1-(4-氯苯基)-2-環(huán)丙基酮肟醚的設(shè)計、 合成及殺蟲活性

李康明,陳 佳,易陽杰,閆忠忠,葉 姣,龍楚云,柳愛平,胡艾希,李建明

(1.湖南大學(xué)化學(xué)化工學(xué)院,長沙 410082;2.湖南化工研究院有限公司,國家農(nóng)藥創(chuàng)制工程技術(shù)研究中心,長沙 410007)

在新農(nóng)藥創(chuàng)制中,肟醚類化合物因具有高效、 低毒及低殘留等優(yōu)點而常被用作有效活性基團.該類化合物具有廣泛的生物活性[1],如殺蟲[2]、 殺菌[3]和除草[4]等.目前,已上市的肟醚類衍生物有肟醚菊酯[5]、 唑螨酯[6]、 氟環(huán)脲[7]和肟菌酯[8]等.Liu等[9,10]報道了聯(lián)苯類肟醚化合物和苯氧基芐基肟醚類化合物,部分化合物對黏蟲具有較好的抑制活性,LC50<10 mg/L.Hu等[11]報道了β-甲氧基丙烯酸酯類肟醚化合物,部分化合物在100 mg/L濃度下對蚜蟲的致死率為100%,活性優(yōu)異的化合物對蚜蟲的LC50值低至4.4 mg/L.王勝得等[12]報道了含硫甲基的4-氯苯乙酮肟醚化合物,其在500 mg/L濃度下對蚜蟲的致死率為100%.許艷等[13]合成了4-氯苯乙酮肟醚類衍生物,在500 mg/L濃度下對蚜蟲的抑制作用為100%.Philip等[14]報道了由擬除蟲菊酯類殺蟲劑改造獲得的4-氯芳烷基酮肟芐基醚類化合物,其中活性優(yōu)異的化合物的LC50值最大為13.0 mg/L.Liu等[15]設(shè)計合成了含肟酯結(jié)構(gòu)的鄰氨基苯甲酰胺類化合物,在200 mg/L濃度下該化合物表現(xiàn)出了一定的殺蟲活性.

本文采用中間體衍生化方法,以環(huán)唑醇中間體1-(4-氯苯基)-2-環(huán)丙基丙酮作為基本骨架,引入肟醚活性片段,合成了14個1-(4-氯苯基)-2-環(huán)丙基酮肟芐基醚化合物(1a～1n),再應(yīng)用生物電子等排原理,將苯環(huán)替換為含氮雜環(huán)得到化合物2a～2r.共制得32個1-(4-氯苯基)-2-環(huán)丙基酮肟醚類化合物,測試了其殺蟲活性,并解析了化合物2n的單晶結(jié)構(gòu).化合物的結(jié)構(gòu)經(jīng)核磁共振波譜(NMR)及質(zhì)譜(ESI-MS)確認(rèn),設(shè)計思路及合成路線如Scheme 1所示.

1a: R=H; 1b: R=2-CH3; 1c: R=2-F; 1d: R=2-Cl; 1e: R=2-Br; 1f: R=2-NO2; 1g: R=2-CN; 1h: R=3-NO2; 1i: R=3-OC6H5; 1j: R=4-CH3; 1k: R=4-Cl; 1l: R=4-CF3; 1m: R=2,4-Cl2; 1n: R=2,5-F2

2b: R=3,5-(CH3)2; 2c: R=3,5-(CH3)2-4-OCH3; 2e: R=H; 2f: R=4-F; 2g: R=4-Cl; 2h: R=4-CF3; 2i: R=4-CH3; 2j: R=2-CF3; 2k: R=2-CH3; 2l: R=H; 2m: R=4-F; 2n: R=4-Cl; 2o: R=4-CF3; 2p: R=4-CH3; 2q: R=2-CF3; 2r: R=2-CH3 Scheme 1 Design strategy and synthetic routes for target compounds

1 實驗部分

1.1 試劑與儀器

苯甲酸、 4-氟苯甲酸、 4-氯苯甲酸、 五硫化二磷、 4-三氟甲基苯甲酸、 4-甲基苯甲酸、 2-三氟甲基苯甲酸、 2-甲基苯甲酸和1-(4-氯苯基)-2-環(huán)丙基丙酮均為分析純,購自湖南化工研究院有限公司; 1,3-二氯丙酮、 二氯亞砜、 氫氧化鈉、 氨水、 四丁基溴化銨(TBAB)、 甲苯(PhMe)、 碘化鉀和鹽酸羥胺均為分析純,購自上海泰坦科技股份有限公司.

INOVA 400 MB型核磁共振波譜儀(美國Varian公司,TMS為內(nèi)標(biāo),1H NMR 頻率為400 MHz,13C NMR頻率為100 MHz); RY-1型熔點測定儀(天津市天分儀器廠); ZF-2型三用紫外顯色儀(上海安亭電子儀器廠); MAT 95XP型高分辨質(zhì)譜儀(美國Thermo公司); APEX-II型CCD衍射儀(瑞士Bruker公司).

1.2 合成方法

1.2.1 中間體5e～5k和5l～5r的合成 參照文獻[26]方法合成中間體5e～5k和5l～5r,收率分別為36.4%～56.1%和50.2%～84.9%.

1.2.2 目標(biāo)化合物1a～1n和2a～2r的合成 將(E)-1-(4-氯苯基)-2-環(huán)丙基丙酮肟[(E)-3,0.224 g,1.0 mmol]、 芐氯(4a,0.152 g,1.2 mmol)、 NaOH溶液(4.000 g,20.0 mmol,質(zhì)量分?jǐn)?shù)20%)、 四丁基溴化銨(TBAB,0.025 g,0.078 mmol)、 碘化鉀(0.033 g,0.2 mmol)和8 mL甲苯混合,于60 ℃反應(yīng)4 h,旋轉(zhuǎn)蒸發(fā)回收甲苯,用二氯甲烷萃取,再用飽和氯化鈉溶液洗滌,脫除溶劑,經(jīng)柱層析分離得黃色液體(1a),收率73.3%.

采用相同方法合成目標(biāo)化合物1b～1n和2a～2r,收率為38.6%～80.4%.目標(biāo)化合物的理化性質(zhì)列于表1,核磁共振波譜數(shù)據(jù)分別見表2和表3.

Table 1 Appearance,melting points,yields and HRMS data of compounds 1a—1n and 2a—2r

Table 2 1H NMR data of compounds 1a—1n

Continued

Compd.1H NMR(400 MHz, CDCl3), δ1c7.44—6.98(m, 8H, C6H4, C6H4), 5.22(s, 1.33H, OCH2), 5.11(s, 0.67H, OCH2), 1.88—1.77(m, 1H, CH), 1.26(d, J=6.8Hz, 2H, CH3), 1.15(d, J=7.2Hz, 1H, CH3), 0.96—0.07(m, 5H, Cyclo-C3H5)1d7.47—7.14(m, 8H, C6H4, C6H4), 5.27(s, 2H, OCH2), 2.69—2.61(m, 1H, CH), 1.30(d, J=7.2Hz, 3H, CH3), 0.96—0.17(m, 5H, Cyclo-C3H5)1e7.56—7.10(m, 8H, C6H4, C6H4), 5.24(s, 1.4H, OCH2), 5.12(s, 0.6H, OCH2), 1.85—1.78(m, 1H, CH), 1.31(d, J=7.2Hz, 2.1H, CH3), 1.16(d, J=6.8Hz, 0.9H, CH3), 0.97—0.12(m, 5H, Cyclo-C3H5)1f8.08—7.21(m, 8H, C6H4, C6H4), 5.57(s, 1.33H, OCH2), 5.44(s, 0.67H, OCH2), 1.78—1.73(m, 1H, CH), 1.34(d, J=7.2Hz, 2H, CH3), 1.27(d, J=6.8Hz, 1H, CH3), 1.10—0.15(m, 5H, Cyclo-C3H5)1g7.67—7.15(m, 8H, C6H4, C6H4), 5.34(s, 2H, OCH2), 2.69—2.62(m, 1H, CH), 1.29(d, J=7.2 Hz, 3H, CH3), 0.97—0.11(m, 5H, Cyclo-C3H5)1h8.24—7.17(m, 8H, C6H4, C6H4), 5.25(s, 2H, OCH2), 2.68—2.61(m, 1H, CH), 1.30(d, J=7.2Hz, 3H, CH3), 0.94—0.17(m, 5H, Cyclo-C3H5)1i7.36—6.87(m, 13H, C6H5, C6H4, C6H4), 5.10, 5.00(2×s, 2H, OCH2), 1.83—1.75(m, 1H, CH), 1.22, 1.12(2×d, J1=7.1 Hz, J2=7.0 Hz, 3H, CH3), 0.89—0.07(m, 5H, Cyclo-C3H5)1j7.40—7.10(m, 8H, C6H4, C6H4), 5.12(s, 1.36H, OCH2), 5.00(s, 0.64H, OCH2), 2.35(s, 2H, CH3), 2.33(s, 1H, CH3), 1.87—1.79(m, 1H, CH), 1.26(d, J=7.2Hz, 2H, CH3), 1.15(d, J=6.8Hz, 1H, CH3), 0.92—0.13(m, 5H, Cyclo-C3H5)1k7.37—7.11(m, 8H, C6H4, C6H4), 5.11, 4.98(2×s, 2H, OCH2), 2.68—1.74(m, 1H, CH), 1.26, 1.14(2×d, J1=7.0 Hz, J2=7.0 Hz, 3H, CH3), 0.89—0.03(m, 5H, Cyclo-C3H5)1l7.60—7.16(m, 8H, C6H4, C6H4), 5.21(s, 1.35H, OCH2), 5.07(s, 0.65H, OCH2), 1.83—1.78(m, 1H, CH), 1.30(d, J=7.2Hz, 2H, CH3), 1.16(d, J=7.2Hz, 1H, CH3), 0.96—0.07(m, 5H, Cyclo-C3H5)1m7.38—7.15(m, 7H, C6H4, C6H3), 5.10, 4.47(2×s, 2H, OCH2), 1.87—1.79(m, 1H, CH), 1.16(d, J=7.0 Hz, 3H, CH3), 0.72—0.08(m, 5H, Cyclo-C3H5)1n6.92—7.87(m, 7H, C6H4, C6H3), 5.20(s, 1.35H, OCH2), 5.08(s, 0.65H, OCH2), 1.83—1.81(m, 1H, CH), 1.29(d, J=7.2Hz, 2H, CH3), 1.16(d, J=6.8Hz, 1H, CH3), 0.95—0.09(m, 5H, Cyclo-C3H5)

Table 3 1H NMR and 13C NMR data of compounds 2a—2r

Continued

Compd.1H NMR(400 MHz, CDCl3), δ13C NMR(100 MHz, CDCl3), δ2f7.95—7.10(m, 4H, C6H4), 7.42(d, J=8.4 Hz, 2H, ClC6H4 3,5-H), 7.32(d, J=8.4 Hz, 2H, ClC6H4 2,6-H), 7.20(s, 1H, Thi-azole-H), 5.33(s, 2H, OCH2), 2.71—2.64(m, 1H, CH), 1.31(d, J=7.2 Hz, 3H, CH3), 0.97—0.19(m, 5H, Cyclo-C3H5)166.96, 165.10, 163.47, 162.61, 154.81, 134.67, 134.47, 130.00, 129.28, 128.52, 128.44, 128.34, 116.11, 115.89, 71.93, 39.32, 17.33, 14.82, 5.29, 4.352g7.88(d, J=8.0 Hz, 2H, C6H4), 7.42—7.39(m, 4H, C6H4, C6H4), 7.32(d, J=8.4 Hz, 2H, C6H4), 7.22(s, 1H, Thiazole-H), 5.34(s, 2H, OCH2), 2.71—2.63(m, 1H, CH), 1.31(d, J=7.2 Hz, 3H, CH3), 0.95—0.19(m, 5H, Cyclo-C3H5)166.79, 163.50, 155.00, 135.97, 134.68, 134.46, 132.14, 129.28, 129.16, 128.35, 127.76, 116.20, 71.90, 39.33, 17.33, 14.83, 5.31, 4.352h8.07(d, 2H, J=8.4 Hz, C6H4 3,5-H), 7.69(d, 2H, J=8.0 Hz, C6H4 2,6-H), 7.42(d, J=8.0 Hz, 2H, ClC6H4 3,5-H), 7.33(d, J=8.4 Hz, 2H, ClC6H4 2,6-H), 7.29(s, 1H, Thiazole-H), 5.36(s, 2H, OCH2), 2.71—2.64(m, 1H, CH), 1.31(d, J=7.2 Hz, 3H, CH3), 0.96—0.19(m, 5H, Cyclo-C3H5)166.22, 163.59, 155.42, 136.70, 134.72, 134.42, 131.62, 129.27, 128.36, 126.76, 125.97, 125.93, 125.26, 122.56, 117.00, 71.85, 39.35, 17.32, 14.82, 5.31, 4.352i7.85(d, J=7.6 Hz, 2H, C6H4), 7.43(d, J=8.4 Hz, 2H, ClC6H4 3,5-H), 7.33(d, J=8.4 Hz, 2H, ClC6H4 2,6-H), 7.24(d, J=7.6 Hz, 2H, C6H4), 7.17(s, 1H, Thiazole-H), 5.35(s, 2H, OCH2), 2.72—2.64(m, 1H, CH), 2.40(s, 3H, CH3), 1.31(d, J=7.2 Hz, 3H, CH3), 0.97—0.20(m, 5H, Cyclo-C3H5)168.39, 163.39, 154.56, 140.26, 134.63, 134.54, 131.02, 129.61, 129.30, 128.33, 126.51, 115.45, 72.04, 39.32, 21.43, 17.34, 14.84, 5.30, 4.362j7.81—7.56(m, 4H, C6H4), 7.42(d, J=8.0 Hz, 2H, ClC6H4 3,5-H), 7.37(s, 1H, Thiazole-H), 7.33(d, J=8.0 Hz, 2H, ClC6H4 2,6-H), 5.37(s, 2H, OCH2), 2.71—2.63(m, 1H, CH), 1.30(d, J=7.2 Hz, 3H, CH3), 0.96—0.19(m, 5H, Cyclo-C3H5)164.22, 163.50, 154.13, 134.64, 134.54, 132.34, 131.61, 129.67, 129.29, 128.34, 126.67, 118.08, 71.83, 39.39, 17.28, 14.79, 5.25, 4.312k7.72—7.70(m, 1H, C6H4), 7.44(d, J=8.4 Hz, 2H, ClC6H4 3,5-H), 7.35—7.29(m, 5H, ClC6H4 2,6-H, C6H4), 7.27(s, 1H, Thiazole-H), 5.38(s, 2H, OCH2), 2.72—2.64(m, 1H, CH), 2.58(s, 3H, CH3), 1.32(d, J=7.2 Hz, 3H, CH3), 0.98— 0.20(m, 5H, Cyclo-C3H5)167.72, 163.32, 153.98, 136.55, 134.65, 134.57, 133.02, 131.40, 129.96, 129.42, 129.29, 128.36, 126.05, 116.54, 72.11, 39.41, 21.35, 17.34, 14.84, 5.31, 4.392l7.68(s, 1H, Oxazole-H), 8.05—7.45(m, 5H, C6H5), 7.42(d, J=8.4 Hz, 2H, C6H4 3,5-H), 7.33(d, J=8.4 Hz, 2H, C6H4 2,6-H), 5.17(s, 2H, OCH2), 2.69—2.62(m, 1H, CH), 1.28(d, J=6.8 Hz, 3H, CH3), 0.92—0.19(m, 5H, Cyclo-C3H5)163.54, 161.79, 139.07, 136.47, 134.64, 134.49, 130.41, 129.30, 128.77, 128.33, 127.45, 126.42, 68.17, 39.18, 17.32, 14.83, 5.27, 4.312m8.05—7.12(m, 4H, C6H4), 7.66(s, 1H, Oxazole-H), 7.41(d, J=8.4 Hz, 2H, ClC6H4 3,5-H), 7.32(d, J=8.4 Hz, 2H, ClC6H4 2,6-H), 5.15(s, 2H, OCH2), 2.68—2.61(m, 1H, CH), 1.27(d, J=7.2 Hz, 3H, CH3), 0.91—0.18(m, 5H, Cyclo-C3H5)165.34, 163.59, 162.84, 160.98, 139.09, 136.50, 134.66, 134.44, 129.29, 128.58, 128.50, 128.33, 123.81, 116.08, 115.86, 68.08, 39.16, 17.31, 14.82, 5.26, 4.302n7.97(d, J=8.4 Hz, 2H, C6H4), 7.67(s, 1H, Oxazole-H), 7.44—7.40(m, 4H, C6H4, C6H4), 7.32(d, J=8.0 Hz, 2H, C6H4), 5.15(s, 2H, OCH2), 2.68—2.60(m, 1H, CH), 1.27(d,J=7.2 Hz, 3H, CH3), 0.91—0.17(m, 5H, Cyclo-C3H5)163.61, 160.86, 139.28, 136.67, 136.53, 134.68, 134.43, 129.28, 129.10, 128.33, 127.68, 125.93, 68.06, 39.17, 17.31, 14.82, 5.27, 4.312o8.16—7.72(m, 4H, C6H4), 7.70(s, 1H, Oxazole-H), 7.41(d, J=8.0 Hz, 2H, ClC6H4 3,5-H), 7.32(d, J=8.4 Hz, 2H, ClC6H4 2,6-H), 5.17(s, 2H, OCH2), 2.69—2.61(m, 1H, CH), 1.28(d, J=7.2 Hz, 3H, CH3), 0.92—0.18(m, 5H, Cyclo-C3H5)163.67, 160.36, 139.66, 137.22, 134.71, 134.41, 131.98, 130.55, 129.27, 128.34, 126.63, 125.81, 125.78, 125.19, 122.49, 68.00, 39.21, 17.28, 14.81, 5.27, 4.30

Continued

Compd.1H NMR(400 MHz, CDCl3), δ13C NMR(100 MHz, CDCl3), δ2p7.94—7.27(m, 4H, C6H4), 7.65(s, 1H, Oxazole-H), 7.41(d, J=8.0 Hz, 2H, ClC6H4 3,5-H), 7.33(d, J=8.0 Hz, 2H, ClC6H4 2,6-H), 5.15(s, 2H, OCH2), 2.69—2.61(m, 1H, CH), 2.40(s, 3H, CH3), 1.27(d, J=7.2 Hz, 3H, CH3), 0.91—0.18(m, 5H, Cyclo-C3H5)163.53, 162.02, 140.71, 138.87, 136.15, 134.62, 134.50, 129.48, 129.30, 128.32, 126.39, 124.76, 68.20, 39.16, 21.52, 17.31, 14.82, 5.25, 4.292q8.02—7.57(m, 4H, C6H4), 7.77(s, 1H, Oxazole-H), 7.41(d, J=8.4 Hz, 2H, ClC6H4 3,5-H), 7.33(d, J=8.0 Hz, 2H, ClC6H4 2,6-H), 5.19(s, 2H, OCH2), 2.68—2.60(m, 1H, CH), 1.28(d, J=6.8 Hz, 3H, CH3), 0.92—0.18(m, 5H, Cyclo-C3H5)163.70, 159.75, 139.19, 137.71, 134.67, 134.46, 131.83, 131.62, 130.31, 129.29, 128.34, 126.85, 68.07, 39.28, 17.27, 14.79, 5.25, 4.272r7.99—7.28(m, 3H, C6H4), 7.70(s, 1H, Oxazole-H), 7.42(d, J=8.4 Hz, 2H, ClC6H4 3,5-H), 7.34—7.32(m, 3H, ClC6H4 2,6-H, C6H4), 5.19(s, 2H, OCH2), 2.69(s, 3H, CH3), 2.67—2.61(m, 1H, CH), 1.29(d, J=7.2 Hz, 3H, CH3), 0.94—0.19(m, 5H, Cyclo-C3H5)163.45, 162.22, 138.76, 137.48, 136.02, 134.64, 134.54, 131.56, 129.99, 129.28, 128.95, 128.34, 126.56, 125.93, 68.31, 39.28, 21.87, 17.30, 14.82, 5.27, 4.33

1.3 目標(biāo)化合物1a～1n和2a～2r的殺蟲活性測定

委托湖南化工研究院國家農(nóng)藥創(chuàng)制工程技術(shù)研究中心測定了目標(biāo)化合物對黏蟲、 蠶豆蚜及棉紅蜘蛛的抑制效果.參考文獻[27]方法,依次對3種靶標(biāo)進行殺蟲活性測試,并分別以氯蟲苯甲酰胺、 吡蟲啉和螺蟲乙酯作為陽性對照.

1.4 化合物2n的晶體結(jié)構(gòu)解析

將(E)-1-(4-氯苯基)-2-環(huán)丙基丙酮肟2-(4-氯苯基)-4-唑甲基醚(2n)溶于無水乙醇中,培養(yǎng)得到無色晶體.選取大小為0.12 mm×0.11 mm×0.1 mm的晶體進行X射線單晶衍射分析,采用λ=0.071073 nm的射線,在273.15 K下以ω-φ掃描方式收集數(shù)據(jù),利用SHELXS-97和SHELXL-97程序[28～30]進行結(jié)構(gòu)解析.

2 結(jié)果與討論

2.1 目標(biāo)化合物的合成

采用NaOH/TBAB/KI/PhMe體系來合成目標(biāo)化合物,并以化合物2k為底物,采用單因素優(yōu)化法[31]考察了反應(yīng)溫度、 1-(4-氯苯基)-2-環(huán)丙基丙酮肟和4-氯甲基-2-(2-甲基苯基)噻唑投料比以及堿用量對醚化反應(yīng)的影響.實驗結(jié)果表明,當(dāng)反應(yīng)溫度為60 ℃,1-(4-氯苯基)-2-環(huán)丙基丙酮肟與4-氯甲基-2-(2-甲基苯基)噻唑摩爾比為1∶1.2,1-(4-氯苯基)-2-環(huán)丙基丙酮肟與氫氧化鈉摩爾比為1∶20時,目標(biāo)化合物的收率最高.

2.2 目標(biāo)化合物的NMR表征

由1H NMR數(shù)據(jù)可知,目標(biāo)產(chǎn)物中環(huán)丙基上的5個氫主要集中在δ0～1.2之間的高場區(qū),呈多重峰形態(tài).另外,由于環(huán)丙基為三元環(huán),環(huán)上的氫存在平伏鍵和直立鍵,使得環(huán)丙基上氫的裂分比較復(fù)雜.由13C NMR數(shù)據(jù)可知,化合物符合出峰規(guī)律,烷基碳化學(xué)位移在δ0～80之間,芳香碳化學(xué)位移在δ110～170之間.對于苯基噻唑肟醚(2e～2k),特征片段OCH2的烷氧基碳化學(xué)位移約δ72; 對于苯基唑肟醚(2l～2r),特征片段OCH2的烷氧基碳化學(xué)位移約δ68.

2.3 殺蟲活性及其構(gòu)效關(guān)系

采用農(nóng)藥生物活性篩選技術(shù)測試了目標(biāo)化合物的殺蟲活性.結(jié)果表明,絕大部分化合物在500 mg/L濃度下對黏蟲表現(xiàn)出弱活性甚至無活性,只有化合物1i和2m對黏蟲的致死率為100%,與陽性對照氯蟲苯甲酰胺活性相當(dāng).而大部分化合物對蚜蟲表現(xiàn)出了較好的殺蟲活性,其中,化合物1m,2c,2d和2k對蚜蟲的致死率均大于70%,化合物1i對蚜蟲的致死率達到了99.03%,與陽性對照吡蟲啉相當(dāng); 化合物1e,1h和1j對紅蜘蛛的致死率均大于70%,與陽性對照螺蟲乙酯活性相當(dāng); 化合物1a,1d和1g對紅蜘蛛的致死率分別為91.94%,100%和100%,均優(yōu)于陽性對照螺蟲乙酯.化合物對黏蟲、 蠶豆蚜及棉紅蜘蛛的殺蟲活性數(shù)據(jù)見表4.

Table 4 Insecticidal activity of compounds 1a—1n and 2a—2r*

*Ms:mythimnasepatara;Af:aphisfabae;Tu:tetranychusurticae.

Fig.1 Crystal structure(A) and cell stacking diagram(B) of compound 2n

2.4 化合物2n的晶體結(jié)構(gòu)解析

3 結(jié) 論