl]-2-yl)oxy)-5-(trifluoromethyl)-1,3,4-thiadiazole (1) or 6-(benzothiazol-2-yloxy)-3’-(trifluoromethyl)-[1,1’-biphenyl]-3-carbaldehyde (2) and 5-chloro-2-phenyl-7-(3-(trifluoromethyl)phenyl)benzoxazole (3) as bleaching herbicides candidates [23,27]. The introduction of trifluoromethyl into N-methyl group of pyrazole ring would be expected to improve herbicidal activity due to the intrinsic properties of trifluoromethyl, such as high thermal stability, increased lipophilicity, its electronegativity, and relatively small size [28,29]. The chemical structures of the compounds mentioned above was represented in Figure 1. The pyrazolylpyrimidine derivatives have been reported to show inhibition of chlorophyll and carotenoid biosynthesis in our previous work [30,31]. In view of the above mentioned facts and in continuation of our interest in the synthesis of pyrazole heterocycles, the synthesis and herbicidal activities of these novel pyrazole derivatives are described in this paper.
Molecules 21 00039 g001 550
Figure 1. Structural importance of few of the molecules.
Figure 1. Structural importance of few of the molecules.
Molecules 21 00039 g001

2. Results and Discussion

2.1. Synthesis

The synthetic route of a series of pyrazole derivatives were shown in Scheme 1. The chemical structures of fourteen target compounds were listed in Table 1. The structures of these compounds were confirmed by 1H-NMR (see Supplementary Materials), 13C-NMR (see Supplementary Materials), MS, Elemental analysis, and FT-IR. The compound 5b was synthesized according to the method of preparing 3,5-dimethyl-1-(2,2,2-trifluoroethyl)-1-H-pyrazole reported in the literature [29].
Molecules 21 00039 g002 550
Scheme 1. Synthetic route of target compounds. Reagents and conditions: (a) C2H5OH, reflux, 3 h; (b) C2H5OH/H2O = 1:2, HCl, rt, 5 min, 60 °C, 1.5 h, pH = 7; (c) R1-Cl, DMSO, K2CO3, 3 h; (d) NBS, DMF, rt, overnight.
Scheme 1. Synthetic route of target compounds. Reagents and conditions: (a) C2H5OH, reflux, 3 h; (b) C2H5OH/H2O = 1:2, HCl, rt, 5 min, 60 °C, 1.5 h, pH = 7; (c) R1-Cl, DMSO, K2CO3, 3 h; (d) NBS, DMF, rt, overnight.
Molecules 21 00039 g002
Table
Table 1. Chemical structure of target compounds
Table 1. Chemical structure of target compounds
Compd.RR1Compd.RR1
6aCH2CF3 Molecules 21 00039 i0016hC6H5 Molecules 21 00039 i002
6bCH2CF3 Molecules 21 00039 i0036iC6H5 Molecules 21 00039 i004
6cCH2CF3 Molecules 21 00039 i0057aCH2CF3 Molecules 21 00039 i006
6dCH2CF3 Molecules 21 00039 i0077bCH2CF3 Molecules 21 00039 i008
6eC6H5 Molecules 21 00039 i0097cCH2CF3 Molecules 21 00039 i010
6fC6H5 Molecules 21 00039 i0117dCH2CF3 Molecules 21 00039 i012
6gC6H5 Molecules 21 00039 i0137eC6H5 Molecules 21 00039 i014

2.2. Growth Inhibition of Weed Roots and Shoots

The herbicidal activities of the target compounds were determined with Brassica campestris L. (B. campestris), Amaranthus retroflexus L. (A. retroflexus) and Portulaca oleracea L. (P. oleracea) as samples of annual dicotyledonous plants and Pennisetum alopecuroides L. (P. alopecuroides), Echinochloa crus-galli L. (E. crus-galli), and Digitaria sanguinalis L. (D. sanguinalis) as samples of annual monocotyledonous plants. The results of the inhibition effect were shown in Table 2. All compounds showed inhibitory effect on the roots growth of B. campestris, A. retroflexus, P. oleracea, and D. sanguinalis and the shoots growth of P. alopecuroides and E. crus-galli. Compounds 6d and 7d showed excellent inhibition effect against all tested dicotyledonous and monocotyledonous plants at 100 mg/L. Compound 6d exhibited excellent bleaching activities to B. campestris, P. alopecuroides, E. crus-galli, and D. sanguinalis, and even bleached D. sanguinalis at the concentration of 10 mg/L. Among these target compounds, only compound 6d showed best bleaching activity. It was possible that pyrimidine group played a key role in bleaching phytotoxicity. Comparing the compounds 6d and 7d, the presence of bromine at the 4-position on the pyrazole ring had a negative effect on bleaching activity.
It could be seen from Table 2, compounds 6a–6d showed better herbicidal effect than compounds 6e–6i. The derivatives with 2,2,2-trifluoroethyl at the 1-position on pyrazole showed better inhibition effect than that of compounds substituted with the phenyl group, indicating the 2,2,2-trifluoroethyl group on the pyrazole ring played an important role in inhibition. Compounds 6d and 6h had better inhibition activities than compounds 6a–6c and 6e–6g, indicating that the bulkiness of fused heterocyclic substitute at pyrazole ring might be attributable to the decreased of herbicidal activity. Comparing the activities of compounds 6 and compounds 7, the electron-withdrawing bromine group at C-4 had no beneficial effect on activity.
Table
Table 2. Inhibition of target compounds on the growth of weed.
Table 2. Inhibition of target compounds on the growth of weed.
Compd.Relative Inhibition (%)
B. campestrisA. retroflexusP. oleraceaP. alopecuroidesE. crus-galliD. sanguinalis
RootRootRootShootShootRoot
10 mg/L100 mg/L10 mg/L100 mg/L10 mg/L100 mg/L10 mg/L100 mg/L10 mg/L100 mg/L10 mg/L100 mg/L
6a69 ± 2.178 ± 1.139 ± 1.158 ± 2.13 ± 1.348 ± 1.647 ± 1.059 ± 0.547 ± 1.157 ± 2.327 ± 1.558 ± 1.1
6b80 ± 1.281 ± 1.153 ± 1.760 ± 2.429 ± 1.250 ± 0.856 ± 2.259 ± 1.660 ± 0.670 ± 1.331 ± 2.975 ± 0.7
6c37 ± 1.546 ± 2.026 ± 3.358 ± 1.530 ± 1.774 ± 2.138 ± 2.755 ± 1.026 ± 1.461 ± 0.69 ± 2.421 ± 0.8
6d49 ± 2.4W41 ± 0.310042 ± 1.810034 ± 1.6W30 ± 2.0WWW
6e21 ± 0.522 ± 1.60 ± 1.227 ± 2.54 ± 2.232 ± 1.922 ± 1.232 ± 1.233 ± 2.436 ± 2.72 ± 1.428 ± 0.7
6f42 ± 1.354 ± 2.10 ± 1.37 ± 1.73 ± 2.023 ± 2.030 ± 1.958 ± 1.930 ± 2.452 ± 0.536 ± 1.346 ± 1.3
6g16 ± 1.036 ± 1.03 ± 1.813 ± 0.311 ± 0.553 ± 0.721 ± 1.434 ± 1.112 ± 1.624 ± 1.52 ± 4.47 ± 3.5
6h17 ± 1.662 ± 3.09 ± 0.235 ± 1.541 ± 1.066 ± 0.740 ± 1.963 ± 1.629 ± 1.553 ± 0.81 ± 1.5W
6i61 ± 1.464 ± 0.56 ± 1.129 ± 1.23 ± 2.632 ± 0.948 ± 1.354 ± 1.731 ± 1.437 ± 2.19 ± 2.822 ± 2.2
7a27 ± 1.459 ± 2.425 ± 2.253 ± 0.611 ± 2.255 ± 0.524 ± 2.841 ± 0.827 ± 2.354 ± 2.332 ± 2.474 ± 0.3
7b36 ± 1.753 ± 0.939 ± 1.058 ± 1.034 ± 0.761 ± 0.448 ± 1.778 ± 1.753 ± 1.778 ± 1.744 ± 1.967 ± 1.9
7c22 ± 1.272 ± 0.58 ± 3.520 ± 2.125 ± 1.849 ± 2.037 ± 2.156 ± 1.418 ± 0.168 ± 0.228 ± 2.163 ± 0.2
7d46 ± 1.679± 0.546 ± 1.879 ± 1.048 ± 2.172 ± 0.849 ± 2.277 ± 0.622 ± 0.683 ± 1.145 ± 1.577 ± 0.7
7e32 ± 3.564 ± 1.74 ± 0.715 ± 0.73 ± 1.323 ± 1.432 ± 1.561 ± 0.421 ± 1.743 ± 2.513 ± 1.422 ± 2.5
W: Leaves were completely white after treatment; B. campestris, Brassica campestris L.; A. retroflexus, Amaranthus retroflexus L.; P. oleracea, Portulaca oleracea L.; P. alopecuroides, Pennisetum alopecuroides L.; E. crus-galli, Echinochloa crus-galli L.; D. sanguinalis, Digitaria sanguinalis L.

2.3. Screening in Greenhouse Conditions

Seven target compounds 6a–6d, 7a, 7b, 7d with higher inhibitory effects on the growth of tested plants in preliminary herbicidal bioassays were further screened in greenhouse conditions. From the biological assay results in Table 3, each compound showed herbicidal activities in postemergence treatment at the dosage of 750 g a. i. ha−1, especially monocotyledonous weed D. sanguinalis was most sensitive to compound 6d. It was also found that when the 5-position of the pyrazole was modified by a pyrimidine group, compound 6d had better inhibitory effect on D. sanguinalis than other target compounds, the inhibition rate of the fresh weights reaching 82%. The bioassay results indicated that the substituted group at the 5-position of the pyrazole ring played an important role for herbicidal activity. The 4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-6-(prop-2-yn-1-yloxy)pyrimidine reported in our previous work [30] was very close to compound 6d, structurally, but it showed less herbicidal activity than compound 6d in greenhouse conditions, the difference between these two structures lay in that the pyrimidine was substituted at the 1-position of the pyrazole ring [30] and at the 5-position of the pyrazole ring in this paper, we might conclude that the substituted position on the pyrazole ring also played an important role for herbicidal activity.
Table
Table 3. Herbicidal activities of compounds in greenhouse conditions
Table 3. Herbicidal activities of compounds in greenhouse conditions
Compd.Relative Inhibition (%)
A. theophrastiA. retroflexusP. oleraceaP. alopecuroidesE. crus-galliD. sanguinalis
6a22 ± 1.327 ± 1.430 ± 1.242 ± 1.434 ± 2.621 ± 2.7
6b35 ± 2.029 ± 0.740 ± 1.125 ± 0.826 ± 2.217 ± 2.0
6c40 ± 1.044 ± 0.338 ± 1.732 ± 1.630 ± 1.633 ± 2.6
6d42 ± 2.050 ± 0.930 ± 0.76 ± 2.741 ± 2.682 ± 0.9
7a21 ± 0.646 ± 1.634 ± 2.612 ± 3.160 ± 0.556 ± 0.6
7b9 ± 0.656 ± 0.934 ± 1.55 ± 2.150 ± 2.346 ± 1.7
7d11 ± 2.237 ± 1.828 ± 1.317 ± 2.748 ± 0.452 ± 0.3
A. theophrasti, Abutilon theophrasti M.; A. retroflexus, Amaranthus retroflexus L.; P. oleracea, Portulaca oleracea L.; P. alopecuroides, Pennisetum alopecuroides L.; E. crus-galli, Echinochloa crus-galli L.; D. sanguinalis, Digitaria sanguinalis L.

2.4. Inhibitory Effect of the Compound 6d on Chlorophyll of Weed

In order to evaluate the bleaching activities of compound 6d, the changes in chlorophyll contents of treated seedlings were tested. The IC50 value of compound 6d and positive control (diflufenican) were shown in Table 4. Compound 6d inhibited the synthesis of chlorophyll, and showed the same inhibition activity as commercial standard diflufenican against B. campestris. Gramineous weed P. alopecuroides, E. crus-galli, and D. sanguinalis were slightly sensitive to diflufenican than compound 6d and compound 6d deserved further studies on structure optimization and biological efficacy as the bleaching herbicidal inhibitor.
Table
Table 4. Determination of chlorophyll inhibition of compound 6d.
Table 4. Determination of chlorophyll inhibition of compound 6d.
Species6dDiflufenican
IC50 (95% Confidence Intervals) (mg·L−1)Slope (±SE)IC50 (95% Confidence Intervals) (mg·L−1)Slope (±SE)
B. campestris20.01 (16.48–24.28)3.54 ± 0.3219.79 (11.23–34.90)1.15 ± 0.39
P. alopecuroides11.71 (10.57–12.98)1.53 ± 0.085.97 (4.04–8.82)0.45 ± 0.06
E. crus-galli6.14 (5.83–6.46)2.09 ± 0.040.88 (0.07–9.81)2.24 ± 0.28
D. sanguinalis8.09 (6.08–10.76)4.17 ± 0.341.09 (0.36–3.24)3.12 ± 0.16
B. campestris, Brassica campestris L.; P. alopecuroides, Pennisetum alopecuroides L.; E. crus-galli, Echinochloa crus-galli L.; D. sanguinalis, Digitaria sanguinalis L.

3. Experimental Section

3.1. Analysis and Instruments

Elemental analyses (C, H, N) were performed with a Vario EL III elemental analyzer (Elementar Analysensysteme Gmbh, Hanau, Germany) at the Institute of Chemistry, Chinese Academy of Sciences. Infrared spectra were taken on a Nicolet IR 200 FT-IR instrument (Thermo Scientific, Waltham, MA, USA). 1H-NMR spectra and 13C-NMR were obtained at 400 MHz using a Bruker AVANCE III 400 spectrometer (Bruker Corp., Billerica, MA, USA) in CDCl3 solution with TMS as an internal standard. Mass spectra (MS) were recorded in a Agilent 6110 spectrometer (Agilent, Santa Clara, CA, USA). Melting points were measured on a SGW X-4 melting point apparatus (Shanghai Precision Scientific Instrument Co., Ltd., Shanghai, China) and are uncorrected. All reagents and solvents were obtained from commercial suppliers.

3.2. Synthesis and Characterization of Target Compounds

3.2.1. Synthesis of Compounds 5a and 5b

A solution of 2,2,2-trifluoroethylhydrazine (0.03 mol, 70% in water) and ethyl acetoacetate (0.03 mol) in ethanol (50 mL) was stirred at 60 °C for 3 h. The solvent was removed in vacuo, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether: 1/4 as the eluent) to give the white solid 3-methyl-1-(2,2,2-trifluoromethyl)-1H-pyrazol-3-one (5a). Yield 60.2%; m.p. 105–106 °C; 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.13 (s, 3H, CH3), 3.25 (s, 2H, CH2), 4.19–4.25 (q, 2H, J = 8.8 Hz, CH2CF3,); ESI-MS [M + H]+: 181.1.
To a solution of ethyl acetoacetate (0.03 mol) in water (12 mL) and ethanol (6 mL) phenylhydrazine (0.03 mol) was added. After stirring for 2 min at room temperature, 1 mL of 36.5% concentrated hydrochloric acid was added and stirred at room temperature for 5 min, then at 60 °C for 1.5 h. The reaction mixture was treated with 10% sodium hydroxide solution to pH 7, after stirring for 10 min, the precipitate was filtered, washed with distilled water, and dried to give a light yellow solid as 3-methyl-1-phenyl-2-pyrazoline-5-one (5b). Yield 80.5%; m.p. 126–127 °C; 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.27 (s, 3H, CH3), 3.43 (s, 2H, pyrazole-4H), 7.18–7.23 (m, 1H, ArH,), 7.37–7.43 (m, 2H, ArH), 7.84–7.87 (t, 2H, J= 8.8 Hz, ArH); ESI-MS [M + H]+: 175. The compound 5b was a known compound and its experimental data in the literature [32,33] was shown as follows: m.p., 126–128 °C, 1H-NMR (400 MHz, CDCl3), δ (ppm): 2.13 (s, 3H, CH3), 3.37 (s, 2H, pyrazole-4H), 7.13 (t, J = 7.6 Hz, 1H, ArH), 7.35 (t, J = 8.0 Hz, 2H, ArH), 7.81 (d, J = 7.6 Hz, 2H, ArH).

3.2.2. Synthesis of Compounds 6a–6i

Compound 5a (1.5 mmol) and powdered potassium carbonate (2.25 mmol) were added into dimethylsulfoxide (20 mL). 2, 6-Dichlorobenzoxazole (1.5 mmol) was added to the solution and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (20 mL) and extracted with diethyl ether (30 mL × 2). The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, the filtrate was concentrated in vacuo. The residue was further purified by silica gel column chromatography (ethyl acetate/petroleum ether: 1/10 as the eluent) to give compound 6a as a white solid. Compounds 6b–i were synthesized using the same procedures.
6-Chloro-2-((1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)benzoxazole (6a), white solid, yield 69.6%, m.p. 105–106 °C; IR (KBr, νmax, cm−1): 2919 (CH3), 1637 (-C=N-), 1355 (C-F), 1260 (=C-O-C), 1164 (-C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.24 (s, 3H, CH3), 4.55–4.62 (q, 2H, J = 8.24 Hz, CH2CF3), 6.33 (s, 1H, pyrazole-4H), 7.25–7.27 (dd, 1H, J = 8.5, 1.8 Hz, ArH), 7.42–7.43 (d, 1H, J = 1.8 Hz, ArH), 7.43–7.45 (d, 1H, J = 8.6 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.57, 47.60 (q, 2JC,F = 36 Hz), 92.38, 110.04, 118.87, 121.65 (q, 1JC,F = 278 Hz), 124.69, 128.97, 137.74, 145.39, 147.39, 148.73, 157.90; ESI-MS [M + H]+: 332.1. Anal. Calcd for C13H9ClF3N3O2: C, 47.08; H, 2.74; N, 12.67. Found: C, 47.11; H, 2.72; N, 12.68.
2-((1-(2,2,2-Trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)benzoxazole (6b), white solid, yield 69.7%, m.p. 83–84 °C; IR (KBr, νmax, cm−1): 2969 (CH3), 1629 (-C=N-), 1318 (C-F), 1257 (=C-O-C), 1175 (-C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.31 (s, 3H, CH3), 4.63–4.69 (q, 2H, J = 8.24 Hz, CH2CF3), 6.40 (s, 1H, pyrazole-4H), 7.29–7.36 (m, 2H, ArH), 7.45–7.48 (m, 1H, ArH), 7.59–7.61 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.57, 47.60 (q, 2JC,F = 36 Hz), 92.39, 110.04, 118.87, 121.65 (q, 1JC,F = 278 Hz), 124.69, 128.99, 137.75, 145.40, 147.40, 148.73, 157.90; ESI-MS [M + H]+: 298.2. Anal. Calcd for C13H10F3N3O2: C, 52.53; H, 3.39; N, 14.14; Found: C, 52.50; H, 3.36; N, 14.13.
5-Chloro-2-((1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)benzoxazole (6c), white solid, yield 71.2%, m.p. 85–86 °C; IR (KBr, νmax, cm−1): 2924 (CH3), 1623 (-C=N-), 1307 (C-F), 1254 (=C-O-C), 1149 (-C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.33 (s, 3H, CH3), 4.65–4.71 (q, 2H, J = 8.24 Hz, CH2CF3), 6.42 (s, 1H, pyrazole-4H), 7.30–7.33 (dd, 1H, J = 8.68, 2.12 Hz, ArH), 7.40–7.42 (d, 1H, J = 8.64 Hz, ArH); 7.60–7.61 (d, 1H, J = 2.0 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.59, 47.60 (q, 2JC,F = 36 Hz), 93.44, 111.05, 119.51, 122.88 (q, 1JC,F = 278 Hz), 124.72, 130.61, 141.14, 146.35, 146.92, 149.75, 159.40; ESI-MS [M + H]+: 332.1. Anal. Calcd for C13H9ClF3N3O2: C, 47.08; H, 2.74; N, 12.67; Found: C, 47.12; H, 2.72; N, 12.68.
5-Chloro-2-((1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)pyrimidine (6d), yellow solid, yield 47.9%, m.p. 56–57 °C; IR (KBr, νmax, cm−1): 2968 (CH3), 1626 (-C=N-), 1307 (C-F), 1259 (=C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.31 (s, 3H, CH3), 4.60–4.67 (q, 2H, J = 8.36 Hz, CH2CF3), 6.07 (s, 1H, pyrazole-4H), 8.59 (s, 2H, pyrimidine-4, 6H); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.57, 47.42 (q, 2JC,F = 36 Hz), 93.23, 121.77 (q, 1JC,F = 278 Hz), 126.24, 146.36, 148.47, 157.16, 159.74; ESI-MS [M + H]+: 293.1. Anal. Calcd for C10H8ClF3N4O: C, 41.04; H, 2.76; N, 19.14; Found: C, 41.08; H, 2.75; N, 19.17.
6-Chloro-2-((3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy)benzoxazole (6e), white solid, yield 64.5%, m.p. 78–79 °C; IR (KBr, νmax, cm−1): 2928 (CH3), 1634 (-C=N-), 1258 (=C-O-C), 1147 (-C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.40 (s, 3H, CH3), 6.46 (s, 1H, pyrazole-4H), 7.31–7.37 (m, 2H, ArH), 7.45–7.52 (m, 4H, ArH), 7.63–7.65 (d, 2H, J = 7.6 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.66, 94.53, 110.97, 119.80, 123.06, 125.57, 127.50, 129.22, 129.74, 137.64, 138.90, 145.08, 148.46, 149.11, 159.66; ESI-MS [M + H]+: 326.1. Anal. Calcd for C17H12ClN3O2: C, 62.68; H, 3.71; N, 12.90; Found: C, 62.75; H, 3.69; N, 12.92.
2-((3-Methyl-1-phenyl-1H-pyrazol-5-yl)oxy)benzoxazole (6f), white solid, yield 58.9%, m.p. 42–43 °C; IR (KBr, νmax, cm−1): 2927 (CH3), 1631 (-C=N-), 1256 (=C-O-C), 1153 (-C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.40 (s, 3H, CH3), 6.47 (s, 1H, pyrazole-4H), 7.29–7.36 (m, 3H, ArH), 7.44–7.49 (m, 3H, ArH), 7.59–7.61 (dd, 1H, J = 8.88, 1.64 Hz, ArH), 7.65–7.66 (d, 2H, J = 7.72 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.66, 94.54, 110.18, 119.26, 123.05, 124.21, 124.92, 127.40, 129.18, 137.63, 140.21, 145.34, 148.51, 149.10, 159.45; ESI-MS [M + H]+: 292.2. Anal. Calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42; Found: C, 70.05; H, 4.46; N, 14.42.
5-Chloro-2-((3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy)benzoxazole (6g), white solid, yield 49.3%, m.p. 82–83 °C; IR (KBr, νmax, cm−1): 2924 (CH3), 1630 (-C=N-), 1254 (=C-O-C), 1174 (-C-O-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.40 (s, 3H, CH3), 6.46 (s, 1H, pyrazole-4H), 7.26–7.28 (m, 1H, ArH), 7.33–7.38 (m, 2H, ArH), 7.45–7.49 (t, 2H, J = 7.34 Hz, ArH), 7.58 (d, 1H, J = 1.72 Hz, ArH), 7.63–7.65 (d, 2H, J = 7.88 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.68, 94.91, 121.47, 122.26, 122.90, 124.79, 126.59, 127.23, 129.15, 132.37, 137.80, 147.36, 148.48, 149.03, 168.84. ESI-MS [M + H]+: 326.1. Anal. Calcd for C17H12ClN3O2: C, 62.68; H, 3.71; N, 12.90; Found: C, 62.75; H, 3.69; N, 12.92.
5-Chloro-2-((3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy)pyrimidine (6h), yellow solid, yield 65.4%, m.p. 49–50 °C; IR (KBr, νmax, cm−1): 2951 (CH3), 1560 (-C=N-), 1290 (=C-O-C), 758 (C-Cl). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.39 (s, 3H, CH3), 6.08 (s, 1H, pyrazole-4H), 7.24–7.28 (t, 1H, J = 7.48 Hz, ArH), 7.36–7.40 (t, 2H, J = 7.64 Hz, ArH), 7.62–7.64 (d, 2H, J = 7.68 Hz, ArH), 8.48 (s, 2H, pyrimidine-H); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.65, 95.67, 122.68, 126.76, 126.96, 129.06, 138.07, 146.12, 149.02, 158.09, 161.49; ESI-MS [M + H]+: 287.1. Anal. Calcd for C14H11ClN4O: C, 58.65; H, 3.87; N, 19.54; Found: C, 58.72; H, 3.84; N, 19.57.
2-((3-Methyl-1-phenyl-1H-pyrazol-5-yl)oxy)benzothiazole (6i), yellow solid, yield 65.7%, m.p. 82–83 °C; IR (KBr, νmax, cm−1): 2925 (CH3), 1558 (-C=N-), 1217 (=C-O-C), 689(-C-S-C). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.40 (s, 3H, CH3), 6.35 (s, 1H, pyrazole-4H), 7.30–7.36 (m, 2H, ArH), 7.43–7.47 (m, 3H, ArH), 7.64–7.66 (d, 2H, J = 8.2 Hz, ArH), 7.70–7.72 (d, 1H, J = 8.08 Hz, ArH), 7.81-7.83 (d, 1H, J = 8.12 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.67, 18.43, 94.90, 121.46, 122.27, 122.92, 124.79, 126.59, 127.24, 129.15, 132.37, 137.79, 147.36, 148.48, 149.04, 168.85; ESI-MS [M + H]+: 308.2. Anal. Calcd for C17H13N3OS: C, 66.43; H, 4.26; N, 13.67; Found: C, 66.40; H, 4.23; N, 13.67.

3.2.3. Synthesis of Compounds 7a–7e

Compound 6a (0.5 mmol) was dissolved in N,N-Dimethylformamide (DMF, 6 mL) and N-bromosuccinimide (NBS, 0.6 mmol) was added in this solution, this mixture was stirred at room temperature overnight. Then, the mixture was poured into water (10 mL) and stored overnight, filtered, and the residue was the desired product 7a. Compounds 7b–7e were synthesized using the same procedures.
2-((4-Bromo-1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)-6-chlorobenzoxazole (7a), white solid, yield 49.8%, m.p. 131–132 °C; IR (KBr, νmax, cm−1): 2982 (CH3), 1625 (-C=N-), 1375 (C-F), 1253 (=C-O-C), 1170 (-C-O-C), 598 (C-Br). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.64 (s, 3H, CH3), 4.93–4.99 (q, 2H, J = 8.24 Hz, CH2CF3), 7.40–7.43 (dd, 1H, J = 8.48, 1.8 Hz, ArH), 7.59 (d, 1H, J = 1.4 Hz, ArH), 7.61–7.63 (d, 1H, J = 8.52 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 14.24, 45.62 (q, 2JC,F = 35 Hz), 96.28, 111.30, 120.48, 122.85 (q, 1JC,F = 280 Hz), 126.37, 131.15, 138.46, 149.10, 151.88, 152.43, 163.48; ESI-MS [M + H]+: 410, 412. Anal. Calcd for C13H8BrClF3N3O2: C, 38.03; H, 1.96; N, 10.23; Found: C, 37.96; H, 1.95; N, 10.22.
2-((4-Bromo-1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)benzoxazole (7b), white solid, yield 52.2%, m.p. 107–108 °C; IR (KBr, νmax, cm−1): 2925 (CH3), 1622 (-C=N-), 1319 (C-F), 1267 (=C-O-C), 1162 (-C-O-C), 745 (C-Br). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.28 (s, 3H, CH3), 4.62–4.68 (q, 2H, J = 8.16 Hz, CH2CF3), 7.31–7.36 (m, 2H, ArH), 7.48–7.50 (m, 1H, ArH), 7.57–7.59 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.14, 49.42 (q, 2JC,F = 36 Hz), 84.38, 110.47, 119.52, 122.34 (q, 1JC,F = 278 Hz), 124.56, 125.20, 139.90, 144.29, 149.03, 149.05, 158.77; ESI-MS [M + H]+: 376.1, 378.1; Anal. Calcd for C13H9BrF3N3O2: C, 41.51; H, 2.41; N, 11.17; Found: C, 47.47; H, 2.39; N, 11.16.
2-((4-Bromo-1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)-5-chlorobenzoxazole (7c), white solid, yield 83.2%, m.p. 112–113 °C; IR (KBr, νmax, cm−1): 2955 (CH3), 1627 (-C=N-), 1349 (C-F), 1253 (=C-O-C), 1172 (-C-O-C), 698 (C-Br). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.61 (s, 3H, CH3), 4.91–4.97 (q, 2H, J = 8.36 Hz, CH2CF3), 7.38–7.40 (dd, 1H, J = 8.52, 1.92 Hz, ArH), 7.56–7.57 (d, 1H, J = 1.84 Hz, ArH), 7.58–7.61 (d, 1H, J = 8.52 Hz, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.13, 49.61 (q, 2JC,F = 36 Hz), 84.38, 110.47, 118.18, 122.39 (q, 1JC,F = 278 Hz), 124.20, 130.25, 134.33, 145.97, 146.82, 148.91, 168.23; ESI-MS [M + H]+: 410.1, 412.1. Anal. Calcd for C13H8BrClF3N3O2: C, 38.03; H, 1.96; N, 10.23. Found: C, 37.96; H, 1.95; N, 10.22.
2-((4-Bromo-1-(2,2,2-trifluoroethyl)-3-methyl-1H-pyrazol-5-yl)oxy)-5-chloropyrimidine (7d), white solid, yield 86.4%, m.p. 101–102 °C; IR (KBr, νmax, cm−1): 2993(CH3), 1562 (-C=N-), 1279 (C-F), 1160 (=C-O-C), 641 (C-Br). 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.27 (s, 3H, CH3), 4.54–4.60 (q, 2H, J = 8.24 Hz, CH2CF3), 8.55 (s, 2H, pyrimidine-4,6H); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.12, 49.27 (q, 2JC,F = 36 Hz), 84.73, 122.42 (q, 1JC,F = 278 Hz), 127.61, 145.12, 148.72, 158.34, 160.60; ESI-MS [M + H]+: 371, 373. Anal. Calcd for C10H7BrClF3N4O: C, 32.33; H, 1.90; N, 15.08. Found: C, 32.26; H, 1.88; N, 15.05.
5-(Benzyloxy)-4-bromo-3-methyl-1-phenyl-1H-pyrazole (7e), yellow liquid, yield 35.4%; 1H-NMR (CDCl3, 400 MHz), δ (ppm): 2.30 (s, 3H, CH3), 5.18 (s, 2H, CH2), 7.25–7.33 (m, 6H, ArH), 7.37–7.42 (td, 2H, J = 7.4, 1.88 Hz, ArH), 7.53–7.54 (d, 1H, J = 0.88 Hz, ArH), 7.55–7.56 (m, 1H, ArH); 13C-NMR (CDCl3, 100 MHz), δ (ppm): 13.15, 75.96, 82.42, 122.62, 126.89, 128.49, 128.64, 128.76, 128.91, 134.99, 138.36, 147.49, 149.84; ESI-MS [M + H]+: 343, 345. Anal. Calcd for C17H15BrN2O: C, 59.49; H, 4.41; N, 8.16. Found: C, 59.30; H, 4.36; N, 8.14.

3.3. Biological Evaluation

3.3.1. Inhibitory Effect of the Target Compounds on the Growth of Weed Roots and Shoots

Solutions of 1 g/L and 10 g/L of the tested compounds in DMF were prepared. Agar powder (5 g) was put into boiling distilled water (1 L) until it dissolved, and then cooled down to 40–50 °C. The solution (0.2 mL) containing testing compound and melting agar (19.8 mL) was mixed, and this mixture was added to a 120 mL cup with 4.5 cm diameter. The agar plate without test compound was used as an untreated control. The 15 seeds of B. campestris, A. retroflexus, P. oleracea, P. alopecuroides, E. crus-galli, and D. sanguinalis were put on the surface of the agar plate. These cups were covered with glass lids, and the cultivation conditions were kept at 25 ± 1 °C, 50%–55% relative humidity, and 12 h in the light and 12 h in the dark alternating for seven days. The experiments were conducted in three replicates. Seven days later, the roots lengths of B. campestris, A. retroflexus, P. oleracea, and D. sanguinalis and the shoots lengths of P. alopecuroides, and E. crus-galli were measured. The growth inhibitory rate related to untreated control was determined.

3.3.2. Treatment in Greenhouse Conditions

Twenty seeds of test plants were planted (0.6 cm depth) in plastic boxes (9 cm diameter) containing sandy soil. The plastic boxes were placed at 22–25 °C in a greenhouse. The experiments were conducted in three replicates. The seedlings (one leaf and one stem) of the dicotyledonous weed and the seedlings (two leaf and one stem) of the monocotyledonous weed were sprayed with the test compounds at the concentration of 750 g a. i. ha−1. The emulsions of tested compounds were prepared by dissolving them in DMF with the addition proper water contained 0.1% Triton X-100. The fresh weights were determined 15 days later, and the percentage inhibition relative to the water-sprayed controls was calculated.

3.3.3. Inhibitory Effect of the Compound 6d on Chlorophyll of Weeds

To evaluate the bleaching activity of compound 6d, the changes in chlorophyll contents of treated seedlings were evaluated by Arnon’s method [34] as modified by Lichtenthaler [35]. Bleached seedlings of B. campestris, P. alopecuroides, E. crus-galli, and D. sanguinalis with different concentrations were obtained by the method described above. Chlorophyll a and b were extracted from 50 mg of leaf tissue per treatment in 8 mL of 80% acetone in water for 24 h. The absorbance was measured at 663 nm and 646 nm, respectively. The contents of chlorophyll a and b in leaf tissue were finally calculated by the following formula: for chlorophyll a, Ca = 12.21A663 − 2.81A646; for chlorophyll b, Cb = 20.13A646 − 5.03A663. The concentration causing 50% inhibition (IC50) of in vitro activity for the selected compounds were obtained by analyzing inhibition curves of the activity values (%) versus the logarithm of inhibitory concentration. Diflufenican was selected as the positive control. At least five doses in the inhibitory range were considered, and three replicates were performed under the same conditions.

4. Conclusions

In conclusion, the design, synthesis, and structure–activity relationships of a series of pyrazoyl derivatives have been described. Some compounds displayed an efficient bleaching effect and herbicidal activities against monocotyledonous and dicotyledonous weeds. The herbicidal tests showed that when the 5-position of the pyrazole ring was substituted by heterocycle, the corresponding compounds presented herbicidal activities, especially compound 6d possessed good herbicidal activity against D. sanguinalis at the dosage of 750 g a. i. ha−1.

Supplementary Materials

The following 1H-NMR and 13C-NMR spectra are available online at https://www.mdpi.com/1420-3049/21/1/39/s1.

Acknowledgments

This work was financially supported by the Special Fund for Agro-scientific Research in the Public Interest (Program No.201303031), the National Natural Science Foundation of China (program No. 31201554), and the Key Project in the National Science and Technology Pillar Program of China (Program No. 2012BAD27B00).

Author Contributions

J.K., X.L.Y., C.S.C. and J.H.L. performed research and analyzed the data; and H.J.M. performed research, analyzed the data and 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 6a–6i are available from the authors.

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Kang, J.; Yue, X.L.; Chen, C.S.; Li, J.H.; Ma, H.J. Synthesis and Herbicidal Activity of 5-Heterocycloxy-3-methyl-1-substituted-1H-pyrazoles. Molecules 2016, 21, 39. https://doi.org/10.3390/molecules21010039

AMA Style

Kang J, Yue XL, Chen CS, Li JH, Ma HJ. Synthesis and Herbicidal Activity of 5-Heterocycloxy-3-methyl-1-substituted-1H-pyrazoles. Molecules. 2016; 21(1):39. https://doi.org/10.3390/molecules21010039

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Kang, Jing, Xia Li Yue, Chang Shui Chen, Jian Hong Li, and Hong Ju Ma. 2016. "Synthesis and Herbicidal Activity of 5-Heterocycloxy-3-methyl-1-substituted-1H-pyrazoles" Molecules 21, no. 1: 39. https://doi.org/10.3390/molecules21010039

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