Abstract
A new series of 1,3,4-oxadiazole derivatives with a 3-chloropyridin-2-yl-1H-pyrazole moiety was designed, synthesized, and characterized. The results of bioassay against Helicoverpa armigera and Plutella xylostella indicated that some of the synthesized compounds showed remarkable larvicidal activity. In particular, the LC50 values of the most active compounds against P. xylostella were 46.5, 23.9, and 13.9 mg/dm3, and against Helicoverpa armigera were 88.3 and 69.5 mg/dm3, the latter being slightly better than commercial chlorpyrifos (LC50 103.77 mg/dm3). Preliminary SAR was also discussed.
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Introduction
In recent years, because of the continued warming weather and the resistance of insecticide, the pests in agriculture have become more and more difficult to prevent and control, which brought about enormous economic losses all over the world annually [1]. For example, the diamondback moth (Plutella xylostella) is a seriously harmful pest in many countries [2] and has caused a significant loss to oilseed plants and crucifers [3]. Hence, the discovery of novel molecules with excellent insecticidal activity has been attracting more and more attention in recent years.
1,3,4-Oxadiazole, a highly active pharmacophore, is widely used in pesticide design. Many compounds containing such a scaffold with excellent activity have been reported as insecticides (such as compounds 1–5 in Fig. 1) [4,5,6,7,8,9,10,11,12,13,14], fungicides [15,16,17], and herbicides [18,19,20,21]. For example, Liu and co-workers developed a series of anthranilic diamides analogs containing 1,3,4-oxadiazole that showed excellent insecticidal activity against P. xylostella [11]. As well as some insecticidal sarisan analogues with an 1,3,4-oxadiazole scaffold were developed by Guo et al. [4,5,6].
The structures of insecticidal molecules containing a structure of 1,3,4-oxadiazole
3-Chloropyridin-2-yl-1H-pyrazole is another important heterocyclic group and appears in many insecticidal molecules [22,23,24,25,26,27], the commercial chlorantraniliprole [22], cyantraniliprole [23, 24], and SYP-9080 (Fig. 2) [25] containing this type of scaffold. And in recent years, a large number of 3-chloropyridin-2-yl-1H-pyrazole derivatives with excellent larvicidal activity were reported (such as compounds 5, 6 in Fig. 1 and compounds 6–10 in Fig. 2) [9, 10, 25,26,27]. Most of them are anthranilic diamide derivatives and shown excellent insecticidal activities against various pests including diamondback moth, cotton bollworm, beet armyworm, oriental leafworm moth, etc. in our previous work [28,29,30,31,32,33]. A series of diamide derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold and 1,3,4-oxadiazole substructure has been developed; some of them (such compounds 9 and 10 in Fig. 2) showed excellent larvicidal activity against not only lepidoptera but also diptera and homoptera.
The structures of commercial insecticides and insecticidal molecules containing the substructures of 3-chloropyridin-2-yl-1H-pyrazole
Encouraged by above reports and as a continuation of work on finding potential insecticidal molecule, an attempt was made in this work by incorporation of the scaffolds of 3-chloropyridin-2-yl-1H-pyrazole and 1,3,4-oxadiazole, then structural variation by the introduction of different kinds of moiety via an ether linkage, resulting in 1,3,4-oxadiazole derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold with good insecticidal activity (Fig. 3). Structures of the synthesized compounds were characterized by 1H NMR, 19F NMR, 13C NMR, and HR-MS. Results of larvicidal assays indicated that some of synthesized compounds exhibited good larvicidal activities. In particular, the compounds 16u, 16v, and 16w exhibited good larvicidal activities against P. xylostella and H. armigera; the LC50 values of them against P. xylostella were 46.5, 23.9, and 13.9 mg/dm3, respectively, and the LC50 values of compounds 16u, 16v against H. armigera were 88.3, 69.5 mg/dm3, respectively.
The design of title compound
Results and discussion
Synthesis
The synthetic route for the title compounds are depicted in Scheme 1. First, the key intermediates substituted ethyl 2-phenoxyacetates 13 were easily obtained in good yield via reactions of ethyl 2-chloroacetate with different substituted phenols in the present of K2CO3 in solvent of acetonitrile, which further reacted with hydrazine hydrate (80%) to yield substituted 2-phenoxyacetohydrazides 14 in > 90% yields. Subsequent treatment of substituted 2-phenoxyacetohydrazides 14, with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (15, prepared according to reported protocols [19, 26, 27]) in the presence of phosphorus oxychloride at refluxing temperature afforded the title compounds 16 with excellent yield by employed known protocol [34].
In the 1H NMR spectra, the proton at position 5 of pyridine ring appeared as a doublet of doublets near δ = 8.45 ppm due to the coupling coefficients from the protons at positions 3 and 4 of the pyridine; the coupling constants were 4.6 and 1.5 Hz, respectively. Pyrazole-H exhibited a singlet near 7.15 ppm. The two protons (–CH2–) appeared as a singlet near 5.10 ppm; in the 13C NMR of F-contained compound, because of the coupling coefficient from F, the carbon was split into multiplet. For instance, the carbon connected to F resonance frequency is near δ = 155 ppm as a doublet and with the coupling constant (1JC–F) range from 240 to 250 Hz; and the carbon at ortho position of fluorine atom was also split into doublet with coupling constant (2JC–F) ranged from 20 to 26 Hz; for the compound with a group of trifluoromethyl (–CF3), the carbon (in –CF3) was split as a quartet, the coupling coefficient ranged from 256 to 275 Hz, as well as the carbon linked to –CF3 was split into a quartet with 2JF–C was about 31 Hz. The properties, 1H NMR, 13C NMR, 19F NMR, and HR-MS data of the synthesized compounds 16a to 16ad are summarized in more detail in the “Experimental”.
Insecticidal activity
The larvicidal activities of the synthesized compounds against both H. armigera and P. xylostella were evaluated using procedures reported previously [29, 30, 33, 35, 36] and summarized in Tables 1 and 2, respectively.
The results listed in Table 1 revealed that some of the synthesized compounds showed weak to good larvicidal activity against H. armigera at the corresponding concentration. For example, the larvicidal activities of compounds 16i, 16 s, 16u-16w, 16z, and 16ab were > 50% at 500 mg/dm3 and the larvicidal activities of compounds 16u, 16v, 16w, and 16ab were 80.0, 83.3, 66.7, and 70.0%, respectively. Whereas the concentration was 100 mg/dm3, the mortalities of compounds 16u and 16w were still over 50%. These results indicated that compounds 16u and 16w showed equivalent activity to that of commercial chlorpyrifos.
As shown in Table 2, some of the synthesized compounds showed no or weak larvicidal activity against P. xylostella. But several title compounds showed moderate to good larvicidal activity, for instance, the larvicidal activities of compounds 16f, 16i, 16k, 16l, 16r, 16s, 16u, 16v, 16w, 16aa, and 16ab at 500 mg/dm3 were 63.3, 80.0, 76.7, 73.3, 83.3, 90.0, 96.7, 100, 100, 63.3, and 93.3%, respectively. And compounds 16u, 16v, 16w showed > 70% activities at 100 mg/dm3. In particularly, the activity of compound 16w was up to 93.3%. When the concentration decreased to 50 mg/dm3, the activities of compounds 16u, 16v, and 16w were 56.7, 73.3, and 80%, respectively. And compounds 16v, 16w showed moderated larvicidal activity at 25 mg/dm3.
The median lethal concentrations (LC50) for parts of the synthesized compounds were further evaluated by using previous protocols [33, 35, 36]. For comparison, the LC50 value of chlorpyrifos (a commonly used insecticide) was also evaluated. The LC50 values given in Table 3 indicated that the compounds 16r, 16s, 16u, 16v, 16w, 16ab against P. xylostella were 162.5, 100.6, 46.5, 23.9, 13.9, 69.7 mg/dm3, respectively. And the LC50 values of compounds 16u, 16v, 16w were 88.3, 69.5, and 190.1 mg/dm3, in particularly, compounds 16u and 16v showed slightly better activity than commercial chlorpyrifos.
As revealed by data in Tables 1 and 2, the larvicidal activity of the title compound was affected by R group on benzene. When R was a hydrogen (16ac), the compound showed very weak larvicidal activity, and the activity could be further deceased by introduction of a monosubstitution group at 4 position of benzene (such as compounds 16a, 16c, 16d, 16n, and 16q), as well as the compounds containing a monosubstitution at 3 position of benzene showed weak activities (e.g. compounds 16b, 16g, 16o, 16p, and 16q etc.). In addition, the activity was disfavored when benzene was substituted by two groups at 3 and 5 positions, as well as decreased by introducing other substituents, such as 2-fluorine-5-(trifluoromethyl), 3,4-difluorine, and 3-bromine-4-fluorine. However, the activities could be slightly improved by introducing an appropriate bulky group at 4 position (16i > 16c, 16q > 16ad) or 2 position (16v > 16t) of benzene, but a much larger group was not favored (16i > 16n). Moreover, the introduction of a methoxyl (16x) could slightly improve the activity, and the methylthio (16ab) was much more favored than methoxyl. Furthermore, the larvicidal activity could be enhanced by two fluorines at 2 and 4 positions (16u) or three chlorines at 2, 3, and 5 positions (16w) on benzene ring, simultaneously. And a compound containing a 4-(2-phenylpropan-2-yl) (16aa) was found to show moderate larvicidal activity.
Conclusions
Thirty novel 1,3,4-oxadiazole derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold (16a–16ad) were designed and synthesized based on combination of the sub-structures of chlorantraniliprole and 1,3,4-oxadiazole. The structures of these compounds were characterized and confirmed by 1H NMR, 19F NMR, 13C NMR, HR-MS. A preliminary evaluation of the larvicidal activities of the synthesized compounds against both H. armigera and P. xylostella was conducted. The results indicated that some of the synthesized compounds exhibited good larvicidal activity against the tested pests. In particular, the LC50 values of compounds 16r, 16s, 16u, 16v, 16w, and 16ab against P. xylostella were 162.5, 100.6, 46.5, 23.9, 13.9, and 69.7 mg/dm3, respectively. And the LC50 values of compounds 16u, 16v, and 16w against H. armigera were 88.3, 69.5, and 190.1 mg/dm3, respectively. Compounds 16u and 16v showed slightly better activity against H. armigera than commercial chlorpyrifos (LC50 103.77 mg/dm3). Preliminary SAR study revealed that an appropriate bulky group at 4 position or 2 position of benzene can slightly improve the activities, and the larvicidal activity could be enhanced by 2,4-difluorine and 2,3,5-trichlorine on benzene ring. Further structural modifications and biological evaluation to explore the full potential of this kind of 1,3,4-oxadiazole derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold are currently in progress in our laboratory.
Experimental
All chemical reagents were of analytical grade and purchased from Accela ChemBio Co., Ltd. (Shanghai, China). Melting points were determined using a XT-4 melt point instrument (Beijing Tech Instrument Co., China). 1H and 13C NMR were gauged on an AVANCE III HD 400 M NMR (Bruker corporation, Switzerland) or JEOL ECX 500 NMR spectrometer (JEOL Ltd., Japan) operating at room temperature using DMSO-d6 or CDCl3 as solvents. HR-MS was collected on an Orbitrap LC–MS instrument (Q-Exative, Thermo Scientific™, American). The course of the reactions was monitored by TLC.
General procedure for intermediates 14
Intermediates 14 were prepared by following the known procedure [22, 29, 30]. The mixture of ethyl 2-chloroacetate (1 mmol), substituted phenols (1 mmol), and K2CO3 (1.2 mmol) in acetonitrile was stirred in refluxing for 2 h (the course of the reactions was monitored by TLC), then filtered, and the mother liquid was evaporated in vacuo to afford corresponding substituted ethyl 2-phenoxyacetates, which were then reacted with hydrazine hydrate (80%) to yield substituted 2-phenoxyacetohydrazides 14 in > 90% yield.
General procedure for the synthesis of title compounds 16a–16ad
Different fresh substituted 2-phenoxyacetohydrazides 14 (0.5 mmol), 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.5 mmol), and phosphorus oxychloride (3 cm3) were added to a flask. The resulting mixture was stirred for 120 min at refluxing temperature; the resulting mixture was poured into crushed ice, neutralized with 10% NaOH, and then filtered and recrystallized from ethanol in good yield.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazole (16a, C17H10BrCl2N5O2)
Yield 78.2%; white solid; m.p.: 82–83 °C; 1H NMR (500 MHz, CDCl3): δ = 8.44 (dd, 3J = 4.6 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.90 (dd, 3J = 8.1 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.46 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.26 (d, J = 7.0 Hz, 2H, benzene-H), 7.11 (s, 1H, pyrazole-H), 6.87 (d, J = 7.0 Hz, 2H, benzene-H), 5.20 (s, 2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.16, 156.59, 155.95, 147.86, 147.31, 139.71, 129.92, 129.78, 129.45, 128.99, 127.54, 126.66, 116.20, 112.58, 59.90 ppm; HR-MS (ESI+): m/z calcd for C17H10BrCl2N5O2 ([M+H]+) 465.94677, found 465.94672.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(3-(trifluoromethyl)phenoxy]methyl)-1,3,4-oxadiazole (16b, C18H10BrClF3N5O2)
Yield 78.2%; white solid; m.p.: 97–98 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.51 (dd, 3J = 4.7 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 8.25 (dd, 3J = 8.1 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 7.69 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.55 (d, 4J = 3.3 Hz, 1H, benzene-H), 7.53 (t, 3J = 8.3 Hz, 1H, benzene-H), 7.36-7.33 (m, 2H, benzene-H + pyrazole-H), 7.29 (dd, 3J = 8.1 Hz, 4J = 2.2 Hz, 1H, benzene-H), 5.52 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, DMSO-d6): δ = −61.01 ppm; 13C NMR (126 MHz, DMSO-d6): δ = 163.23, 157.91, 156.17, 148.28, 147.49, 140.70, 131.45, 131.06 (q, J = 31.7 Hz), 130.25, 128.88, 128.71, 128.24, 123.29 (q, J = 272.6 Hz), 119.74, 119.04, 119.01, 112.91, 112.11, 112.08, 60.19, 40.53, 40.36, 40.19, 40.03, 39.86, 39.69, 39.53 ppm; HR-MS (ESI+): m/z calcd for C18H10BrClF3N5O2 ([M+H]+) 499.97313, found 499.97275.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(4-fluorophenoxy)methyl]-1,3,4-oxadiazole (16c, C17H10BrClFN5O2)
Yield 78.2%; white solid; m.p.: 85–87 °C; 1H NMR (500 MHz, CDCl3): δ = 8.45 (dd, 3J = 4.7 Hz, 4J = 1.6 Hz, 1H), 7.90 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz, 1H), 7.44 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H), 7.11 (s, 1H, pyrazole-H), 7.00-6.95 (m, 2H, benzene-H), 6.91-6.87 (m, 2H, benzene-H), 5.19 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −121.29 ppm; 13C NMR (126 MHz, CDCl3): δ = 162.33, 159.18, (d, J = 240.8 Hz), 156.56, 153.50, 147.91, 147.31, 139.68, 129.97, 129.72 (d, J = 63.9 Hz), 128.96, 126.62, 116.42, 116.29, 116.23, 112.52, 60.42 ppm; HR-MS (ESI+): m/z calcd for C17H10BrClFN5O2 ([M+H]+) 499.97632, found 499.97635.
4-[[5-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-1,3,4-oxadiazol-2-yl]methoxy]benzonitrile (16d, C18H10BrClN6O2)
Yield 78.2%; white solid; m.p.: 88–90 °C; 1H NMR (400 MHz, CDCl3): δ = 8.47 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1H), 7.93 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H), 7.62 (d, 3J = 8.9 Hz, 2H, benzene-H), 7.47 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H), 7.12 (s, 1H, pyrazole-H), 7.05 (d, 3J = 8.9 Hz, 2H, benzene-H) ppm; 13C NMR (126 MHz, CDCl3): δ = 164.60, 162.63, 161.57, 156.66, 147.84, 139.72, 129.84, 129.41, 128.96, 126.70, 112.62, 99.00, 98.77, 98.16, 97.96, 59.92 ppm; HR-MS (ESI+): m/z calcd for C18H10BrClN6O2 ([M+H]+) 446.98099, found 446.98092.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(2,3-difluorophenoxy)methyl]-1,3,4-oxadiazole (16e, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 103–104 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.54 (dd, 3J = 4.6 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 8.26 (dd, 3J = 8.1 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 7.69 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.58–7.51 (m, 1H, benzene-H, pyridine-H), 7.17–6.98 (m, 3H, benzene-H), 5.53 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, DMSO-d6): δ = −137.60, −159.54 ppm; 13C NMR (126 MHz, DMSO-d6): δ = 162.99, 156.24, 150.97 (dd, J = 245.1, 10.1 Hz), 148.28, 147.47, 140.83 (dd, J = 246.3, 14.6 Hz), 140.71, 130.21, 128.92, 128.70, 124.82 (d, J = 8.8 Hz), 124.78, 112.99, 111.77, 111.74, 111.07 (d, J = 17.2 Hz), 61.20 ppm; HR-MS (ESI+): m/z calcd for C17H9BrClF2N5O2 ([M+H]+) 467.96690, found 467.96698.
4-[[5-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-1,3,4-oxadiazol-2-yl]methoxy]-2,6-difluorobenzonitrile (16f, C18H8BrClF2N6O2)
Yield 78.2%; white solid; m.p.: 76–77 °C; 1H NMR (500 MHz, CDCl3): δ = 8.48 (dd, 3J = 4.5 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.87 (d, 3J = 8.0 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.40 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.07 (s, 1H, pyrazole-H), 6.64 (s, 1H, benzene-H), 6.62 (s, 1H, benzene-H), 4.87 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −101.86 ppm; 13C NMR (126 MHz, CDCl3): δ = 163.74 (d, J = 247.9 Hz), 163.62 (d, J = 247.9 Hz), 159.04 (t, J = 13.5 Hz), 156.66, 147.84, 147.32, 139.72, 129.84, 129.41, 128.96, 126.70, 115.17, 112.62, 98.98 (d, J = 7.2 Hz), 98.81 (d, J = 7.2 Hz), 98.37, 98.16, 97.96, 59.92 ppm; HR-MS (ESI+): m/z calcd for C18H8BrClF2N6O2 ([M+H]+) 492.96215, found 492.96211.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(3,5-difluorophenoxy)methyl]-1,3,4-oxadiazole (16g, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 91–92 °C; 1H NMR (500 MHz, CDCl3): δ = 8.43 (dd, 3J = 4.6 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 7.90 (d, 3J = 8.1 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 7.44 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.10 (s, 1H, pyrazole-H), 6.51–6.39 (m, 3H, benzene-H), 5.18 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −107.64 ppm; 13C NMR (126 MHz, CDCl3): δ = 163.74 (d, J = 247.9 Hz), 163.62 (d, J = 247.9 Hz), 159.04 (t, J = 13.5 Hz), 156.66, 147.84, 147.32, 139.72, 129.84, 129.41, 128.96, 126.70, 112.62, 98.97 (d, J = 7.2 Hz), 98.80 (d, J = 7.2 Hz), 98.37, 98.16, 97.96, 59.92 ppm; HR-MS (ESI+): m/z calcd for C17H9BrClF2N5O2 ([M+H]+) 467.96690, found 467.96698.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(5-fluoro-2-methylphenoxy)methyl]-1,3,4-oxadiazole (16h, C18H12BrClFN5O2)
Yield 78.2%; white solid; m.p.: 95–97 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.49 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 8.24 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.68 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H), 7.16 (dd, 3JF–H = 11.3 Hz, 4JH–H = 4.0 Hz, 1H, benzene-H), 6.95 (dd, 3JF–H = 11.1 Hz, 4JH–H = 2.5 Hz, 1H, benzene-H), 6.72 (td, 3JH–H = 8.4 Hz, 4JH–H = 2.5 Hz, 1H, benzene-H), 5.43 (s, 2H, –CH2–), 2.04 (s, 3H, –CH3) ppm; 19F NMR (471 MHz, DMSO-d6): δ = −114.33 ppm; 13C NMR (126 MHz, DMSO-d6): δ = 161.70 (d, J = 244.2 Hz), 162.22, 156.59, 156.12, 156.04, 147.86, 147.30, 139.71, 131.58, 131.50, 129.98, 129.41, 128.98, 126.66, 122.74, 122.71, 112.57, 108.44 (d, J = 20.7 Hz), 100.08 (d, J = 25.9 Hz), 59.95, 15.64 ppm; HR-MS (ESI+): m/z calcd for C18H12BrClFN5O2 ([M+H]+) 463.99197, found 463.99213.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(4-(trifluoromethyl)phenoxy]methyl)-1,3,4-oxadiazole (16i, C18H10BrClF3N5O2)
Yield 78.2%; white solid; m.p.: 97–98 °C; 1H NMR (500 MHz, CDCl3): δ = 8.44 (dd, 3J = 4.6 Hz, 4J = 1.3 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.0 Hz, 4J = 1.3 Hz, 1H, pyridine-H), 7.56 (d, 3J = 8.6 Hz, 2H, benzene-H), 7.42 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.11 (s, 1H, pyrazole-H), 7.02 (d, 3J = 8.6 Hz, 2H, benzene-H), 5.27 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −61.60 ppm; 13C NMR (126 MHz, CDCl3): δ = 161.84, 159.67, 156.66, 147.86, 147.29, 139.69, 129.86, 129.42, 128.97, 127.34, 127.31, 126.65, 124.68 (q, J = 32.8 Hz), 124.17 (d, J = 271.2 Hz), 114.85, 112.61, 59.59 ppm; HR-MS (ESI+): m/z calcd for C18H10BrClF3N5O2 ([M+H]+) 499.97313, found 499.97339.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(3-bromo-4-fluorophenoxy)methyl]-1,3,4-oxadiazole (16j, C17H9Br2ClFN5O2)
Yield 78.2%; white solid; m.p.: 117–118 °C; 1H NMR (500 MHz, CDCl3): δ = 8.44 (dd, 3J = 4.6 Hz, 4J = 1.5 Hz, 1H), 7.90 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H), 7.44 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H), 7.12 (dd, 3J = 5.4 Hz, 4J = 3.1 Hz, 1H), 7.11 (s, 1H, pyrazole-H), 7.03 (t, J = 8.5 Hz, 1H, benzene-H), 6.85 (dt, J = 9.0, 3.4 Hz, 1H, benzene-H), 5.18 (s, 2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3): δ = 161.87, 156.61, 154.82 (d, J = 242.2 Hz), 153.68, 147.85, 147.32, 139.71, 129.88, 129.42, 128.97, 126.67, 119.99, 116.98 (d, J = 24.3 Hz), 115.26, 112.60, 109.51 (d, J = 22.9 Hz), 60.42 ppm; HR-MS (ESI+): m/z calcd for C17H9Br2ClFN5O2 ([M+H]+) 527.88683, found 527.88596.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[4-fluoro-3-(trifluoromethyl)phenoxy]methyl]-1,3,4-oxadiazole (16k, C18H9BrClF4N5O2)
Yield 78.2%; white solid; m.p.: 86–88 °C; 1H NMR (500 MHz, CDCl3): δ = 8.43 (dd, 3J = 4.5 Hz, 4J = 1.7 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.0 Hz, 4J = 1.7 Hz, 1H, pyridine-H), 7.43 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.15 (s, 1H, pyrazole-H), 7.13–7.05 (m, 3H, benzene-H), 5.22 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −61.50, −122.78 ppm; 13C NMR (126 MHz, CDCl3): δ = 161.72, 156.64, 154.87 (d, J = 249.6 Hz), 153.07, 147.83, 147.32, 139.73, 129.84, 129.42, 128.95, 126.73, 122.16 (q, J = 271.2 Hz), 119.18 (dq, J = 33.3, 14.3 Hz) 119.10, 118.22 (d, J = 22.5 Hz), 113.80, 112.57, 60.37 ppm; HR-MS (ESI+): m/z calcd for C18H9BrClF4N5O2 ([M+H]+) 517.96371, found 517.96412.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(2-chloro-4-fluorophenoxy)methyl]-1,3,4-oxadiazole (16l, C17H9BrCl2FN5O2)
Yield 78.2%; white solid; m.p.: 110–112 °C; 1H NMR (500 MHz, CDCl3): δ = 8.46 (dd, 3J = 4.7 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.92 (dd, 3J = 8.1 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.46 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.26 (s, 1H, pyrazole-H), 6.97 (d, J = 4.8 Hz, 1H, benzene-H), 6.91 (d, J = 3.0 Hz, 1H, benzene-H), 6.85 (dd, 3J = 9.1 Hz, 4J = 4.9 Hz, 2H, benzene-H) ppm; 19F NMR (471 MHz, CDCl3): δ = −119.23 ppm; 13C NMR (126 MHz, CDCl3): δ = 163.04, 159.02 (d, J = 246.1 Hz), 157.68, 157.60, 156.18, 148.29, 147.48, 140.70, 131.42, 130.23, 128.90, 128.72, 128.26, 112.99 (d, J = 14.1 Hz), 112.53, 104.82 (d, J = 24.6 Hz), 60.46 ppm; HR-MS (ESI+): m/z calcd for C17H9BrCl2FN5O2 ([M+H]+) 483.93735, found 483.93530.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(3,4-difluorophenoxy)methyl]-1,3,4-oxadiazole (16m, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 85–86 °C; 1H NMR (500 MHz, CDCl3): δ = 8.42 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H), 7.43 (dd, 3J = 8.1 Hz, 4J = 4.9 Hz, 1H), 7.09 (s, 1H, pyrazole-H), 7.04 (dd, JF–H = 18.7 Hz, JF–H = 9.2 Hz, 1H), 6.76 (ddd, JF–H = 11.4 Hz, JF–H = 6.4 Hz, JF–H = 2.9 Hz, 1H, benzene-H), 6.67-6.61 (m, 1H, benzene-H), 5.16 (s, 2H, –CH2–) ppm; 19F NMR (470 MHz, CDCl3): δ = −134.08 (d, J = 21.2 Hz), −145.50 (d, J = 21.1 Hz) ppm; 13C NMR (126 MHz, CDCl3): δ = 161.91, 156.59, 153.53, 150.51 (dd, J = 249.2, 14.0 Hz), 147.84, 147.32, 146.05 (dd, J = 242.6, 12.6 Hz), 139.72, 129.89, 129.42, 128.93, 126.72, 117.74, 117.66 (d, J = 18.6 Hz), 112.56, 110.26, 105.15 (d, J = 20.6 Hz), 60.33 ppm; HR-MS (ESI+): m/z calcd for C17H9BrClF2N5O2 ([M + H]+) 467.96690, found 467.96674.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[4-(trifluoromethoxy)phenoxy]methyl]-1,3,4-oxadiazole (16n, C18H10BrClF3N5O3)
Yield 78.2%; white solid; m.p.: 62–64 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.51 (dd, 3J = 4.6 Hz, 4J = 1.4 Hz, 1H, pyridine-H), 8.27 (dd, 3J = 8.1 Hz, 4J = 1.3 Hz, 1H, pyridine-H), 7.71 (dd, 3J = 8.1 Hz, 4J = 4.8 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H), 7.30 (d, 3J = 9.0 Hz, 2H, benzene-H), 7.08 (d, 3J = 9.1 Hz, 2H, benzene-H), 5.43 (s, 2H) ppm; 19F NMR (471 MHz, CDCl3): δ = −58.18 ppm; 13C NMR (126 MHz, CDCl3): δ = 162.12, 156.57, 155.80, 147.84, 147.30, 143.92, 139.70, 129.94, 129.39, 128.93, 126.69, 122.76, 120.56 (q, J = 256.5 Hz), 115.85, 112.54, 60.00 ppm; HR-MS (ESI+): m/z calcd for C18H10BrClF3N5O3 ([M+H]+) 515.96804, found 515.96674.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(3-fluorophenoxy)methyl]-1,3,4-oxadiazole (16o, C17H10BrClFN5O2)
Yield 78.2%; white solid; m.p.: 78–79 °C; 1H NMR (500 MHz, CDCl3): δ = 8.40 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.86 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.40 (dd, 3J = 8.1 Hz, 4J = 4.8 Hz, 1H, pyridine-H), 7.21 (dd, 3J = 8.3 Hz, 4J = 6.8 Hz, 1H, benzene-H), 7.09 (s, 1H, pyrazole-H), 5.18 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −110.37 ppm; 13C NMR (126 MHz, CDCl3): δ = 163.52 (d, J = 246.7 Hz), 162.11, 158.56, 156.55, 147.81, 147.31, 139.7, 130.77, 129.96, 129.36, 128.92, 126.72, 112.56, 110.33, 109.37 (d, J = 21.3 Hz), 103.00 (d, J = 25.2 Hz), 59.79 ppm; HR-MS (ESI+): m/z calcd for C17H10BrClFN5O2 ([M+H]+) 449.97632, found 449.97424.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(3-chlorophenoxy)methyl]-1,3,4-oxadiazole (16p, C17H10BrCl2N5O2)
Yield 78.2%; white solid; m.p.: 98–99 °C; 1H NMR (500 MHz, CDCl3): δ = 8.43 (dd, 3J = 4.7 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.89 (dd, 3J = 8.1 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.44 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.21 (d, 3J = 8.2 Hz, 1H, benzene-H), 7.12 (s, 1H, pyrazole-H), 7.01 (dd, 3J = 8.1 Hz, 4J = 1.9 Hz, 1H, benzene-H), 6.94–6.92 (m, 1H, benzene-H), 6.82 (dd, 3J = 8.3 Hz, 4J = 2.5 Hz, 1H, benzene-H), 5.21 (s, 2H, -CH2-) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.05, 157.98, 156.61, 147.84, 147.32, 139.72, 135.28, 130.69, 129.92, 129.41, 129.00, 126.65, 122.74, 115.64, 112.93, 112.61, 59.75 ppm; HR-MS (ESI+): m/z calcd for C17H10BrCl2N5O2 ([M+H]+) 465.94677, found 465.94492.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[4-(tert-butyl)phenoxy]methyl]-1,3,4-oxadiazole (16q, C21H19BrClN5O2)
Yield 78.2%; white solid; m.p.: 53–54 °C; 1H NMR (500 MHz, CDCl3): δ = 8.43 (dd, 3J = 4.7 Hz, 4J = 1.6 Hz, 1H), 7.85 (d, 3J = 8.0 Hz, 4J = 1.6 Hz, 1H), 7.39 (dd, 3J = 8.0 Hz, 4J = 4.7 Hz, 1H), 7.30 (d, 3J = 7.2 Hz, 2H, benzene-H), 7.11 (s, 1H, pyrazole-H), 6.86 (d, J = 7.2 Hz, 2H, benzene-H), 5.18 (s, 2H, –CH2–), 1.28 (s, 9H, –CH3) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.78, 156.46, 155.20, 147.86, 147.33, 145.21, 139.72, 130.13, 129.38, 128.91, 126.72, 126.66, 114.39, 112.49, 77.61, 77.36, 77.10, 59.79, 34.29, 31.61 ppm; HR-MS (ESI+): m/z calcd for C21H19BrClN5O2 ([M+H]+) 488.04835, found 488.04849.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(4-chloro-3-fluorophenoxy)methyl]-1,3,4-oxadiazole (16r, C17H9BrCl2FN5O2)
Yield 78.2%; white solid; m.p.: 124–126 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.58–8.46 (dd, 1H, 3J = 4.7 Hz, 4J = 1.5 Hz, pyridine-H), 8.32 (dd, 1H, 3J = 7.9, 4J = 1.5 Hz, 1H, pyridine-H), 7.70 (dd, 3J = 7.9 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H), 7.48 (t, J = 8.8 Hz, 1H, benzene-H), 7.17 (dd, J = 11.2, 2.6 Hz, 1H, benzene-H), 6.87 (d, J = 8.6 Hz, 1H, benzene-H), 5.45 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, DMSO-d6): δ = −113.29 ppm; 13C NMR (126 MHz, DMSO-d6): δ = 163.04, 159.02 (d, J = 246.1 Hz), 157.68, 157.60, 156.18, 148.29, 147.48, 140.70, 131.42, 130.23, 128.90, 128.72, 128.26, 112.99 (d, J = 14.1 Hz), 112.53, 104.82 (d, J = 24.6 Hz), 60.46 ppm; HR-MS (ESI+): m/z calcd for C17H9BrCl2FN5O2 ([M+H]+) 483.93735, found 483.93729.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(4-chloro-2-fluorophenoxy)methyl]-1,3,4-oxadiazole (16s, C17H9BrCl2FN5O2)
Yield 78.2%; white solid; m.p.: 83–84 °C; 1H NMR (500 MHz, CDCl3): δ = 8.46 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1H), 7.92 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H), 7.45 (dd, 3J = 7.8 Hz, 4J = 4.9 Hz, 1H), 7.13 (s, 1H, pyrazole-H), 7.12 (s, 1H, benzene-H), 7.04 (dt, J = 6.2, 2.0 Hz, 2H, benzene-H), 5.26 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −129.45 ppm; 13C NMR (126 MHz, CDCl3): δ = 156.73, 153.80, 152.97 (d, J = 208.9 Hz), 147.32, 139.71, 129.87, 128.17, 126.65, 125.25, 124.70, 118.92, 117.82 (d, J = 6.5 Hz), 117.59 (d, J = 7.9 Hz), 112.65, 111.17, 61.49 ppm; HR-MS (ESI+): m/z calcd for C17H9BrCl2FN5O2 ([M+H]+) 483.93735, found 483.93515.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(2-fluorophenoxy)methyl]-1,3,4-oxadiazole (16t, C17H10BrClFN5O2)
Yield 78.2%; white solid; m.p.: 74–75 °C; 1H NMR (500 MHz, CDCl3): δ = 8.39 (dd, 3J = 4.6 Hz, 4J = 1.3 Hz, 1H), 7.86 (dd, 3J = 8.1 Hz, 4J = 1.3 Hz, 1H), 7.40 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H), 7.09 (s, 1H, pyrazole-H), 7.06-6.92 (m, 4H, benzene-H), 5.24 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −132.95 ppm; 13C NMR (126 MHz, CDCl3): δ = 162.16, 156.60, 152.93 (d, J = 247.0 Hz), 147.78, 147.33, 145.26 (d, J = 10.7 Hz), 139.73, 130.00, 129.32, 128.92, 126.74, 124.72, 123.57, 116.86 (d, J = 18.1 Hz) 116.54, 112.55, 61.19 ppm; HR-MS (ESI+): m/z calcd for C17H10BrClFN5O2 ([M+H]+) 449.97632, found 449.97446.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(2,4-difluorophenoxy)methyl]-1,3,4-oxadiazole (16u, C17H9BrClF2N5O2)
Yield 78.2%; white solid; m.p.: 93–94 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.51 (dd, 3J = 4.5 Hz, 4J = 1.2 Hz, 1H, pyridine-H), 8.26 (dd, 3J = 8.1 Hz, 4J = 1.3 Hz, 1H, pyridine-H), 7.70 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.56 (s, 1H, pyrazole-H), 7.33–7.20 (m, 2H, benzene-H), 7.01 (t, J = 8.7 Hz, 1H, benzene-H), 5.45 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, DMSO-d6): δ = −117.96, −129.00 ppm; 13C NMR (126 MHz, DMSO-d6): δ = 163.15, 157.08 (dd, J = 240.8, 10.8 Hz), 156.21, 152.22 (dd, J = 247.9, 12.7 Hz),148.30, 147.48, 142.14 (dd, J = 10.7, 3.3 Hz), 140.71, 130.23, 128.91, 128.71, 128.29, 117.78, 117.77, 117.71, 117.69, 112.94, 111.63 (dd, J = 22.6, 3.9 Hz), 105.70 (dd, J = 27.5, 22.4 Hz), 61.56 ppm; HR-MS (ESI+): m/z calcd for C17H9BrClF2N5O2 ([M+H]+) 467.96690, found 467.96680.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[2-(trifluoromethyl)phenoxy]methyl]-1,3,4-oxadiazole (16v, C18H10BrClF3N5O2)
Yield 78.2%; white solid; m.p.: 76–77 °C; 1H NMR (500 MHz, DMSO-d6): δ = 8.46 (dd, 3J = 4.6 Hz, 3J = 1.5 Hz, 1H, pyridine-H), 8.23 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.70–7.64 (dd, 3J = 8.1 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.61 (t, J = 7.7 Hz, 2H, benzene-H), 7.50 (s, 1H, benzene-H), 7.34 (dd, 3J = 8.6 Hz, 4J = 3.1 Hz, 1H, benzene-H), 7.19 (s, 1H, pyrazole-H), 5.58 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, DMSO-d6): δ = −60.62 ppm; 13C NMR (126 MHz, DMSO-d6): δ = 163.12, 156.21, 155.33, 148.24, 147.39, 140.70, 134.84, 130.21, 128.92, 128.60, 128.23, 127.53, 127.49, 123.95 (q, J = 272.6 Hz),122.35, 118.17 (q, J = 30.6 Hz), 114.91, 112.91, 60.64 ppm; HR-MS (ESI+): m/z calcd for C18H10BrClF3N5O2 ([M+H]+) 499.97313, found 499.97113.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(2,4,6-trichlorophenoxy)methyl]-1,3,4-oxadiazole (16w, C17H8BrCl4N5O2)
Yield 78.2%; white solid; m.p.: 123–124 °C; 1H NMR (500 MHz, CDCl3): δ = 8.48 (d, 3J = 4.7 Hz, 1H, pyridine-H), 7.92 (d, 3J = 8.0 Hz, 1H, pyridine-H), 7.45 (dd, 3J = 8.0 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.29 (d, 4J = 0.9 Hz, 2H, benzene-H), 7.13 (s, 1H, pyrazole-H), 5.18 (s, 2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3): δ = 161.53, 156.76, 148.76, 147.91, 147.38, 139.72, 131.19, 130.03, 129.51, 129.14, 128.98, 126.73, 112.57, 63.50 ppm; HR-MS (ESI+): m/z calcd for C17H8BrCl4N5O2 ([M+H]+) 533.86883, found 533.86873.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(4-methoxyphenoxy)methyl]-1,3,4-oxadiazole (16x, C18H13BrClN5O3)
Yield 78.2%; white solid; m.p.: 94–95 °C; 1H NMR (500 MHz, CDCl3): δ = 8.42 (dd, 3J = 4.3 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.88 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz, 1H, pyridine-H), 7.42 (dd, 3J = 8.0 Hz, 4J = 4.3 Hz, 1H, pyridine-H), 7.10 (s, 1H, pyrazole-H), 6.86 (d, J = 9.0 Hz, 2H, benzene-H), 6.81 (d, J = 9.1 Hz, 2H, benzene-H), 5.15 (s, 2H, –CH2–), 3.74 (s, 3H, –CH3–) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.74, 156.46, 155.08, 151.51, 147.90, 147.32, 139.68, 130.09, 129.43, 128.92, 126.64, 116.22, 114.90, 112.47, 60.64, 55.78 ppm; HR-MS (ESI+): m/z calcd for C18H13BrClN5O3 ([M+H]+) 461.99631, found 461.99411.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[2-fluoro-5-(trifluoromethyl)phenoxy]methyl]-1,3,4-oxadiazole (16y, C18H9BrClF4N5O2)
Yield 78.2%; white solid; m.p.: 64–66 °C; 1H NMR (500 MHz, CDCl3): δ = 8.44 (d, 3J = 4.6 Hz, 4J = 1.5 Hz, 1H), 7.89 (dd, 3J = 8.0 Hz, 4J = 1.5 Hz, 1H), 7.43 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H), 7.29 (d, 3J = 5.9 Hz, 2H, benzene-H), 7.20 (t, 3J = 9.2 Hz, 1H, benzene-H), 7.13 (s, 1H, pyrazole-H), 5.31 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −61.90, −126.72 ppm; 13C NMR (126 MHz, CDCl3): δ = 161.43, 156.74, 154.79 (d, J = 253.7 Hz), 147.80, 147.34, 145.53 (d, J = 11.5 Hz), 139.74, 129.85, 129.37, 128.96, 127.25 (d, J = 29.5 Hz), 126.74, 123.37 (q, J = 272.4 Hz), 120.91, 117.40 (d, J = 19.4 Hz) 113.87, 112.62, 61.33 ppm; HR-MS (ESI+): m/z calcd for C18H9BrClF4N5O2 ([M+H]+) 517.96371, found 517.96343.
2-[[3,5-Bis(trifluoromethyl)phenoxy]methyl]-5-[3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-1,3,4-oxadiazole (16z, C19H9BrClF6N5O2)
Yield 78.2%; white solid; m.p.: 73–74 °C; 1H NMR (500 MHz, CDCl3): δ = 8.44 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.90 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1H, pyridine-H), 7.54 (s, 1H, benzene-H), 7.44 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.39 (s, 2H, benzene-H), 7.10 (s, 1H, pyrazole-H), 5.33 (s, 2H, –CH2–) ppm; 19F NMR (471 MHz, CDCl3): δ = −62.93 ppm; 13C NMR (126 MHz, CDCl3): δ = 161.16, 157.82, 156.76, 147.84, 147.32, 139.72, 133.33 (q, J = 33.7 Hz), 129.74, 129.42, 128.97, 126.70, 124.01, 121.84, 116.13, 115.28, 112.64, 60.02 ppm; HR-MS (ESI+): m/z calcd for C19H9BrClF6N5O2 ([M+H]+) 567.96051, found 567.96055.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[4-(2-phenylpropan-2-yl)phenoxy]methyl]-1,3,4-oxadiazole (16aa, C26H21BrClN5O2)
Yield 78.2%; white solid; m.p.: 191–192 °C; 1H NMR (500 MHz, CDCl3): δ = 8.42 (d, 3J = 4.6 Hz, 1H, pyridine-H), 7.87 (d, 3J = 8.0 Hz, 1H, pyridine-H), 7.40 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H, pyridine-H), 7.32–7.22 (m, 5H, benzene-H), 7.17 (d, J = 7.7 Hz, 2H, benzene-H), 7.12 (s, 1H, pyrazole-H), 6.84 (d, J = 7.9 Hz, 2H, benzene-H), 5.20 (s, 2H, –CH2–), 1.67 (s, 6H, –CH3) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.69, 156.50, 155.32, 150.61, 147.91, 147.35, 144.89, 139.73, 130.10, 129.43, 128.97, 128.20, 128.06, 126.80, 126.67, 125.83, 114.93, 114.30, 112.52, 59.74, 42.51, 30.94 ppm; HR-MS (ESI+): m/z calcd for C26H21BrClN5O2 ([M+H]+) 550.06400, found 550.06398.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[[4-(methylthio)phenoxy]methyl]-1,3,4-oxadiazole (16ab, C18H13BrClN5O2S)
Yield 78.2%; white solid; m.p.: 78–80 °C; 1H NMR (500 MHz, CDCl3): δ = 8.43 (dd, 3J = 4.7 Hz, 4J = 1.6 Hz, 1H), 7.89 (dd, 3J = 8.1 Hz, 4J = 1.6 Hz, 1H), 7.42 (dd, 3J = 8.0 Hz, 4J = 4.6 Hz, 1H), 7.22 (d, 3J = 8.7 Hz, 2H, benzene-H), 7.11 (s, 1H, pyrazole-H), 6.87 (d, 3J = 8.8 Hz, 2H, benzene-H), 5.19 (s, 2H, –CH2–), 2.43 (s, 3H, CH3) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.41, 156.53, 155.68, 147.87, 147.30, 139.69, 131.38, 129.99, 129.57, 129.42, 128.95, 126.64, 115.72, 115.60, 112.53, 59.87, 17.45 ppm; HR-MS (ESI+): m/z calcd for C18H13BrClN5O2S ([M+H]+) 477.97347, found 477.97360.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-(phenoxymethyl)-1,3,4-oxadiazole (16ac, C17H11BrClN5O2)
Yield 78.2%; white solid; m.p.: 72–73 °C; 1H NMR (500 MHz, CDCl3): δ = 8.42 (dd, 3J = 4.6 Hz, 4J = 1.0 Hz, 1H, pyridine-H), 7.87 (dd, 3J = 8.0 Hz, 4J = 1.0 Hz, 1H, pyridine-H), 7.41 (dd, 3J = 8.1 Hz, 4J = 4.7 Hz, 1H, pyridine-H), 7.29 (t, J = 7.6 Hz, 2H, benzene-H), 7.11 (s, 1H, pyrazole-H), 7.02 (t, J = 7.4 Hz, 1H, benzene-H), 6.92 (d, J = 8.7 Hz, 2H, benzene-H), 5.21 (s, 2H, –CH2–) ppm; 13C NMR (126 MHz, CDCl3): δ = 162.58, 157.40, 156.51, 147.87, 147.32, 139.70, 130.05, 129.88, 129.41, 128.94, 126.66, 122.47, 114.82, 112.51, 59.65 ppm; HR-MS (ESI+): m/z calcd for C17H11BrClN5O2 ([M+H]+) 431.98574, found 431.98380.
2-[3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl]-5-[(p-tolyloxy)methyl]-1,3,4-oxadiazole (16ad, C18H13BrClN5O2)
Yield 78.2%; white solid; m.p.: 61–62 °C; 1H NMR (500 MHz, CDCl3): δ = 8.41 (d, 3J = 4.4 Hz, 1H), 7.86 (d, 3J = 8.0 Hz, 1H), 7.40 (dd, 3J = 7.9 Hz, 4J = 4.7 Hz, 1H), 7.10 (s, 1H, pyrazole-H), 7.07 (d, J = 8.1 Hz, 2H, benzene-H), 6.81 (d, J = 8.4 Hz, 2H, benzene-H), 5.17 (s, 2H, –CH2–), 2.27 (s, 3H, –CH3) ppm; 13C NMR (101 MHz, CDCl3): δ = 162.63, 156.41, 155.28, 147.84, 147.24, 139.60, 131.82, 130.20, 130.03, 130.01, 129.38, 128.86, 126.53, 114.69, 112.41, 77.40, 77.08, 76.76, 59.84, 20.53 ppm; HR-MS (ESI+): m/z calcd for C18H13BrClN5O2 ([M+H]+) 446.00139, found 446.00139.
Insecticidal activity
The larvicidal activity was conducted on organism reared in the lab and repeated at 25 ± 1 °C according to statistical requirements. Mortalities were disposed according to Abbott’s formula [37]. Evaluations were based on a percentage scale (0 = no activity and 100 = complete eradication).
Insecticidal activity against H. armigera
The insecticidal activity of the synthesized compounds against H. armigera was tested by the diet-incorporated method [29]. A quantity of 3 cm3 of solution containing the synthesized compound was added to the prepared forage (27 g), subsequently diluted to corresponding concentrations, and then placed in a 24-pore plate. One larva of H. armigera was placed in each of the pores on the plate. Mortalities were calculated after 72–96 h. Commercial insecticides chlorantraniliprole (with a 3-chloropyridin-2-yl-1H-pyrazole scaffold) and chlorpyrifos (an effective organophosphorus pesticide against lepidoptera) were used as positive controls under the same conditions.
Insecticidal activity against P. xylostella
The insecticidal activities against the P. xylostella were determined according to previously determined protocols [29, 30, 33]. Fresh cabbage discs (diameter was 2 cm) were dipped into the prepared solutions containing compounds 16a–16ad for 10 s, dried in the air, and then placed in a Petri dish (diameter 9 cm) lined with filter paper. Then, ten third instar larvae were carefully transferred to the Petri dish. Each assay was conducted in triplicate. Mortalities were determined after 72 h. The commercial chlorantraniliprole, chlorpyrifos, and avermectins were tested under the same condition for positive controls.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (nos. 21562012, 21132003 and 21162004), the Special Foundation of S&T for Outstanding Young Talents in Guizhou (no. 2015-15#) and the S&T Foundation of Guizhou Province (no. J[2014]2056#).
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Yanyan Wang and Xiumian Lu are Co-first authors.
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Wang, Y., Lu, X., Shi, J. et al. Synthesis and larvicidal activity of 1,3,4-oxadiazole derivatives containing a 3-chloropyridin-2-yl-1H-pyrazole scaffold. Monatsh Chem 149, 611–623 (2018). https://doi.org/10.1007/s00706-017-2060-3
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DOI: https://doi.org/10.1007/s00706-017-2060-3