Research Article Received: 10 April 2014
Revised: 29 April 2014
Accepted article published: 9 May 2014
Published online in Wiley Online Library: 5 June 2014
(wileyonlinelibrary.com) DOI 10.1002/ps.3827
Design, synthesis and insecticidal activity of novel 1,1-dichloropropene derivatives Jun Li,a Zhen-Yu Wang,a Qiong-You Wua and Guang-Fu Yanga,b* Abstract BACKGROUND: Pyridalyl is a highly active insecticide against lepidopterous larvae, with a novel chemical structure not related to any other existing insecticide. To discover new pyridalyl analogues with high activity against resistant pests, a series of 1,1-dichloropropene derivatives bearing structurally diverse substituted heterocycle rings in place of the pyridine ring of pyridalyl were designed and synthesised. RESULTS: All of the title compounds were confirmed by 1 H NMR, 13 C NMR and high-resolution mass spectra. Two representative compounds (Ic and IIa) were further characterised by X-ray diffraction analysis. In addition, bioassays showed that most of the newly synthesised compounds displayed good insecticidal activity against Prodenia litura. Further determination of LD50 values and field trials identified compound IIa as the most promising candidate, which produced a much better 14 day control effect against diamondback moths and longer duration of efficacy than pyridalyl, indicating its potential for further development as a new insecticide for the control of lepidopteran insects. CONCLUSION: Compound IIa has great potential for further development as a new insecticide for the control of lepidopteran insects. © 2014 Society of Chemical Industry Keywords: 1,1-dichloropropene; insecticide; pyridalyl; heterocycle
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INTRODUCTION
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Chemical insecticides are efficient tools for controlling pests in agriculture. However, pest resistance to insecticides is rapidly increasing in occurrence. Over 500 species of pests have evolved resistance to conventional insecticides, including organophosphates, carbamates and synthetic pyrethroids. Therefore, the discovery of insecticides with a novel mode of action is urgent for plant protection and is vital for managing pest strains that have become resistant to existing products.1 Pyridalyl, discovered at the Agricultural Chemicals Research Laboratory of Sumitomo Chemical Co. Ltd (Tokyo, Japan), belongs to a new class of insecticide and has a novel chemical structure not related to any other existing insecticide (Fig. 1). It is used for the control of various lepidopteran larvae and shows no cross-resistance with the existing insecticides, such as synthetic pyrethroids, organic phosphates, benzoylphenylureas, nicotinic insecticides and ryanodine insectides.2,3 Although pyridalyl was discovered almost 20 years ago, its mode of action is still unknown. Recent research demonstrated that pyridalyl can cause cell apoptosis in BM36 cells, and so its insecticidal activity may be related to the generation of active oxygen species of a pyridalyl metabolite.4 Since its appearance on the market in 2004, many pyridalyl analogues with high insecticidal activity have been reported.5 – 7 However, the structural diversity claimed in the patent is still limited; no new compounds within this family have been developed as commercial insecticides since pyridalyl.8 In ongoing research to find new insecticides, the present authors have focused on new pyridalyl analogues with structural diversity. Various N- or S-containing heterocyclic derivatives, such as pyridine, pyrimidine, Pest Manag Sci 2015; 71: 694–700
pyridazine, pyridazinone and benzothiazole, have always displayed broad-spectrum biological activity.9 – 13 It was suggested that replacement of the pyridine moiety of pyridalyl with these heterocycles might produce new lead compounds with higher insecticidal activity. Therefore, the authors designed and synthesised a series of 1,1-dichloropropene derivatives containing structurally diverse heterocycles (Fig. 1). Some compounds that displayed promising insecticidal activity against lepidopteran larvae were identified. Further field trials showed that compound IIa displayed higher insecticidal activity against diamondback moths than did the parent compound pyridalyl.
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MATERIALS AND METHODS
2.1 General Unless otherwise noted, all chemical reagents were commercially available and treated with standard methods before use. Silica gel column chromatography (CC) (silica gel 200–300 mesh) (Qingdao Makall Group Co., Ltd, Qingdao, China). Solvents were dried in a routine way and redistilled. 1 H NMR and 13 C NMR spectra were
∗
Correspondence to: Guang-Fu Yang, Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China. E-mail: [email protected]
a Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China b Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin, China
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Insecticidal activity of novel 1,1-dichloropropene derivatives Cl
Cl Cl Cl
O
O
Cl
N O
Cl Pyridalyl
CF3
Cl
O
O
n
O Het
Cl In,n = 1; IIa,n = 2 Het: substituted pyridines, pyrimidines, pyridazines, quinazoline, pyridazinones, benzothiazoles, etc.,
Figure 1. The chemical structure of pyridalyl and the designed analogues I and II.
recorded in CDCl3 or DMSO-d6 on a Mercury 400 or 600 spectrometer (Varian, Palo Alto, CA), and resonances (𝛿) were given in ppm relative to tetramethylsilane (TMS). The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad. High-resolution mass spectra (HRMS) were acquired in positive mode on a MALDI SYNAPT G2 high-definition mass spectrometer (Waters, Milford, MA). Melting points were taken on a Büchi B-545 melting point apparatus (Büchi Labortechnik AG, Flawil, Switzerland) and were uncorrected. The insecticidal and field trials were provided courtesy of the Bioassay Centre of the Zhejiang Chemical Industry Research Institute. The LC50 values were tested at Nanjing Agriculture University. The intermediates 1, 2, 3 and 4 were prepared according to the reported methods.7,10 All other heterocyclic intermediates were also prepared according to existing methods.14 – 21
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69.32, 69.26, 65.45, 29.42. HRMS [M + H+ ] calcd 513.9417, found 513.9417. 2-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6fluorobenzothiazole (Id). Yield 43%; white soild; mp 58–59 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.63–7.61 (m, 1H), 7.35–7.33 (m, 1H), 7.10–7.07 (m, 1H), 6.83 (s, 2H), 6.11 (t, J = 4.4 Hz, 1H), 4.84 (t, J = 4.0 Hz, 2H), 4.58 (d, J = 4.0 Hz, 2H), 4.14 (t, J = 4.0 Hz, 2H), 2.38–2.34 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 160.42, 158.02, 154, 145.71, 145.65, 129.71, 124.92, 124.48, 121.53, 121.44, 115.19, 113.96, 113.72, 107.96, 107.69, 69.46, 68.64, 65.43, 29.48. HRMS [M + H+ ] calcd 495.9511, found 495.9525. 3-Chloro-6-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}pro poxy)pyridazine (Ie). Yield 62%; yellow oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.38 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.4 Hz, 1H), 4.78 (t, J = 6.4 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 2.35–2.32 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 164.20, 153.95, 150.88, 145.69, 130.73, 129.66, 124.47, 120.06, 115.19, 114.51, 69.88, 65.43, 64.64, 29.38. HRMS [M + H+ ] calcd 456.9447, found 456.9470. 3-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6(trifluoromethyl)-pyridazine (If). Yield 50%; white solid; mp 46–47 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.70 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.84 (s, 2H), 6.12 (t, J = 6.0 Hz, 1H), 4.91 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 2.40–2.35 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.01, 154.03, 147.21, 145.69, 129.69, 126.34, 125.01 124.96, 124.48, 122.38, 122.29, 122.06, 117.82, 115.24, 69.78, 65.45, 65.22, 29.39. HRMS [M + H+ ] calcd 490.9711, found 490.9727. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-2methyl-6-(trifluoro-methyl)pyrimidine (Ig). Yield 32%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 6.88 (s, 1H), 6.84 (s, 2H), 6.12 (t, J = 6.4 Hz, 1H), 4.71 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 2.69 (s, 3H), 2.32–2.28 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 170.13, 169.68, 156.21, 155.86, 154.10, 145.82, 129.72, 125.07, 124.50, 121.96, 119.23, 115.66, 102.27, 69.82, 65.57, 63.96, 29.38, 25.89. HRMS [M + H+ ] calcd 504.9867, found 504.9883. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-2, 6-dimethylpyrimidine (Ih). Yield 41%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 6.84 (s, 2H), 6.39 (s, 1H), 6.12 (t, J = 6.0 Hz, 1H), 4.61–4.58 (m, 4H), 4.12 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 2.28–2.26 (m, 2H). HRMS [M + H+ ] calcd 451.0150, found 451.0171. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)qui nazoline (Ii). Yield 52%; white solid; mp 63–64 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 8.82 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 6.84 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.89 (t, J = 6.4 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 2.44–2.41 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.68, 154.38, 154, 150.76, 145.74, 133.53, 129.72, 127.57, 127.01, 124.96, 124.45, 123.45, 116.61, 115.23, 69.82, 65.46, 63.72, 29.42. HRMS [M + H+ ] calcd 472.9993, found 473.0009. 6-Chloro-4-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}pro poxy)quinazoline (Ij). Yield 68%; white solid; mp 82–83 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 8.80 (s, 1H), 8.11 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 6.0 Hz, 1H), 6.83 (s, 2H), 6.10 (t, J = 6.0 Hz, 1H), 4.88 (t, J = 4.4 Hz, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.19 (t, J = 4.4 Hz, 2H), 2.42–2.40 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.54, 155.54, 155.48, 154.44, 151.57, 145.65, 139.68, 129.67, 127.94, 126.90, 124.94, 124.44, 115.21, 114.95, 69.70, 65.45, 63.98, 29.35. HRMS [M + H+ ] calcd 506.9604, found 506.9618. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6fluoroquinazoline (Ik). Yield 59%; white solid; mp 65–66 ∘ C. 1 H
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2.2 Synthetic procedure for title compounds 3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propan-1-ol (4) (172 mg, 0.5 mmol), NaH (24 mg, 1 mmol) and the substituted Cl-Het (0.5 mmol) were dissloved in 10 mL of tetrahydrofuran (THF). The mixture was refluxed and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, the solvent was removed under reduced pressure and the residue was purifed by flash column chromatography to give the title compounds Ia to In. 6-Chloro-2-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)benzothiazole (Ia). Yield 57%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.62–7.59 (m, 2H), 7.33–7.26 (m, 1H), 6.83 (s, 1H), 6.11 (t, J = 4.4 Hz, 1H), 4.85 (t, J = 4.4 Hz, 2H), 4.58 (d, J = 4.4 Hz, 2H), 4.14 (t, J = 4.4 Hz, 2H), 2.37–2.35 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 172.87, 154.05, 147.94, 145.67, 133.03, 129.73, 128.85, 126.52, 124.99, 124.48, 121.59, 120.90, 115.25, 69.45, 68.81, 65.49, 29.48. HRMS [M + H+ ] calcd 511.9215, found 511.9239. 2-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-5methoxybenzothiazole (Ib). Yield 68%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.48 (d, J = 6.0 Hz, 1H), 6.86 (d, J = 6.0 Hz, 1H), 6.83 (s, 2H), 6.10 (t, J = 4.0 Hz, 1H), 4.84 (t, J = 4.0 Hz, 2H), 4.57 (d, J = 4.0 Hz, 2H), 4.14 (t, J = 4.0 Hz, 2H), 3.85 (s, 3H), 2.36–2.34 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 173.82, 158.71, 153.89, 150.32, 145.56, 129.61, 124.76, 124.46, 123.07, 121.38, 115.08, 112.17, 104.78, 69.43, 68.34, 65.33, 55.38, 29.44. HRMS [M + H+ ] calcd 507.9711, found 507.9738. 2-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6, 7-difluorobenzothiazole (Ic). Yield 49%; white solid; mp 62–63 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.42–7.39 (m, 1H), 7.22–7.15 (m, 1H), 6.84 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.86 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H), 2.39–2.33 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 172.54, 154.04, 147.80, 146.94, 145.79, 145.59, 145.39, 143.13, 129.69, 124.95, 124.47, 116.17, 115.20, 115.02,
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NMR (400 MHz, CDCl3 ) 𝛿 8.79 (s, 1H), 8.19 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 10 Hz, 1H), 7.31 (t, J = 10 Hz, 1H), 6.83 (s, 2H), 6.10 (t, J = 6.0 Hz, 1H), 4.88 (t, J = 6.0 Hz, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 2.43–2.40 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.81, 166.38, 16429, 155.52, 153.94, 145.56, 129.61, 126.22, 124.41, 117.05, 116.80, 115.12, 113.44, 111.94, 111.74, 69.65, 65.37, 63.86, 29.31. HRMS [M + H+ ] calcd 490.9899, found 490.9906. 2-(tert-Butyl)-4-chloro-5-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy] phenoxy}propoxy)-pyridazin-3(2H)-one (Il). Yield 58%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.64 (s, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.74 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H), 2.30–2.25 (m, 2H), 1.66 (s, 9H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 157.81, 153.79, 150.97, 145.69, 134.85, 129.58, 124.73, 124.45, 123.48, 115.04, 69.87, 69.34, 65.57, 65.33, 30.87. 27.71. HRMS [M + H+ ] calcd 550.9842, found 550.9822. 4-Chloro-5-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}pro poxy)-2-methylpyridazin-3(2H)-one (Im). Yield 42%; colourless oil. 1 H NMR (600 MHz, CDCl3 ) 𝛿 7.69 (s, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.87 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.6 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.76 (s, 3H), 2.28–2.26 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 157.50, 154.03, 150.60, 145.93, 137.21, 129.78, 125.01, 124.56, 123.66, 115.33, 69.89, 69.79, 65.58, 31.03, 29.69. HRMS [M + H+ ] calcd 508.9372, found 508.9361. 4-Chloro-2-(cyclopropylmethyl)-5-(3-{2,6-dichloro-4-[(3,3-dichlo roallyl)oxy]phenoxy}-propoxy)pyridazin-3(2H)-one (In). Yield 30%; colourless oil. 1 H NMR (600 MHz, CDCl3 ) 𝛿 7.71 (s, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.85 (t, J = 6.6 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H), 3.99 (d, J = 6.6 Hz, 2H), 2.28–2.25 (m, 2H), 1.34 (t, J = 6.6 Hz, 1H), 0.53–0.52 (m, 2H), 0.41 (d, J = 4.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 157.23, 153.89, 150.64, 145.75, 137.11, 129.67, 124.86, 124.50, 123.54, 115.14, 69.81, 69.61, 65.42, 56.40, 30.94, 10.05, 3.58. HRMS [M + H+ ] calcd 526.9866, found 526.9862. 3-[(5-Chloropyridin-2-yl)oxy]propan-1-ol (5). In a 250 mL roundbottomed flask, butane-1,4-diol (50 mL) and NaH (2.97 g, 124 mmol) were dissolved in 20 mL of distilled THF. The temperature was slowly raised to 100 ∘ C. 2,5-Dichloropyridine (9.3 g, 62.84 mmol) in 30 mL of THF was slowly added to the above mixture. The reaction was monitored by TLC. When the reaction was completed, the mixture was cooled to room temperature. The solvent THF was removed under reduced pressure; the residue was washed with water and saturated brine and finally extracted with CH2 Cl2 . The organic layer was dried over anhydrous Na2 SO4 . The solvent was removed under reduced pressure to obtain the product (8.85 g). Yield 70%; white solid. 1 H NMR (600 MHz, CDCl3 ) 𝛿 8.08 (s, 1H), 7.51 (d, J = 9.6 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.72 (t, J = 6.0 Hz, 2H), 1.87–1.85 (m, 2H), 1.74–1.71 (m, 3H). 3-[(5-Chloropyridin-2-yl)oxy]propyl 4-methylbenzenesulfonate (6). 3-[(5-Chloropyridin-2-yl)oxy]propan-1-ol (5) (26.9 g, 133.83 mmol), Et3 N (40.55 g, 401.49 mmol) and dimethylaminopyridine (1.63 g, 13.36 mmol) were dissolved in 50 mL of distilled CH2 Cl2 . TsCl (30.51 g, 160.60 mmol) in 50 mL of CH2 Cl2 was slowly added to the stirring mixture. The reaction was stirred at room temperature and monitored by TLC. When the reaction was completed, the mixture was washed 3 times with 150 mL of water and once with saturated citric acid (100 mL). The organic layer was dried with anhydrous Na2 SO4 . The solvent was removed under reduced pressure to obtain the product (41.46 g). Yield 87%; white solid. 1 H NMR (600 MHz, CDCl3 ) 𝛿 8.05 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.64 (d, J = 9.0 Hz, 1H), 4.22 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H), 1.82–1.80 (m, 4H).
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2.3 Synthetic procedure for title compound IIa 3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propan-1-ol (4) (20 g, 69.44 mmol) and K2 CO3 (19.16 g, 138.88 mmol) were dissloved in 50 mL of dimethyl ether (DME). The resulting mixture was heated to reflux, and 3-[(5-chloropyridin-2-yl)oxy]propyl 4-methylbenzenesulfonate (6) (22.4 g, 63.12 mmol) in 50 mL of DME was slowly added. The reaction was monitored by TLC. When the reaction was completed, the mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with water, 15% NaOH (aq.) and saturated brine. The organic layer was dried over anhydrous Na2 SO4 . The solvent was evaporated under reduced pressure, and the residue was purifed by flash column chromatography to give the title compound IIa (20.87 g). Yield 70%; mp 55–56 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 8.09 (d, J = 2.4 Hz, 1H), 7.52 (dd, J1 = 2.8 Hz, J2 = 2.8 Hz, 1H), 6.84 (s, 2H), 6.70 (d, J = 8.8 Hz, 1H), 6.11 (t, J = 6.4 Hz, 1H), 4.58 (d, J = 6.4 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 1.96–2.06 (m, 4H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 162.35, 153.86, 145.94, 145.09, 138.42, 129.75, 124.91, 124.54, 123.83, 115.18, 112.04, 73.16, 66.01, 66.45, 26.69, 25.56. HRMS [M + H+ ] calcd 469.9651, found 469.9660. 2.4 X-ray diffraction Colourless crystals of compounds Ic and IIa (0.26 mm × 0.20 mm × 0.10 mm) were mounted on quartz fibre with protective oil. Cell dimensions and intensities were measured at 299 K on a Smart CCD area detector diffractometer (Bruker Corp., Billerica, MA) with graphite monochromated MoK𝛼 radiation (𝜆 = 0.71073 Å); 𝜃 max = 20.30; 3172 measured reflections; 1809 independent reflections (Rint = 0.0275), of which 557 had I > 2𝜎 (I) .22 The structure was solved by direct methods using SHELXS-97; all other calculations were performed with the Bruker SAINT system and Bruker Smart programs. 2.5 Biological assay A bioassay was performed on test plant organisms raised in a greenhouse to determine insecticidal activity against oriental armyworm (Mythimna separata) and Prodenia litura. The bioassay was replicated at 25 ± 1 ∘ C according to statistical requirements. Assessments were made on a dead/alive basis, and mortality rates were corrected applying Abbott’s formula. Evaluation was based on a percentage scale of 0–100, where 0 equals no activity and 100 equals total kill. The error of the experiments was 5%. For comparative purposes, pyridalyl was tested as the control under the same conditions. Insecticidal activity is summarised in Table 1. 2.5.1 LC50 values of Ic and IIa against beet armyworm, bollworm, P. litura and diamondback moths The LC50 values were tested at Nanjing Agriculture University. The bioassay was replicated at 27 ± 1 ∘ C according to statistical requirements. The leaves were then sprayed with the test solution and allowed to dry. The dishes were infested with ten third-instar beet armyworm, P. litura, bollworm and diamondback moths. The percentage mortalities were evaluated 3–5 days after treatment. Each treatment was replicated 4 times. 2.5.2 Field trials against diamondback moths The field trials were carried out in Ningbo, Zhejiang Province, China. Compound IIa (5% EC) and pyridalyl (5% EC) were sprayed
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Insecticidal activity of novel 1,1-dichloropropene derivatives
Table 1. Insecticidal activity of compounds against P. litura Larvicidal activity (%) Compound Ia Ib Ic Id Ie If Ig Ih Ii Ij Ik Il Im In IIa Pyridalyl
R 6-Cl 5-OMe 6,7-diF 6-F 6-Cl 6-CF3 – – H 6-Cl 6-F t-Bu cyclopropyl methyl Me 5-Cl
100 mg L−1 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
20 mg L−1
4 mg L−1
0 60 100 60 45 47 85 0 60 60 40 0 0 0 100 100
0 0 10 0 0 0 40 0 0 0 0 0 0 0 0 0
uniformly on positive and negative plant leaves. The research was conducted according to the pesticide efficacy field trial procedure GB-T 17980.13-2000. The test data for statistical analysis were evaluated using Duncan’s multiple range test.
3
RESULTS AND DISCUSSION
3.1 Chemistry The synthetic routes of the title compounds Ia to In and IIa are shown in Schemes 1 and 2 respectively. As shown in Scheme 1, a five-step route was carried out to synthesise the target molecules Ia to In. Compound 2 was selected as a key intermediate, which can be prepared by condensation of hydroquinone and 1,1,3-trichloroprop-1-ene (1), as described in the literature. Although the compound 1,1,3-trichloroprop-1-ene
www.soci.org (1) can be easily prepared by elimination of the starting material 1,1,1,3-tetrachloropropane, when the mixture of hydroquinone and 1,1,3-trichloroprop-1-ene (1) is refluxed in the presence of K2 CO3 as a base in acetone, as described in the literature, the isolated yield of intermediate 2 is very low, mainly owing to the formation of a large amount of disubstituted byproduct 1,4-bis[(3,3-dichloroallyl)oxy]benzene. Therefore, the reaction conditions were optimised. The yield of intermediate 2 was finally improved to 77% by slowly adding a solution of 1,1,3-trichloroprop-1-ene (1) in acetone to a mixture of 5 equ. hydroquinone and K2 CO3 at 50 ∘ C. Afterwards, compound 3 was prepared by treatment of intermediate 2 with SOCl2 in toluene at 60 ∘ C. It should be noted that the reaction time is critical to this transformation. The reaction mixture should be quenched immediately after the addition of SOCl2 , and prolonging the reaction time would lead to a polychlorinated product. Further transformation of compound 3 to product 4 was achieved by nucleophilic substitution of compound 3 with 3-bromopropan-1-ol, with a yield of 81%. Finally, coupling of intermediate 4 with diverse heterocylic halide or heterocyclic mesylate furnished the corresponding desired pyridalyl analogues. The synthesis of compound IIa by the route shown in Scheme 1 was unsuccessful, and so an alternative route was designed, as shown in Scheme 2. Initially, 2,5-dichloropyridine was selected as the starting material, which performed the nucleophilc substitution reaction with 1,4-butanediol to afford the monoether 5 chemoselectively. The primary hydroxyl group in molecule 5 was then transferred to the tosylate leaving group by treatment with tosyl chloride in the presence of Et3 N in good yield. The resulting product 6 was reacted with intermediate 3 to generate the target product IIa. It is worth noting that it was difficult to consume the dichlorophenol 3 completely during this nucleophilic substitution process even by increasing the amount of tosylate or prolonging the reaction time. The small amount of unreacted intermediate 3 should be removed by washing with aqueous NaOH solution before further flash chromatography, otherwise it will interfere with the purification step owing to its similar polarity to compound IIa.
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Scheme 1. Synthetic route of the title compounds Ia to In. Reagent and conditions: a – FeCl3 , 90 ∘ C; b – hydroquinone, K2 CO3 , Me2 CO, reflux; c – SO2 Cl2 , toluene, 65 ∘ C; d – Br(CH2 )3 OH, K2 CO3 , Me2 CO, reflux; e – NaH, THF, Het-Cl or Het-SO2 CH3 , reflux.
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Scheme 2. Synthetic route of the title compound IIa. Reagent and conditions: a – HO(CH2 )4 OH, NaH, THF, reflux; b – TsCl, Et3 N, CH2 Cl2 , room temperature; c – 3, K2 CO3 , DME, reflux.
larvicidal activity, much higher than the monofluorosubstituted compound Id (60%) and 5-methoxyl-substituted compound Ib (60%), whereas the 6-chlorosubstituted compound Ia lost its insecticidal activity totally at a concentration of 20 mg L−1 . Of the pyrimidine derivatives, 2,6-dimethyl-substituted product Ih had no insecticidal activity at a concentration of 20 mg L−1 . In comparison, when the methyl substituent at position-6 was changed to a trifluoromethyl group, the resulting compound Ig showed 85% mortality, comparable with that of the control pyridalyl. Compound IIa, which is most similar in character to the parent pyridalyl, with a four-carbon linker and a chlorine substitution rather than the three-carbon spacer and trifluoromethyl group in pyridalyl, displayed similar insecticidal activity to the mother structure. Interestingly, although most compounds lost insecticidal activity when the concentration was reduced to 4 mg L−1 , compounds Ig and Ic retained 40% and 10% larvicidal activity respectively. They are superior to the commercial control pyridalyl, which did not show any insecticidal activity at 4 mg L−1 .
Figure 2. The crystal structure of compound Ic.
Figure 3. The crystal structure of compound IIa.
The structures of all intermediates and title compounds were confirmed by 1 H NMR, 13 C NMR and HRMS data. Furthermore, the structures of Ic and IIa were unambiguously determined by X-ray diffraction (Figs 2 and 3 respectively).
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3.2 Insecticidal activity and structure–activity relationships against P. litura The newly prepared compounds Ia to In and IIa were evaluated for insecticidal activity against P. litura. The commercial insecticide pyridalyl was used as a control. The larvicidal activities at different concentrations are presented in Table 1. The results indicate that all of these compounds displayed excellent insecticidal activity at a concentration of 100 mg L−1 . Further assays at a lower concentration of 20 mg L−1 showed that the heterocyclic moiety had a significant effect on their insecticidal activity. The larvicidal activity ranged from 0 to 100%, depending on the heterocycle backbone introduced. In general, conjugated heterocyclic moieties such as benzothiazoles, pyrimidines and pyridine are more favourable from the viewpoint of conserving insecticidal activity than the non-conjugated pyridazinones. In addition, the substituents introduced into the heterocycles also displayed notable effects on insecticidal activity. Taking benzothiazole derivatives as examples, the 6,7-difluorosubstituted compound Ic showed 100%
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3.3 LC50 values of Ic and IIa against beet armyworm, bollworm, P. litura and diamondback moths The preliminary insecticidal assay against P. litura indicated that compounds Ic and IIa showed excellent potency. Therefore, these two compounds were selected for further assay against four insects: beet armyworm, bollworm, P. litura and diamondback moths. As listed in Table 2, compound Ic exhibited better insecticidal activity (LC50 = 4.90 mg L−1 ) against insect bollworm than pyridalyl (LC50 = 5.79 mg L−1 ) and comparable activity against P. litura (LC50 = 24.94 mg L−1 ) with pyridalyl (LC50 = 21.53 mg L−1 ). However, compound Ic showed much lower insecticidal activity against beet armyworm and diamondback moths (LC50 = 13.75 and 10.12 mg L−1 respectively) than pyridalyl (LC50 = 5.77 and 3.10 mg L−1 respectively). On the basis of the LC50 and the 95% confidence interval values, compound IIa was found to be most effective against diamondback moths and bollworm, with LC50 values of 2.87 and 5.65 mg L−1 respectively, as opposed to the standard control pyridalyl which had LC50 values of 3.10 and 5.79 mg L−1 respectively. 3.4 Field trials of IIa against diamondback moths The results listed in Table 2 indicate that compound IIa displayed excellent insecticidal activity against diamondback moths. Therefore, field trials of compound IIa were carried out in Zhejiang Province in 2013 in order to evaluate further its potency against diamondback moths. As shown in Table 3, compound IIa showed very good control effect against diamondback moths in the dosage range 50–400 mg kg−1 . At concentrations of 50 and
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Insecticidal activity of novel 1,1-dichloropropene derivatives
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Table 2. LC50 values of compounds Ic and IIa and pyridalyl against beet armyworm, bollworm, diamondback moths and P. litura Compound Ic
IIa
Pyridalyl
Insects Beet armyworm Bollworm Diamondback moths P. litura Beet armyworm Bollworm Diamondback moths P. litura Beet armyworm Bollworm Diamondback moths P. litura
1.4534 + 3.1161x 3.3902 + 2.3323x 1.9546 + 3.0298x 2.1024 + 2.0743x 2.1912 + 2.6387x 3.0453 + 2.600x 3.6745 + 2.8978x 1.3940 + 2.3886x 3.0517 + 2.5597x 3.1156 + 2.4719x 3.5877 + 2.8756x 0.7506 + 3.1877x
Table 3. Field trials of compound IIa against diamondback moths Tested insecticide IIa (5% EC)
Pyridalyl (5% EC)
Dosea (mg kg−1 )
95% confidence interval
13.75 4.90 10.12 24.94 11.60 5.65 2.87 32.34 5.77 5.79 3.10 21.53
11.240–16.373 3.812–5.974 8.582–11.722 18.659–31.773 9.128–14.072 4.644–7.153 2.460–3.446 25.257–40.059 4.525–7.017 4.656–7.037 2.649–3.780 17.454–25.435
for further development as a new insecticide for the control of lepidopteran insects.
Control effect (%) 1 dayb
4 days
8 days
59.8 63.8 75.8 80.8 47.2 50.8 53.0
69.2 80.8 86.4 90.9 65.3 75.9 78.9
67.9 81.3 95.4 99.3 66.6 80.9 88.2
50 100 200 400 50 100 200
14 days 70.2 81.8 94.0 98.6 64.0 73.4 83.8
a The amount sprayed is about 750 kg ha−1 b The number of days between spraying insecticides and investigating
the effects.
100 mg kg−1 , the 8 day control effects of compound IIa are 67.9 and 81.3% respectively, comparable with the control effects of pyridalyl (66.6 and 80.9% respectively). However, compound IIa exhibited a better control effect than pyridalyl at a concentration of 200 mg kg−1 . The 8 day control effect reached 95.4%, while pyridalyl only displayed a control effect of 88.2% at the same concentration. Most interestingly, compound IIa showed control for a much longer time than pyridalyl. The 14 day control efficacy of compound IIa was comparable with its 8 day control potency. By comparison, when the duration was prolonged from 8 to 14 days, the control effect of the standard drug pyridalyl declined at the concentration levels investigated.
4
LC50 (mg L−1 )
y = a + bx
CONCLUSIONS
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The research was supported in part by the National Key Technologies R&D Programme (2011BAE06B05).
REFERENCES 1 Sakamoto N, Saito S, Hirose T, Suzuki M, Matsuo S, Izumi K et al., The discovery of pyridalyl: a novel insecticidal agent for controlling lepidopterous pests. Pest Manag Sci 60:25–34 (2003). 2 Saito S, Isayama S, Sakamoto N and Umeda K. Insecticidal activity of pyridalyl: acute and sub-acute symptoms in Spodoptera litura larvae. J Pestic Sci 29:372–375 (2004). 3 Tillman PG and Mulrooney JE, Effect of selected insecticides on the natural enemies Coleomegilla maculata and Hippodamia convergens (Coleoptera: Coccinellidae), Geocoris punctipes (Hemiptera: Lygaeidae) and Bracon mellitor, Cardiochiles nigriceps and Cotesia marginiventris (Hymenoptera: Braconidae) in cotton. J Econ Entomol 93:1638–1643 (2000). 4 Powell GF, Ward DA, Prescott MC, Spiller DG, White MRH, Earley FGP et al., The molecular action of the novel insecticide, pyridalyl. Insect Biochem Mol Biol 41:459–469 (2011). 5 Zhang J, Kang Z, Yang JC, Li M and Liu CL, The research progress of dihalopropenyl aryl ether insecticides. Pesticide 50:313–319 (2011). 6 Feng ML, Li YF, Zhu HJ, Ni JP, Xi BB and Zhao L, Design, synthesis, insecticidal activity and structure–activity relationship of 3,3-dichloro-2-propenyloxy-containing phthalic acid diamide structures. Pest Manag Sci 68:986–994 (2012). 7 Li M, Liu CL, Zhang J, Wu Q, Hao SL and Song YQ, Design, synthesis and structure–activity relationship of novel insecticidal dichloro-allyloxy-phenol derivatives containing substituted pyrazol-3-ols. Pest Manag Sci 69:635–641 (2013). 8 Liu CL, Yang JC, Chang XH, Li M, Li KK, Wu Q et al., Aryloxy dihalopropenyl ether compound and use. World Patent WO 2012130137 (2012). 9 Sun RF, Zhang YL, Bi FC and Wang QM, Design, synthesis, and bioactivity study of novel benzoylpyridazyl ureas. J Agric Food Chem 57:6356–6361 (2009). 10 Wang ZQ, Li Y, Zhou LP and Wang JC, Dichloro-allyloxy-phenol derivatives as insecticide. Chinese Patent CN 1860874 (2006). 11 Huang W, Zhao PL, Liu CL, Chen Q, Liu ZM and Yang GF, Design, synthesis, and fungicidal activities of new strobilurin derivatives. J Agric Food Chem 55:3004–3010 (2007). 12 Zhou XJ, Lai LH, Jin GY and Zhang ZX, Synthesis, fungicidal activity, and 3D-QSAR of pyridazinone-substituted 1,3, 4-oxadiazoles and 1,3,4-thiadiazoles. J Agric Food Chem 50:3757–3760 (2002). 13 Ghanim M, Lebedev G, Kontsedalov S and Isshaaya I, Flufenerim. A novel insecticide acting on diverse insect pests: biological mode of
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In summary, a series of novel 1,1-dichloropropene derivatives bearing diverse heterocycles have been designed and synthesised. The bioassay showed that compound Ic, a benzothiazole-containing analogue, and compound IIa, a pyridine-containing analogue, exhibited good insecticidal activity. Among the four tested insects, compound Ic showed comparable insecticidal activity with pyridalyl against bollworm and P. litura, while compound IIa exhibited comparable insecticidal activity with pyridalyl against bollworm and diamondback moths. Further field trials indicated that compound IIa produced much better 14 day control effects against diamondback moths and a longer duration of control efficacy than pyridalyl, indicating its potential
ACKNOWLEDGEMENTS
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action and biochemical aspects. J Agric Food Chem 59:2839–2844 (2011). Pospíšil J, Robiette R, Satoa H and Debrusa K, Practical synthesis of 𝛽-oxobenzo[d]thiazolyl sulfones: scope and limitations. Org Biomol Chem 10:1225–1234 (2012). Goodman AJ, Stanforth SP and Tarbit B, Desymmetrization of dichloroazaheterocycles. Tetrahedron 55:15 067–15 070 (1999). Mizuno H, Pyrimidine compound and its use in pest control. World Patent WO 2010134478 (2010). Liu ZD, Li DW, Li SK, Bai DL, He XC and Hu YH, Synthesis of novel 5,6-substituted furo[1,3-d]pyrimidines via Pd-catalyzed cyclization of alkynylpyrimidinols with aryl iodides. Tetrahedron 63:1931–1936 (2007). Cesati RR, Cheesman EH, Lazewatsky J, Radeke HS, Castner JF, Mongeaw E et al., Methods and apparatus for synthesizing imaging agents and intermediates thereof. World Patent WO 2011097649 (2011).
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19 Becknell NC, Dandu R, Dun DD, Hudkins RL, Josef KA, Sundar BG et al., Substituted pyridazinone derivatives as Histamine-3 (H3 ) receptor ligands. World Patent WO 2009142732 (2009). 20 Kent B, He W, Gong Y, Dyatkin AB and Miskowski TA, Pyridazinones and antagonists of A4 integrins. World Patent WO 2005077915 (2005). 21 Tao CL, Sun XW, Han HN, Lukasz K and Neil D, Isoquinoline, quinoline, and quinazoline derivatives as inhibitors of hedgehog signaling. World Patent WO 2010144586 (2010). 22 Supplementary material CCDC-967905 and CCDC-967906 contain the supplementary crystallographic data for compounds Ic and IIa. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB 21EZ, UK. Fax: +44-1223-336033. E-mail: [email protected].
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Revised: 29 April 2014
Accepted article published: 9 May 2014
Published online in Wiley Online Library: 5 June 2014
(wileyonlinelibrary.com) DOI 10.1002/ps.3827
Design, synthesis and insecticidal activity of novel 1,1-dichloropropene derivatives Jun Li,a Zhen-Yu Wang,a Qiong-You Wua and Guang-Fu Yanga,b* Abstract BACKGROUND: Pyridalyl is a highly active insecticide against lepidopterous larvae, with a novel chemical structure not related to any other existing insecticide. To discover new pyridalyl analogues with high activity against resistant pests, a series of 1,1-dichloropropene derivatives bearing structurally diverse substituted heterocycle rings in place of the pyridine ring of pyridalyl were designed and synthesised. RESULTS: All of the title compounds were confirmed by 1 H NMR, 13 C NMR and high-resolution mass spectra. Two representative compounds (Ic and IIa) were further characterised by X-ray diffraction analysis. In addition, bioassays showed that most of the newly synthesised compounds displayed good insecticidal activity against Prodenia litura. Further determination of LD50 values and field trials identified compound IIa as the most promising candidate, which produced a much better 14 day control effect against diamondback moths and longer duration of efficacy than pyridalyl, indicating its potential for further development as a new insecticide for the control of lepidopteran insects. CONCLUSION: Compound IIa has great potential for further development as a new insecticide for the control of lepidopteran insects. © 2014 Society of Chemical Industry Keywords: 1,1-dichloropropene; insecticide; pyridalyl; heterocycle
1
INTRODUCTION
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Chemical insecticides are efficient tools for controlling pests in agriculture. However, pest resistance to insecticides is rapidly increasing in occurrence. Over 500 species of pests have evolved resistance to conventional insecticides, including organophosphates, carbamates and synthetic pyrethroids. Therefore, the discovery of insecticides with a novel mode of action is urgent for plant protection and is vital for managing pest strains that have become resistant to existing products.1 Pyridalyl, discovered at the Agricultural Chemicals Research Laboratory of Sumitomo Chemical Co. Ltd (Tokyo, Japan), belongs to a new class of insecticide and has a novel chemical structure not related to any other existing insecticide (Fig. 1). It is used for the control of various lepidopteran larvae and shows no cross-resistance with the existing insecticides, such as synthetic pyrethroids, organic phosphates, benzoylphenylureas, nicotinic insecticides and ryanodine insectides.2,3 Although pyridalyl was discovered almost 20 years ago, its mode of action is still unknown. Recent research demonstrated that pyridalyl can cause cell apoptosis in BM36 cells, and so its insecticidal activity may be related to the generation of active oxygen species of a pyridalyl metabolite.4 Since its appearance on the market in 2004, many pyridalyl analogues with high insecticidal activity have been reported.5 – 7 However, the structural diversity claimed in the patent is still limited; no new compounds within this family have been developed as commercial insecticides since pyridalyl.8 In ongoing research to find new insecticides, the present authors have focused on new pyridalyl analogues with structural diversity. Various N- or S-containing heterocyclic derivatives, such as pyridine, pyrimidine, Pest Manag Sci 2015; 71: 694–700
pyridazine, pyridazinone and benzothiazole, have always displayed broad-spectrum biological activity.9 – 13 It was suggested that replacement of the pyridine moiety of pyridalyl with these heterocycles might produce new lead compounds with higher insecticidal activity. Therefore, the authors designed and synthesised a series of 1,1-dichloropropene derivatives containing structurally diverse heterocycles (Fig. 1). Some compounds that displayed promising insecticidal activity against lepidopteran larvae were identified. Further field trials showed that compound IIa displayed higher insecticidal activity against diamondback moths than did the parent compound pyridalyl.
2
MATERIALS AND METHODS
2.1 General Unless otherwise noted, all chemical reagents were commercially available and treated with standard methods before use. Silica gel column chromatography (CC) (silica gel 200–300 mesh) (Qingdao Makall Group Co., Ltd, Qingdao, China). Solvents were dried in a routine way and redistilled. 1 H NMR and 13 C NMR spectra were
∗
Correspondence to: Guang-Fu Yang, Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China. E-mail: [email protected]
a Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, China b Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin, China
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Insecticidal activity of novel 1,1-dichloropropene derivatives Cl
Cl Cl Cl
O
O
Cl
N O
Cl Pyridalyl
CF3
Cl
O
O
n
O Het
Cl In,n = 1; IIa,n = 2 Het: substituted pyridines, pyrimidines, pyridazines, quinazoline, pyridazinones, benzothiazoles, etc.,
Figure 1. The chemical structure of pyridalyl and the designed analogues I and II.
recorded in CDCl3 or DMSO-d6 on a Mercury 400 or 600 spectrometer (Varian, Palo Alto, CA), and resonances (𝛿) were given in ppm relative to tetramethylsilane (TMS). The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad. High-resolution mass spectra (HRMS) were acquired in positive mode on a MALDI SYNAPT G2 high-definition mass spectrometer (Waters, Milford, MA). Melting points were taken on a Büchi B-545 melting point apparatus (Büchi Labortechnik AG, Flawil, Switzerland) and were uncorrected. The insecticidal and field trials were provided courtesy of the Bioassay Centre of the Zhejiang Chemical Industry Research Institute. The LC50 values were tested at Nanjing Agriculture University. The intermediates 1, 2, 3 and 4 were prepared according to the reported methods.7,10 All other heterocyclic intermediates were also prepared according to existing methods.14 – 21
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69.32, 69.26, 65.45, 29.42. HRMS [M + H+ ] calcd 513.9417, found 513.9417. 2-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6fluorobenzothiazole (Id). Yield 43%; white soild; mp 58–59 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.63–7.61 (m, 1H), 7.35–7.33 (m, 1H), 7.10–7.07 (m, 1H), 6.83 (s, 2H), 6.11 (t, J = 4.4 Hz, 1H), 4.84 (t, J = 4.0 Hz, 2H), 4.58 (d, J = 4.0 Hz, 2H), 4.14 (t, J = 4.0 Hz, 2H), 2.38–2.34 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 160.42, 158.02, 154, 145.71, 145.65, 129.71, 124.92, 124.48, 121.53, 121.44, 115.19, 113.96, 113.72, 107.96, 107.69, 69.46, 68.64, 65.43, 29.48. HRMS [M + H+ ] calcd 495.9511, found 495.9525. 3-Chloro-6-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}pro poxy)pyridazine (Ie). Yield 62%; yellow oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.38 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.4 Hz, 1H), 4.78 (t, J = 6.4 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 2.35–2.32 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 164.20, 153.95, 150.88, 145.69, 130.73, 129.66, 124.47, 120.06, 115.19, 114.51, 69.88, 65.43, 64.64, 29.38. HRMS [M + H+ ] calcd 456.9447, found 456.9470. 3-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6(trifluoromethyl)-pyridazine (If). Yield 50%; white solid; mp 46–47 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.70 (d, J = 9.2 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.84 (s, 2H), 6.12 (t, J = 6.0 Hz, 1H), 4.91 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 2.40–2.35 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.01, 154.03, 147.21, 145.69, 129.69, 126.34, 125.01 124.96, 124.48, 122.38, 122.29, 122.06, 117.82, 115.24, 69.78, 65.45, 65.22, 29.39. HRMS [M + H+ ] calcd 490.9711, found 490.9727. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-2methyl-6-(trifluoro-methyl)pyrimidine (Ig). Yield 32%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 6.88 (s, 1H), 6.84 (s, 2H), 6.12 (t, J = 6.4 Hz, 1H), 4.71 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 2.69 (s, 3H), 2.32–2.28 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 170.13, 169.68, 156.21, 155.86, 154.10, 145.82, 129.72, 125.07, 124.50, 121.96, 119.23, 115.66, 102.27, 69.82, 65.57, 63.96, 29.38, 25.89. HRMS [M + H+ ] calcd 504.9867, found 504.9883. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-2, 6-dimethylpyrimidine (Ih). Yield 41%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 6.84 (s, 2H), 6.39 (s, 1H), 6.12 (t, J = 6.0 Hz, 1H), 4.61–4.58 (m, 4H), 4.12 (t, J = 6.0 Hz, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 2.28–2.26 (m, 2H). HRMS [M + H+ ] calcd 451.0150, found 451.0171. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)qui nazoline (Ii). Yield 52%; white solid; mp 63–64 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 8.82 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 6.84 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.89 (t, J = 6.4 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 2.44–2.41 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.68, 154.38, 154, 150.76, 145.74, 133.53, 129.72, 127.57, 127.01, 124.96, 124.45, 123.45, 116.61, 115.23, 69.82, 65.46, 63.72, 29.42. HRMS [M + H+ ] calcd 472.9993, found 473.0009. 6-Chloro-4-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}pro poxy)quinazoline (Ij). Yield 68%; white solid; mp 82–83 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 8.80 (s, 1H), 8.11 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 6.0 Hz, 1H), 6.83 (s, 2H), 6.10 (t, J = 6.0 Hz, 1H), 4.88 (t, J = 4.4 Hz, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.19 (t, J = 4.4 Hz, 2H), 2.42–2.40 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.54, 155.54, 155.48, 154.44, 151.57, 145.65, 139.68, 129.67, 127.94, 126.90, 124.94, 124.44, 115.21, 114.95, 69.70, 65.45, 63.98, 29.35. HRMS [M + H+ ] calcd 506.9604, found 506.9618. 4-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6fluoroquinazoline (Ik). Yield 59%; white solid; mp 65–66 ∘ C. 1 H
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2.2 Synthetic procedure for title compounds 3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propan-1-ol (4) (172 mg, 0.5 mmol), NaH (24 mg, 1 mmol) and the substituted Cl-Het (0.5 mmol) were dissloved in 10 mL of tetrahydrofuran (THF). The mixture was refluxed and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, the solvent was removed under reduced pressure and the residue was purifed by flash column chromatography to give the title compounds Ia to In. 6-Chloro-2-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)benzothiazole (Ia). Yield 57%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.62–7.59 (m, 2H), 7.33–7.26 (m, 1H), 6.83 (s, 1H), 6.11 (t, J = 4.4 Hz, 1H), 4.85 (t, J = 4.4 Hz, 2H), 4.58 (d, J = 4.4 Hz, 2H), 4.14 (t, J = 4.4 Hz, 2H), 2.37–2.35 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 172.87, 154.05, 147.94, 145.67, 133.03, 129.73, 128.85, 126.52, 124.99, 124.48, 121.59, 120.90, 115.25, 69.45, 68.81, 65.49, 29.48. HRMS [M + H+ ] calcd 511.9215, found 511.9239. 2-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-5methoxybenzothiazole (Ib). Yield 68%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.48 (d, J = 6.0 Hz, 1H), 6.86 (d, J = 6.0 Hz, 1H), 6.83 (s, 2H), 6.10 (t, J = 4.0 Hz, 1H), 4.84 (t, J = 4.0 Hz, 2H), 4.57 (d, J = 4.0 Hz, 2H), 4.14 (t, J = 4.0 Hz, 2H), 3.85 (s, 3H), 2.36–2.34 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 173.82, 158.71, 153.89, 150.32, 145.56, 129.61, 124.76, 124.46, 123.07, 121.38, 115.08, 112.17, 104.78, 69.43, 68.34, 65.33, 55.38, 29.44. HRMS [M + H+ ] calcd 507.9711, found 507.9738. 2-(3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propoxy)-6, 7-difluorobenzothiazole (Ic). Yield 49%; white solid; mp 62–63 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.42–7.39 (m, 1H), 7.22–7.15 (m, 1H), 6.84 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.86 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H), 2.39–2.33 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 172.54, 154.04, 147.80, 146.94, 145.79, 145.59, 145.39, 143.13, 129.69, 124.95, 124.47, 116.17, 115.20, 115.02,
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NMR (400 MHz, CDCl3 ) 𝛿 8.79 (s, 1H), 8.19 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 10 Hz, 1H), 7.31 (t, J = 10 Hz, 1H), 6.83 (s, 2H), 6.10 (t, J = 6.0 Hz, 1H), 4.88 (t, J = 6.0 Hz, 2H), 4.57 (d, J = 6.0 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 2.43–2.40 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 166.81, 166.38, 16429, 155.52, 153.94, 145.56, 129.61, 126.22, 124.41, 117.05, 116.80, 115.12, 113.44, 111.94, 111.74, 69.65, 65.37, 63.86, 29.31. HRMS [M + H+ ] calcd 490.9899, found 490.9906. 2-(tert-Butyl)-4-chloro-5-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy] phenoxy}propoxy)-pyridazin-3(2H)-one (Il). Yield 58%; colourless oil. 1 H NMR (400 MHz, CDCl3 ) 𝛿 7.64 (s, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.74 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H), 2.30–2.25 (m, 2H), 1.66 (s, 9H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 157.81, 153.79, 150.97, 145.69, 134.85, 129.58, 124.73, 124.45, 123.48, 115.04, 69.87, 69.34, 65.57, 65.33, 30.87. 27.71. HRMS [M + H+ ] calcd 550.9842, found 550.9822. 4-Chloro-5-(3-{2,6-dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}pro poxy)-2-methylpyridazin-3(2H)-one (Im). Yield 42%; colourless oil. 1 H NMR (600 MHz, CDCl3 ) 𝛿 7.69 (s, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.87 (t, J = 6.0 Hz, 2H), 4.58 (d, J = 6.6 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.76 (s, 3H), 2.28–2.26 (m, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 157.50, 154.03, 150.60, 145.93, 137.21, 129.78, 125.01, 124.56, 123.66, 115.33, 69.89, 69.79, 65.58, 31.03, 29.69. HRMS [M + H+ ] calcd 508.9372, found 508.9361. 4-Chloro-2-(cyclopropylmethyl)-5-(3-{2,6-dichloro-4-[(3,3-dichlo roallyl)oxy]phenoxy}-propoxy)pyridazin-3(2H)-one (In). Yield 30%; colourless oil. 1 H NMR (600 MHz, CDCl3 ) 𝛿 7.71 (s, 1H), 6.83 (s, 2H), 6.11 (t, J = 6.0 Hz, 1H), 4.85 (t, J = 6.6 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.17 (t, J = 6.0 Hz, 2H), 3.99 (d, J = 6.6 Hz, 2H), 2.28–2.25 (m, 2H), 1.34 (t, J = 6.6 Hz, 1H), 0.53–0.52 (m, 2H), 0.41 (d, J = 4.8 Hz, 2H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 157.23, 153.89, 150.64, 145.75, 137.11, 129.67, 124.86, 124.50, 123.54, 115.14, 69.81, 69.61, 65.42, 56.40, 30.94, 10.05, 3.58. HRMS [M + H+ ] calcd 526.9866, found 526.9862. 3-[(5-Chloropyridin-2-yl)oxy]propan-1-ol (5). In a 250 mL roundbottomed flask, butane-1,4-diol (50 mL) and NaH (2.97 g, 124 mmol) were dissolved in 20 mL of distilled THF. The temperature was slowly raised to 100 ∘ C. 2,5-Dichloropyridine (9.3 g, 62.84 mmol) in 30 mL of THF was slowly added to the above mixture. The reaction was monitored by TLC. When the reaction was completed, the mixture was cooled to room temperature. The solvent THF was removed under reduced pressure; the residue was washed with water and saturated brine and finally extracted with CH2 Cl2 . The organic layer was dried over anhydrous Na2 SO4 . The solvent was removed under reduced pressure to obtain the product (8.85 g). Yield 70%; white solid. 1 H NMR (600 MHz, CDCl3 ) 𝛿 8.08 (s, 1H), 7.51 (d, J = 9.6 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.72 (t, J = 6.0 Hz, 2H), 1.87–1.85 (m, 2H), 1.74–1.71 (m, 3H). 3-[(5-Chloropyridin-2-yl)oxy]propyl 4-methylbenzenesulfonate (6). 3-[(5-Chloropyridin-2-yl)oxy]propan-1-ol (5) (26.9 g, 133.83 mmol), Et3 N (40.55 g, 401.49 mmol) and dimethylaminopyridine (1.63 g, 13.36 mmol) were dissolved in 50 mL of distilled CH2 Cl2 . TsCl (30.51 g, 160.60 mmol) in 50 mL of CH2 Cl2 was slowly added to the stirring mixture. The reaction was stirred at room temperature and monitored by TLC. When the reaction was completed, the mixture was washed 3 times with 150 mL of water and once with saturated citric acid (100 mL). The organic layer was dried with anhydrous Na2 SO4 . The solvent was removed under reduced pressure to obtain the product (41.46 g). Yield 87%; white solid. 1 H NMR (600 MHz, CDCl3 ) 𝛿 8.05 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.64 (d, J = 9.0 Hz, 1H), 4.22 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H), 1.82–1.80 (m, 4H).
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2.3 Synthetic procedure for title compound IIa 3-{2,6-Dichloro-4-[(3,3-dichloroallyl)oxy]phenoxy}propan-1-ol (4) (20 g, 69.44 mmol) and K2 CO3 (19.16 g, 138.88 mmol) were dissloved in 50 mL of dimethyl ether (DME). The resulting mixture was heated to reflux, and 3-[(5-chloropyridin-2-yl)oxy]propyl 4-methylbenzenesulfonate (6) (22.4 g, 63.12 mmol) in 50 mL of DME was slowly added. The reaction was monitored by TLC. When the reaction was completed, the mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with water, 15% NaOH (aq.) and saturated brine. The organic layer was dried over anhydrous Na2 SO4 . The solvent was evaporated under reduced pressure, and the residue was purifed by flash column chromatography to give the title compound IIa (20.87 g). Yield 70%; mp 55–56 ∘ C. 1 H NMR (400 MHz, CDCl3 ) 𝛿 8.09 (d, J = 2.4 Hz, 1H), 7.52 (dd, J1 = 2.8 Hz, J2 = 2.8 Hz, 1H), 6.84 (s, 2H), 6.70 (d, J = 8.8 Hz, 1H), 6.11 (t, J = 6.4 Hz, 1H), 4.58 (d, J = 6.4 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 1.96–2.06 (m, 4H). 13 C NMR (100 MHz, CDCl3 ) 𝛿 162.35, 153.86, 145.94, 145.09, 138.42, 129.75, 124.91, 124.54, 123.83, 115.18, 112.04, 73.16, 66.01, 66.45, 26.69, 25.56. HRMS [M + H+ ] calcd 469.9651, found 469.9660. 2.4 X-ray diffraction Colourless crystals of compounds Ic and IIa (0.26 mm × 0.20 mm × 0.10 mm) were mounted on quartz fibre with protective oil. Cell dimensions and intensities were measured at 299 K on a Smart CCD area detector diffractometer (Bruker Corp., Billerica, MA) with graphite monochromated MoK𝛼 radiation (𝜆 = 0.71073 Å); 𝜃 max = 20.30; 3172 measured reflections; 1809 independent reflections (Rint = 0.0275), of which 557 had I > 2𝜎 (I) .22 The structure was solved by direct methods using SHELXS-97; all other calculations were performed with the Bruker SAINT system and Bruker Smart programs. 2.5 Biological assay A bioassay was performed on test plant organisms raised in a greenhouse to determine insecticidal activity against oriental armyworm (Mythimna separata) and Prodenia litura. The bioassay was replicated at 25 ± 1 ∘ C according to statistical requirements. Assessments were made on a dead/alive basis, and mortality rates were corrected applying Abbott’s formula. Evaluation was based on a percentage scale of 0–100, where 0 equals no activity and 100 equals total kill. The error of the experiments was 5%. For comparative purposes, pyridalyl was tested as the control under the same conditions. Insecticidal activity is summarised in Table 1. 2.5.1 LC50 values of Ic and IIa against beet armyworm, bollworm, P. litura and diamondback moths The LC50 values were tested at Nanjing Agriculture University. The bioassay was replicated at 27 ± 1 ∘ C according to statistical requirements. The leaves were then sprayed with the test solution and allowed to dry. The dishes were infested with ten third-instar beet armyworm, P. litura, bollworm and diamondback moths. The percentage mortalities were evaluated 3–5 days after treatment. Each treatment was replicated 4 times. 2.5.2 Field trials against diamondback moths The field trials were carried out in Ningbo, Zhejiang Province, China. Compound IIa (5% EC) and pyridalyl (5% EC) were sprayed
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Table 1. Insecticidal activity of compounds against P. litura Larvicidal activity (%) Compound Ia Ib Ic Id Ie If Ig Ih Ii Ij Ik Il Im In IIa Pyridalyl
R 6-Cl 5-OMe 6,7-diF 6-F 6-Cl 6-CF3 – – H 6-Cl 6-F t-Bu cyclopropyl methyl Me 5-Cl
100 mg L−1 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
20 mg L−1
4 mg L−1
0 60 100 60 45 47 85 0 60 60 40 0 0 0 100 100
0 0 10 0 0 0 40 0 0 0 0 0 0 0 0 0
uniformly on positive and negative plant leaves. The research was conducted according to the pesticide efficacy field trial procedure GB-T 17980.13-2000. The test data for statistical analysis were evaluated using Duncan’s multiple range test.
3
RESULTS AND DISCUSSION
3.1 Chemistry The synthetic routes of the title compounds Ia to In and IIa are shown in Schemes 1 and 2 respectively. As shown in Scheme 1, a five-step route was carried out to synthesise the target molecules Ia to In. Compound 2 was selected as a key intermediate, which can be prepared by condensation of hydroquinone and 1,1,3-trichloroprop-1-ene (1), as described in the literature. Although the compound 1,1,3-trichloroprop-1-ene
www.soci.org (1) can be easily prepared by elimination of the starting material 1,1,1,3-tetrachloropropane, when the mixture of hydroquinone and 1,1,3-trichloroprop-1-ene (1) is refluxed in the presence of K2 CO3 as a base in acetone, as described in the literature, the isolated yield of intermediate 2 is very low, mainly owing to the formation of a large amount of disubstituted byproduct 1,4-bis[(3,3-dichloroallyl)oxy]benzene. Therefore, the reaction conditions were optimised. The yield of intermediate 2 was finally improved to 77% by slowly adding a solution of 1,1,3-trichloroprop-1-ene (1) in acetone to a mixture of 5 equ. hydroquinone and K2 CO3 at 50 ∘ C. Afterwards, compound 3 was prepared by treatment of intermediate 2 with SOCl2 in toluene at 60 ∘ C. It should be noted that the reaction time is critical to this transformation. The reaction mixture should be quenched immediately after the addition of SOCl2 , and prolonging the reaction time would lead to a polychlorinated product. Further transformation of compound 3 to product 4 was achieved by nucleophilic substitution of compound 3 with 3-bromopropan-1-ol, with a yield of 81%. Finally, coupling of intermediate 4 with diverse heterocylic halide or heterocyclic mesylate furnished the corresponding desired pyridalyl analogues. The synthesis of compound IIa by the route shown in Scheme 1 was unsuccessful, and so an alternative route was designed, as shown in Scheme 2. Initially, 2,5-dichloropyridine was selected as the starting material, which performed the nucleophilc substitution reaction with 1,4-butanediol to afford the monoether 5 chemoselectively. The primary hydroxyl group in molecule 5 was then transferred to the tosylate leaving group by treatment with tosyl chloride in the presence of Et3 N in good yield. The resulting product 6 was reacted with intermediate 3 to generate the target product IIa. It is worth noting that it was difficult to consume the dichlorophenol 3 completely during this nucleophilic substitution process even by increasing the amount of tosylate or prolonging the reaction time. The small amount of unreacted intermediate 3 should be removed by washing with aqueous NaOH solution before further flash chromatography, otherwise it will interfere with the purification step owing to its similar polarity to compound IIa.
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Scheme 1. Synthetic route of the title compounds Ia to In. Reagent and conditions: a – FeCl3 , 90 ∘ C; b – hydroquinone, K2 CO3 , Me2 CO, reflux; c – SO2 Cl2 , toluene, 65 ∘ C; d – Br(CH2 )3 OH, K2 CO3 , Me2 CO, reflux; e – NaH, THF, Het-Cl or Het-SO2 CH3 , reflux.
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Scheme 2. Synthetic route of the title compound IIa. Reagent and conditions: a – HO(CH2 )4 OH, NaH, THF, reflux; b – TsCl, Et3 N, CH2 Cl2 , room temperature; c – 3, K2 CO3 , DME, reflux.
larvicidal activity, much higher than the monofluorosubstituted compound Id (60%) and 5-methoxyl-substituted compound Ib (60%), whereas the 6-chlorosubstituted compound Ia lost its insecticidal activity totally at a concentration of 20 mg L−1 . Of the pyrimidine derivatives, 2,6-dimethyl-substituted product Ih had no insecticidal activity at a concentration of 20 mg L−1 . In comparison, when the methyl substituent at position-6 was changed to a trifluoromethyl group, the resulting compound Ig showed 85% mortality, comparable with that of the control pyridalyl. Compound IIa, which is most similar in character to the parent pyridalyl, with a four-carbon linker and a chlorine substitution rather than the three-carbon spacer and trifluoromethyl group in pyridalyl, displayed similar insecticidal activity to the mother structure. Interestingly, although most compounds lost insecticidal activity when the concentration was reduced to 4 mg L−1 , compounds Ig and Ic retained 40% and 10% larvicidal activity respectively. They are superior to the commercial control pyridalyl, which did not show any insecticidal activity at 4 mg L−1 .
Figure 2. The crystal structure of compound Ic.
Figure 3. The crystal structure of compound IIa.
The structures of all intermediates and title compounds were confirmed by 1 H NMR, 13 C NMR and HRMS data. Furthermore, the structures of Ic and IIa were unambiguously determined by X-ray diffraction (Figs 2 and 3 respectively).
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3.2 Insecticidal activity and structure–activity relationships against P. litura The newly prepared compounds Ia to In and IIa were evaluated for insecticidal activity against P. litura. The commercial insecticide pyridalyl was used as a control. The larvicidal activities at different concentrations are presented in Table 1. The results indicate that all of these compounds displayed excellent insecticidal activity at a concentration of 100 mg L−1 . Further assays at a lower concentration of 20 mg L−1 showed that the heterocyclic moiety had a significant effect on their insecticidal activity. The larvicidal activity ranged from 0 to 100%, depending on the heterocycle backbone introduced. In general, conjugated heterocyclic moieties such as benzothiazoles, pyrimidines and pyridine are more favourable from the viewpoint of conserving insecticidal activity than the non-conjugated pyridazinones. In addition, the substituents introduced into the heterocycles also displayed notable effects on insecticidal activity. Taking benzothiazole derivatives as examples, the 6,7-difluorosubstituted compound Ic showed 100%
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3.3 LC50 values of Ic and IIa against beet armyworm, bollworm, P. litura and diamondback moths The preliminary insecticidal assay against P. litura indicated that compounds Ic and IIa showed excellent potency. Therefore, these two compounds were selected for further assay against four insects: beet armyworm, bollworm, P. litura and diamondback moths. As listed in Table 2, compound Ic exhibited better insecticidal activity (LC50 = 4.90 mg L−1 ) against insect bollworm than pyridalyl (LC50 = 5.79 mg L−1 ) and comparable activity against P. litura (LC50 = 24.94 mg L−1 ) with pyridalyl (LC50 = 21.53 mg L−1 ). However, compound Ic showed much lower insecticidal activity against beet armyworm and diamondback moths (LC50 = 13.75 and 10.12 mg L−1 respectively) than pyridalyl (LC50 = 5.77 and 3.10 mg L−1 respectively). On the basis of the LC50 and the 95% confidence interval values, compound IIa was found to be most effective against diamondback moths and bollworm, with LC50 values of 2.87 and 5.65 mg L−1 respectively, as opposed to the standard control pyridalyl which had LC50 values of 3.10 and 5.79 mg L−1 respectively. 3.4 Field trials of IIa against diamondback moths The results listed in Table 2 indicate that compound IIa displayed excellent insecticidal activity against diamondback moths. Therefore, field trials of compound IIa were carried out in Zhejiang Province in 2013 in order to evaluate further its potency against diamondback moths. As shown in Table 3, compound IIa showed very good control effect against diamondback moths in the dosage range 50–400 mg kg−1 . At concentrations of 50 and
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Table 2. LC50 values of compounds Ic and IIa and pyridalyl against beet armyworm, bollworm, diamondback moths and P. litura Compound Ic
IIa
Pyridalyl
Insects Beet armyworm Bollworm Diamondback moths P. litura Beet armyworm Bollworm Diamondback moths P. litura Beet armyworm Bollworm Diamondback moths P. litura
1.4534 + 3.1161x 3.3902 + 2.3323x 1.9546 + 3.0298x 2.1024 + 2.0743x 2.1912 + 2.6387x 3.0453 + 2.600x 3.6745 + 2.8978x 1.3940 + 2.3886x 3.0517 + 2.5597x 3.1156 + 2.4719x 3.5877 + 2.8756x 0.7506 + 3.1877x
Table 3. Field trials of compound IIa against diamondback moths Tested insecticide IIa (5% EC)
Pyridalyl (5% EC)
Dosea (mg kg−1 )
95% confidence interval
13.75 4.90 10.12 24.94 11.60 5.65 2.87 32.34 5.77 5.79 3.10 21.53
11.240–16.373 3.812–5.974 8.582–11.722 18.659–31.773 9.128–14.072 4.644–7.153 2.460–3.446 25.257–40.059 4.525–7.017 4.656–7.037 2.649–3.780 17.454–25.435
for further development as a new insecticide for the control of lepidopteran insects.
Control effect (%) 1 dayb
4 days
8 days
59.8 63.8 75.8 80.8 47.2 50.8 53.0
69.2 80.8 86.4 90.9 65.3 75.9 78.9
67.9 81.3 95.4 99.3 66.6 80.9 88.2
50 100 200 400 50 100 200
14 days 70.2 81.8 94.0 98.6 64.0 73.4 83.8
a The amount sprayed is about 750 kg ha−1 b The number of days between spraying insecticides and investigating
the effects.
100 mg kg−1 , the 8 day control effects of compound IIa are 67.9 and 81.3% respectively, comparable with the control effects of pyridalyl (66.6 and 80.9% respectively). However, compound IIa exhibited a better control effect than pyridalyl at a concentration of 200 mg kg−1 . The 8 day control effect reached 95.4%, while pyridalyl only displayed a control effect of 88.2% at the same concentration. Most interestingly, compound IIa showed control for a much longer time than pyridalyl. The 14 day control efficacy of compound IIa was comparable with its 8 day control potency. By comparison, when the duration was prolonged from 8 to 14 days, the control effect of the standard drug pyridalyl declined at the concentration levels investigated.
4
LC50 (mg L−1 )
y = a + bx
CONCLUSIONS
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The research was supported in part by the National Key Technologies R&D Programme (2011BAE06B05).
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In summary, a series of novel 1,1-dichloropropene derivatives bearing diverse heterocycles have been designed and synthesised. The bioassay showed that compound Ic, a benzothiazole-containing analogue, and compound IIa, a pyridine-containing analogue, exhibited good insecticidal activity. Among the four tested insects, compound Ic showed comparable insecticidal activity with pyridalyl against bollworm and P. litura, while compound IIa exhibited comparable insecticidal activity with pyridalyl against bollworm and diamondback moths. Further field trials indicated that compound IIa produced much better 14 day control effects against diamondback moths and a longer duration of control efficacy than pyridalyl, indicating its potential
ACKNOWLEDGEMENTS
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