近年来, 含氮杂环化合物由于其多样化的结构形式与广谱的生物活性而成为新药创制研究的热点之一[1~4].吡唑酰胺类化合物作为含氮杂环体系中的一个重要分支, 以其独特的生物活性被广泛用于杀虫[5~8]、杀菌[9]及抗癌[10]等方面.目前, 具有多种生物活性的吡唑酰胺类衍生物相继被开发出来(图 1).如日本三菱化学公司开发的吡螨胺(tebufenpyrad)和唑虫酰胺(tolfen- pyrad)具有良好的杀虫杀螨作用[11, 12], Song等[13]基于唑虫酰胺的结构合成出的化合物A表现出较好的杀虫活性, 在测试浓度为55 μg/mL时, 化合物A对棉铃虫的防治效果为100%, 在测试浓度为200 μg/mL时, 化合物A对蚜虫的杀死率为90%, 美国杜邦公司研制开发的溴氰虫酰胺(cyantraniliprole)对鳞翅目、半翅目类害虫如蚜虫、小菜蛾等显示出优异的杀虫效果[14].另外, 吡啶类衍生物亦为含氮杂环化合物中的重要一员, 因其良好的杀虫、杀菌、除草等活性而倍受药物学工作者的关注[15~18].不少吡啶类化合物在农业生产中发挥着重要的作用.如日本住友化学公司开发的含取代吡啶基杀虫剂啶虫丙醚(pyridalyl)对棉花、蔬菜和果树上多种鳞翅目害虫呈现出较高的生物活性与选择性, 尤其对小菜蛾和烟芽蛾等具有显著防治效果[19, 20].美国陶氏益农公司开发的取代吡啶类杀虫剂氟啶虫胺腈(sulfoxaflor)对蚜虫等有突出的防效[21].近几年来, 活性亚结构拼接原理是发现先导药物的一种重要方法与途径, 在新药创制研究中扮演着十分重要的角色[22~26].因此, 为了寻找具有较高生物活性的新型吡唑酰胺类化合物, 本文以唑虫酰胺为先导化合物, 采用活性亚结构拼接的方法, 将吡啶单元引入到吡唑酰胺分子结构中, 设计合成了一系列新型含取代吡啶结构的吡唑酰胺类衍生物(图 2).借助于1H NMR, 13C NMR和元素分析等手段确证了所合成的目标化合物的结构.此外, 对其标题化合物进行了生物活性测试研究.初步的生物活性测试结果显示, 部分目标化合物具有较好的杀虫活性.其合成路线如Scheme 1所示.
我们以目标化合物11i为研究对象, 尝试了不同的反应条件对化合物11i收率的影响.由表 1可以看出, 采用三乙胺作缚酸剂, 四氢呋喃(THF)为溶剂, 室温反应10 h, 是制备目标物的较佳方法, 化合物11i的收率为53%, 该方法不仅操作简便, 而且后续分离比较容易.采用该方法成功地合成了其它的目标化合物.
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| Entry | Base | Solvent | Reaction condition | Yield/% |
| 1 | Et3N | CH3COCH3 | Room temperature, 10 h | 10 |
| 2 | Et3N | CHCl3 | Room temperature, 10 h | 39 |
| 3 | Et3N | THF | Room temperature, 10 h | 53 |
| 4 | Et3N | CH3CN | Room temperature, 10 h | 29 |
| 5 | Et3N | ClCH2CH2Cl | Room temperature, 10 h | 32 |
| 6 | Et3N | THF | Reflux, 10 h | 46 |
| 7 | Pyridine | CHCl3 | Room temperature, 10 h | 27 |
| 8 | Pyridine | CH3CN | Room temperature, 10 h | 38 |
| 9 | Pyridine | THF | Room temperature, 10 h | 40 |
| 10 | Pyridine | CH3CN | Reflux, 10 h | 32 |
| 11 | Pyridine | THF | Reflux, 10 h | 35 |
| 12 | NaOH | CH3COCH3 | Room temperature, 10 h | 18 |
| 13 | NaOH | CHCl3 | Room temperature, 10 h | 33 |
| 14 | NaOH | THF | Room temperature, 10 h | 13 |
| 15 | NaOH | ClCH2CH2Cl | Room temperature, 10 h | 36 |
| 16 | NaOH | ClCH2CH2Cl | Reflux, 10 h | 30 |
以目标化合物11k的核磁氢谱与碳谱数据为例进行解析. δ在8.39处的单峰为吡啶环上两个氢的吸收峰; δ 7.90处的双二重峰为吡啶环上一个氢的吸收峰; δ 7.69处的双二重峰为吡啶环上一个氢的吸收峰; δ6.92~7.27间的多重峰为苯环上三个氢、吡啶环上两个氢和酰胺基上一个氢的吸收峰; δ 5.76处的单峰为与吡啶环相连的亚甲基上两个氢的吸收峰; δ 4.63处的单峰为与苯环相连的亚甲基上两个氢的吸收峰; δ 3.74处的单峰为苯环上甲氧基三个氢的吸收峰; δ 2.67处的四重峰为吡唑环3-位亚甲基两个氢的吸收峰; δ 1.26处的三重峰为吡唑环3-位与亚甲基相连的甲基三个氢的吸收峰; δ在55.9处的峰为苯环上甲氧基碳原子的信号峰; δ在52.6处的峰为与吡啶环相连的亚甲基碳原子的信号峰; δ在43.3处的峰为与苯环相连的亚甲基碳原子的信号峰; δ 19.3处的峰对应于吡唑环3-位亚甲基碳原子的信号峰; δ 12.7处的峰对应于吡唑环3-位与亚甲基相连的甲基碳原子的信号峰.
目标化合物11a~11o对粘虫(Oriental armyworm)、蚜虫(Aphis medicaginis)和朱砂叶螨(Tetranychus cinnabarinus)的杀虫活性测试结果(表 2)表明, 部分目标化合物对粘虫表现出较好的杀虫活性, 个别化合物对蚜虫或朱砂叶螨显示出一定的杀虫活性, 但无明显的规律.当R2为氢时, 化合物11a, 11c, 11d, 11e, 11f和11g对粘虫的杀死率分别为80%, 80%, 80%, 80%, 80%和60%, 当测试剂量为100 μg/mL时, 化合物11e [R1=4-FC6H4, R3=3, 5-(OCH3)2, R4=H)]和11f (R1=4-FC6H4, R3=3-F, R4=H)对粘虫的杀灭活性分别为30%和70%, 要高于化合物11a, 11b, 11c, 11d, 11g和11h的防效; 当R2为2-氯吡啶-5-基时, 化合物11j, 11k, 11l和11m对粘虫的杀死率分别为85%, 90%, 100%和70%, 其中化合物11k (R1=C2H5, R3=3-OCH3, R4=H)和11l (R1=C2H5, R3=3-Cl, R4=H)对粘虫的防效与对照药唑虫酰胺的防效(100%)相近, 当测试剂量为100 μg/mL时, 化合物11k和11l对粘虫的杀灭活性分别为30%和100%, 其中化合物11l对粘虫的防效要高于对照药唑虫酰胺的防效(50%), 当测试剂量为20 μg/mL时, 化合物11l对粘虫仍显示出较好的杀虫效果, 杀死率达50%, 高于对照药唑虫酰胺的防效(40%).总体来看, 化合物11l对粘虫的杀灭效果要高于其它化合物.在测试浓度为500 μg/mL时, 化合物11a对蚜虫的杀死率为100%, 与对照药吡虫啉(100%)接近; 当测试剂量降至100 μg/mL时, 化合物11a对蚜虫仍呈现出一定的杀虫效果, 其杀死率为30%;另外, 化合物11a在测试浓度为500 μg/mL时对朱砂叶螨的杀灭活性为30%.这为今后继续从事吡唑酰胺类衍生物的分子设计合成与生物活性研究提供了重要的实验数据与结构选择模式.
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| Compd. | Oriental armyworm | Aphis medicaginis | Tetranychus cinnabarinus | ||||||
| 500 μg/mL | 100 μg/mL | 20 μg/mL | 4 μg/mL | 500 μg/mL | 100 μg/mL | 500 μg/mL | |||
| 11a | 80 | 0 | — | — | 100 | 30 | 30 | ||
| 11b | 0 | — | — | — | 0 | — | 0 | ||
| 11c | 80 | 0 | — | — | 0 | — | 0 | ||
| 11d | 80 | 0 | — | — | 0 | — | 0 | ||
| 11e | 80 | 30 | — | — | 0 | — | 0 | ||
| 11f | 80 | 70 | 0 | — | 0 | — | 0 | ||
| 11g | 60 | 0 | — | — | 0 | — | 0 | ||
| 11h | 0 | — | — | — | 0 | — | 0 | ||
| 11i | 0 | — | — | — | 0 | — | 0 | ||
| 11j | 85 | 0 | — | — | 0 | — | 0 | ||
| 11k | 90 | 30 | — | — | 0 | — | 0 | ||
| 11l | 100 | 100 | 50 | 0 | 0 | — | 0 | ||
| 11m | 70 | 0 | — | — | 0 | — | 0 | ||
| 11n | 0 | — | — | — | 0 | — | 0 | ||
| 11o | 0 | — | — | — | 0 | — | 0 | ||
| Tolfenpyrad | 100 | 50 | 40 | — | — | — | — | ||
| Imidacloprid | — | — | — | — | 100 | 100 | — | ||
| Fenpyroximate | — | — | — | — | — | — | 100 | ||
| 空白对照 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| a— refers to not tested. | |||||||||
本文采用活性亚结构拼接方法, 顺利地制备了一系列新型含取代吡啶结构的吡唑酰胺类衍生物.初步的生物活性测试结果表明, 部分目标化合物具有较好的杀虫效果.在测试浓度为500 μg/mL时, 化合物11a, 11c, 11d, 11e, 11f, 11g, 11j, 11k, 11l和11m对粘虫的杀死率分别为80%, 80%, 80%, 80%, 80%, 60%, 85%, 90%, 100%和70%;在测试浓度为100 μg/mL时, 化合物11f和11l对粘虫的杀死率分别为70%和100%;当测试浓度降为20 μg/mL时, 化合物11l对粘虫仍表现出较好的杀虫效果, 其杀死率为50%.在测试浓度为500 μg/mL时, 化合物11a对蚜虫的杀死率为100%.此外, 化合物11a在测试浓度为500 μg/mL时对朱砂叶螨的杀死率为30%.
X-4型数字显示熔点测定仪(北京泰克仪器有限公司), 温度计未经校正; Yanaco-CHN CORDER MT-3自动元素分析仪; Bruker AM-400型核磁共振仪, 以CDCl3为溶剂, TMS为内标; 柱层析硅胶为H型(青岛海洋化工厂, 200~300目).所用试剂均为分析纯.
中间体5参照文献[27, 28]方法制备, 中间体8参照文献[29]方法制备.
在一反应瓶中, 加入15.7 mmol中间体8、20.4 mmol邻苯二甲酰亚胺钾盐及0 mL无水DMF, 室温搅拌6~8 h.停止反应, 向反应液中加入适量水, 抽滤, 所得固体可直接用于下一步反应.为了验证中间体9的结构, 选取其中取代基R3为3, 5-(OCH3)2、R4为3-Cl的化合物为代表, 经乙醇重结晶得到纯品, 收率65%. m.p. 132~133 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.19 (s, 1H, pyridine-H), 7.93 (s, 1H, pyridine-H), 7.86~7.88 (m, 2H, ArH), 7.72~7.74 (m, 2H, ArH), 6.81 (s, 2H, ArH), 4.82 (s, 2H, CH2), 3.77 (s, 6H, 2×OCH3). Anal. calcd for C23H16ClF3N2O5: C 56.05, H 3.27, N 5.68; found C 56.21, H 3.13, N 5.83.
在一反应瓶中, 加入8.1 mmol中间体9及100 mL无水乙醇, 室温搅拌下, 向其中加入16.1 mmol水合肼(质量分数80%), 加热回流反应4~6 h.将反应液冷却至室温, 抽滤, 除去不溶物, 母液减压蒸除溶剂, 得到关键中间体10, 不经纯化可直接用于后面的反应.
目标化合物11参考相关文献[30]制得.在一反应瓶中, 加入3 mmol中间体10、3 mmol三乙胺及15 mL无水THF, 冰浴冷却, 在氮气保护下向其中慢慢滴加3 mmol 1-甲基-3-取代基-4-氯吡唑-5-甲酰氯(5)的无水THF溶液(10 mL).滴毕, 继续室温搅拌8~18 h.停止反应, 减压蒸除溶剂, 向残余物中加入80 mL乙酸乙酯, 用饱和食盐水洗涤数次, 无水硫酸镁干燥, 抽滤, 滤液脱溶, 所得残余物用乙醇重结晶或经柱层析[V(石油醚):V(乙酸乙酯)=4:1]分离得到目标化合物11a~11o.
1-甲基-3-甲基-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11a):灰白色固体, 收率53%. m.p. 123~124 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1H, pyridine-H), 7.89 (dd, J=8.8, 2.4 Hz, 1H, pyridine-H), 7.14 (d, J=8.0 Hz, 1H, ArH), 6.99~7.08 (m, 4H, ArH, NH and pyridine-H), 4.67 (d, J=5.6 Hz, 2H, CH2), 4.15 (s, 3H, NCH3), 3.76 (s, 3H, OCH3), 2.25 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 165.6, 158.5, 151.8, 145.4, 144.6, 141.2, 136.6, 136.2, 130.9, 122.4 (q, J=174 Hz), 120.0, 112.1, 110.8, 108.4, 55.9, 43.3, 40.7, 11.1. Anal. calcd for C20H18ClF3N4O3: C 52.81, H 3.99, N 12.32; found C 52.70, H 4.09, N 12.40.
1-甲基-3-甲基-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3, 5-二甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11b):白色固体, 收率51%. m.p. 117~118 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.38 (s, 1H, pyridine-H), 7.89 (dd, J=8.8, 2.4 Hz, 1H, pyridine-H), 7.07~7.12 (m, 2H, NH and pyridine-H), 6.68 (s, 2H, ArH), 4.67 (d, J=5.6 Hz, 2H, CH2), 4.16 (s, 3H, NCH3), 3.78 (s, 6H, 2×OCH3), 2.26 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 165.3, 158.5, 152.9, 145.3, 144.6, 136.5, 135.8, 131.0, 129.9, 124.1 (q, J=216 Hz), 121.4, 110.7, 108.4, 104.4, 56.3, 43.7, 40.6, 11.1. Anal. calcd for C21H20ClF3N4O4: C 52.02, H 4.16, N 11.56; found C 52.15, H 4.28, N 11.45.
1-甲基-3-甲基-4-氯-N-[4-(3-氯-5-三氟甲基吡啶-2-基氧基)-3-甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11c):白色固体, 收率55%. m.p. 143~144 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.23 (s, 1H, pyridine-H), 7.97 (d, J=2.0 Hz, 1H, pyridine-H), 7.16 (d, J=7.6 Hz, 1H, ArH), 6.99~7.06 (m, 3H, NH and ArH), 4.68 (d, J=6.0 Hz, 2H, CH2), 4.16 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 2.25 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 161.0, 158.5, 151.6, 144.6, 142.6, 141.0, 136.5, 130.9, 123.2 (q, J=217 Hz), 120.0, 118.7, 112.1, 108.4, 56.0, 43.3, 40.7, 11.1. Anal. calcd for C20H17Cl2F3N4O3: C 49.10, H 3.50, N 11.45; found C 49.21, H 3.62, N 11.32.
1-甲基-3-乙基-4-氯-N-[4-(3-氯-5-三氟甲基吡啶-2-基氧基)-3, 5-二甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11d):白色固体, 收率50%. m.p. 181~182 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.22 (s, 1H, pyridine-H), 7.95 (d, J=2.0 Hz, 1H, pyridine-H), 7.04 (s, 1H, NH), 6.67 (s, 2H, ArH), 4.66 (d, J=5.6 Hz, 2H, CH2), 4.16 (s, 3H, NCH3), 3.78 (s, 6H, 2×OCH3), 2.65 (q, J=7.6 Hz, 2H, CH2), 1.25 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 160.7, 158.6, 152.7, 149.7, 142.7, 136.1, 131.0, 129.7, 123.2 (q, J=233 Hz), 118.7, 107.7, 104.4, 56.3, 43.7, 40.6, 19.2, 12.8. Anal. calcd for C22H21Cl2F3N4O4: C 49.54, H 3.97, N 10.51; found C 49.43, H 4.09, N 10.38.
1-甲基-3-(4-氟苯基)-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3, 5-二甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11e):白色固体, 收率52%. m.p. 129~130 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.38 (s, 1H, pyridine-H), 7.89 (dd, J=8.4, 2.0 Hz, 1H, pyridine-H), 7.77~7.83 (m, 2H, ArH), 7.10~7.17 (m, 3H, ArH and pyridine-H), 6.70 (s, 2H, ArH), 4.71 (d, J=5.6 Hz, 2H, CH2), 4.25 (s, 3H, NCH3), 3.79 (s, 6H, 2×OCH3); 13C NMR (100 MHz, CDCl3) δ: 165.2, 162.9 (d, J=247 Hz), 158.4, 152.9, 145.5, 136.5, 135.6, 132.3, 129.8, 129.5, 129.4, 128.8, 126.9, 123.8 (q, J=270 Hz), 115.6 (d, J=22 Hz), 110.7, 106.8, 104.3, 56.3, 43.8, 41.1. Anal. calcd for C26H21ClF4N4O4: C 55.28, H 3.75, N 9.92; found C 55.39, H 3.62, N 9.80.
1-甲基-3-(4-氟苯基)-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-氟苯甲基]-1H-吡唑-5-甲酰胺(11f):白色固体, 收率48%. m.p. 135~136 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1H, pyridine-H), 7.94 (dd, J=8.8, 2.4 Hz, 1H, pyridine-H), 7.77~7.82 (m, 2H, ArH), 7.11~7.26 (m, 7H, ArH, NH and pyridine-H), 4.71 (d, J=5.6 Hz, 2H, CH2), 4.25 (s, 3H, NCH3); 13C NMR (100 MHz, CDCl3) δ: 164.7, 162.9 (d, J=247 Hz), 158.5, 155.9, 153.4, 145.5, 139.6, 136.9, 132.0, 129.5, 128.8, 123.6 (q, J=272 Hz), 116.2, 115.6 (d, J=22 Hz), 111.1, 106.9, 42.7, 41.3. Anal. calcd for C24H16ClF5N4O2: C 55.13, H 3.08, N 10.72; found C 55.05, H 3.19, N 10.83.
1-甲基-3-(4-氯苯基)-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-氟苯甲基]-1H-吡唑-5-甲酰胺(11g):白色固体, 收率48%. m.p. 164~165 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1H, pyridine-H), 7.93 (dd, J=8.8, 2.4 Hz, 1H, pyridine-H), 7.78 (d, J=8.8 Hz, 2H, ArH), 7.42 (d, J=8.8 Hz, 2H, ArH), 7.17~7.26 (m, 4H, ArH and NH), 7.12 (d, J=8.4 Hz, 1H, pyridine-H), 4.71 (d, J=6.0 Hz, 2H, CH2), 4.25 (s, 3H, NCH3); 13C NMR (100 MHz, CDCl3) δ: 164.7, 158.4, 155.9, 153.4, 145.2, 139.6, 139.5, 136.9, 136.7, 134.6, 132.1, 129.3, 128.8, 124.9, 123.7 (q, J=197 Hz), 116.1 (d, J=19 Hz), 111.1, 107.0, 42.7, 41.3. Anal. calcd for C24H16Cl2F4N4O2: C 53.45, H 2.99, N 10.39; found C 53.58, H 2.87, N 10.28.
1-甲基-3-(4-氯苯基)-4-氯-N-[4-(3-氯-5-三氟甲基吡啶-2-基氧基)-3-甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11h):白色固体, 收率49%. m.p. 165~166 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.23 (s, 1H, pyridine-H), 7.97 (d, J=2.0 Hz, 1H, pyridine-H), 7.78 (d, J=8.4 Hz, 2H, ArH), 7.42 (d, J=8.4 Hz, 2H, ArH), 7.12~7.18 (m, 2H, ArH and NH), 7.03 (d, J=8.8 Hz, 2H, ArH), 4.72 (d, J=5.6 Hz, 2H, CH2), 4.25 (s, 3H, NCH3), 3.76 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ: 161.0, 158.3, 151.6, 145.2, 142.6, 141.1, 136.4, 136.2, 134.6, 132.4, 129.3, 128.8, 123.4 (q, J=178 Hz), 121.6, 120.1, 118.8, 115.7, 112.2, 107.0, 56.0, 43.4, 41.2. Anal. calcd for C25H18Cl3F3N4O3: C 51.26, H 3.10, N 9.56; found C 51.15, H 3.20, N 9.63.
1-(2-氯吡啶-5-基)-3-甲基-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-苯甲基]-1H-吡唑-5-甲酰胺(11i):白色固体, 收率53%. m.p. 138~139 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.44 (s, 1H, pyridine-H), 8.39 (d, J=2.0 Hz, 1H, pyridine-H), 7.92 (dd, J=8.4, 2.4 Hz, 1H, pyridine- H), 7.64 (dd, J=8.4, 2.4 Hz, 1H, pyridine-H), 7.35 (d, J=8.8 Hz, 2H, ArH), 7.03~7.27 (m, 5H, ArH, NH and pyridine-H), 5.74 (s, 2H, CH2), 4.64 (d, J=5.6 Hz, 2H, CH2), 2.26 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 165.6, 158.1, 152.6, 150.9, 149.5, 145.9, 145.4, 138.8, 136.8, 134.4, 131.6, 130.5, 129.0, 123.0 (q, J=224 Hz), 111.5, 109.6, 52.6, 42.9, 11.2. Anal. calcd for C24H18Cl2- F3N5O2: C 53.75, H 3.38, N 13.06; found C 53.88, H 3.26, N 13.21.
1-(2-氯吡啶-5-基)-3-甲基-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11j):白色固体, 收率51%. m.p. 158~159 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 2H, pyridine-H), 7.90 (dd, J=8.8, 2.4 Hz, 1H, pyridine-H), 7.67 (dd, J=8.0, 2.4 Hz, 1H, pyridine-H), 6.93~7.27 (m, 6H, ArH, NH and pyridine- H), 5.75 (s, 2H, CH2), 4.64 (d, J=6.0 Hz, 2H, CH2), 3.74 (s, 3H, OCH3), 2.27 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 165.5, 158.1, 151.8, 150.9, 149.4, 146.0, 145.3, 141.2, 138.8, 136.6, 135.9, 131.7, 130.5, 123.3 (q, J=185 Hz), 121.5, 120.0, 112.0, 110.9, 109.6, 55.9, 52.6, 43.4, 11.2. Anal. calcd for C25H20Cl2F3N5O3: C 53.02, H 3.56, N 12.37; found C 53.16, H 3.43, N 12.52.
1-(2-氯吡啶-5-基)-3-乙基-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11k):白色固体, 收率59%. m.p. 139~140 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 2H, pyridine-H), 7.90 (dd, J=8.4, 2.4 Hz, 1H, pyridine-H), 7.69 (dd, J=8.0, 2.4 Hz, 1H, pyridine-H), 6.92~7.27 (m, 6H, ArH, NH and pyridine- H), 5.76 (s, 2H, CH2), 4.63 (d, J=6.0 Hz, 2H, CH2), 3.74 (s, 3H, OCH3), 2.67 (q, J=7.6 Hz, 2H, CH2), 1.26 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 165.5, 158.2, 151.8, 150.9, 149.3, 145.3, 141.2, 138.9, 136.6, 135.9, 131.8, 130.5, 123.3 (q, J=182 Hz), 121.5, 120.0, 112.0, 110.8, 108.8, 55.9, 52.6, 43.3, 19.3, 12.7. Anal. calcd for C26H22Cl2F3N5O3: C 53.81, H 3.82, N 12.07; found C 53.65, H 3.97, N 12.23.
1-(2-氯吡啶-5-基)-3-乙基-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-氯苯甲基]-1H-吡唑-5-甲酰胺(11l):白色固体, 收率55%. m.p. 150~152 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.38 (d, J=2.0 Hz, 1H, pyridine-H), 8.27 (s, 1H, pyridine-H), 7.98 (d, J=2.0 Hz, 1H, pyridine-H), 7.65 (dd, J=8.0, 2.0 Hz, 1H, pyridine-H), 7.37 (d, J=8.8 Hz, 2H, ArH), 7.06~7.27 (m, 4H, ArH, NH and pyridine-H), 5.75 (s, 2H, CH2), 4.64 (d, J=5.6 Hz, 2H, CH2), 2.67 (q, J=7.6 Hz, 2H, CH2), 1.25 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 161.1, 158.2, 152.2, 150.9, 149.4, 142.6, 138.8, 136.4, 134.9, 131.7, 130.5, 129.0, 123.1 (q, J=211 Hz), 121.5, 119.4, 108.9, 52.6, 42.9, 19.3, 12.7. Anal. calcd for C25H19Cl3F3N5O2: C 51.34, H 3.27, N 11.98; found C 51.18, H 3.39, N 11.84.
1-(2-氯吡啶-5-基)-3-(4-氟苯基)-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-甲氧基苯甲基]-1H-吡唑-5-甲酰胺(11m):白色固体, 收率52%. m.p. 151~152 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.47 (s, 1H, pyridine-H), 8.39 (s, 1H, pyridine-H), 7.71~7.91 (m, 4H, ArH and pyridine- H), 6.94~7.45 (m, 7H, ArH and pyridine-H), 5.84 (s, 2H, CH2), 4.67 (d, J=6.0 Hz, 2H, CH2), 3.75 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ: 165.5, 163.0 (d, J=248 Hz), 157.9, 151.8, 151.2, 149.7, 146.6, 146.3, 145.3, 141.2, 138.9, 136.6, 134.9, 131.7, 131.2, 129.6, 128.9, 123.3 (q, J=186 Hz), 121.5, 120.0, 115.6 (d, J=22 Hz), 112.0, 110.9, 108.0, 55.9, 53.0, 43.5. Anal. calcd for C30H21Cl2F4- N5O3: C 55.74, H 3.27, N 10.83; found C 55.89, H 3.13, N 10.70.
1-(2-氯吡啶-5-基)-3-(4-氟苯基)-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-氯苯甲基]-1H-吡唑-5-甲酰胺(11n):白色固体, 收率49%. m.p. 200~202 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.4 Hz, 1H, pyridine-H), 8.27 (s, 1H, pyridine-H), 7.99 (d, J=2.0 Hz, 1H, pyridine- H), 7.77~7.83 (m, 2H, ArH), 7.71 (dd, J=8.4, 2.4 Hz, 1H, pyridine-H), 7.11~7.44 (m, 8H, ArH, NH and pyridine-H), 5.84 (s, 2H, CH2), 4.68 (d, J=5.6 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ: 162.9 (d, J=247 Hz), 161.1, 158.4, 152.2, 145.5, 142.6, 136.5, 136.4, 135.0, 132.2, 129.5, 129.4, 129.1, 127.0, 123.3 (q, J=173 Hz), 121.5, 119.4, 115.6 (d, J=21 Hz), 106.8, 43.0, 41.2. Anal. calcd for C29H18Cl3F4N5O2: C 53.52, H 2.79, N 10.76; found C 53.65, H 2.68, N 10.91.
1-(2-氯吡啶-5-基)-3-(4-氯苯基)-4-氯-N-[4-(5-三氟甲基吡啶-2-基氧基)-3-氯苯甲基]-1H-吡唑-5-甲酰胺(11o):白色固体, 收率57%. m.p. 205~207 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.4 Hz, 1H, pyridine-H), 8.27 (s, 1H, pyridine-H), 7.99 (d, J=2.0 Hz, 1H, pyridine- H), 7.78 (d, J=8.8 Hz, 2H, ArH), 7.71 (dd, J=8.4, 2.4 Hz, 1H, pyridine-H), 7.10~7.44 (m, 8H, ArH, NH and pyri- dine-H), 5.84 (s, 2H, CH2), 4.68 (d, J=5.6 Hz, 2H, CH2); 13C NMR (100 MHz, CDCl3) δ: 161.1, 158.0, 152.3, 151.2, 149.7, 146.3, 142.6, 139.0, 136.5, 134.9, 134.7, 132.0, 131.2, 129.5, 129.0, 128.9, 128.8, 123.2 (q, J=215 Hz), 121.5, 119.4, 115.8, 115.6, 53.1, 43.1. Anal. calcd for C29H18Cl4F3N5O2: C 52.20, H 2.72, N 10.50; found C 52.03, H 2.87, N 10.65.
对于化合物, 用分析天平称取一定质量的原药, 用含吐温-80乳化剂的N, N-二甲基甲酰胺(DMF)溶解配制成1.0%母液, 然后用蒸馏水稀释备用.每个处理3次重复, 设空白对照(蒸馏水).杀虫活性测试所选昆虫分别为粘虫(Oriental armyworm)、蚜虫(Aphis medicaginis)和朱砂叶螨(Tetranychus cinnabarinus).对照药剂分别为唑虫酰胺(Tolfenpyrad)、吡虫啉(Imidacloprid)和唑螨酯(Fenpyroximate).
蚜虫和螨虫:采用喷雾法.首先, 分别将接有蚜虫、朱砂叶螨的蚕豆叶片和接有褐飞虱的水稻苗于Potter喷雾塔下喷雾处理, 处理后蚜虫置于20~22 ℃观察室内培养, 朱砂叶螨置于24~27 ℃观察室内培养, 2 d后观察结果, 检查死活虫数, 并进行统计分析.
粘虫:采用浸叶碟法.首先, 将适量玉米叶在配好的药液中充分浸润后自然阴干, 放入垫有滤纸的培养皿中, 接粘虫3龄中期幼虫10头/皿, 置于24~27 ℃观察室内培养, 调查药后2 d的死活虫数, 并进行统计分析.
辅助材料(Supporting Information) 化合物11a~11o的1H NMR和13C NMR图谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.
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Liu, C. L.; Wang, L. Z.; Lan, J.; Sun, X. F.; Sun, Q.; Zhang, J. B. CN 103081916, 2013 [Chem. Abstr. 2013, 158, 724382].
图 1 吡螨胺、唑虫酰胺、化合物A、溴氰虫酰胺、啶虫丙醚和氟啶虫胺腈的化学结构
Figure 1 Chemical structures of tebufenpyrad, tolfenpyrad, compound A, cyantraniliprole, pyridalyl and sulfoxaflor
表 1 不同反应条件对目标化合物11i合成收率的影响
Table 1. Effects of reaction conditions on the synthesis of the target compound 11i
| Entry | Base | Solvent | Reaction condition | Yield/% |
| 1 | Et3N | CH3COCH3 | Room temperature, 10 h | 10 |
| 2 | Et3N | CHCl3 | Room temperature, 10 h | 39 |
| 3 | Et3N | THF | Room temperature, 10 h | 53 |
| 4 | Et3N | CH3CN | Room temperature, 10 h | 29 |
| 5 | Et3N | ClCH2CH2Cl | Room temperature, 10 h | 32 |
| 6 | Et3N | THF | Reflux, 10 h | 46 |
| 7 | Pyridine | CHCl3 | Room temperature, 10 h | 27 |
| 8 | Pyridine | CH3CN | Room temperature, 10 h | 38 |
| 9 | Pyridine | THF | Room temperature, 10 h | 40 |
| 10 | Pyridine | CH3CN | Reflux, 10 h | 32 |
| 11 | Pyridine | THF | Reflux, 10 h | 35 |
| 12 | NaOH | CH3COCH3 | Room temperature, 10 h | 18 |
| 13 | NaOH | CHCl3 | Room temperature, 10 h | 33 |
| 14 | NaOH | THF | Room temperature, 10 h | 13 |
| 15 | NaOH | ClCH2CH2Cl | Room temperature, 10 h | 36 |
| 16 | NaOH | ClCH2CH2Cl | Reflux, 10 h | 30 |
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表 2 目标化合物11a~11o的杀虫活性(死亡率/%)a
Table 2. Insecticidal activities (mortality/%) of title compounds 11a~11o
| Compd. | Oriental armyworm | Aphis medicaginis | Tetranychus cinnabarinus | ||||||
| 500 μg/mL | 100 μg/mL | 20 μg/mL | 4 μg/mL | 500 μg/mL | 100 μg/mL | 500 μg/mL | |||
| 11a | 80 | 0 | — | — | 100 | 30 | 30 | ||
| 11b | 0 | — | — | — | 0 | — | 0 | ||
| 11c | 80 | 0 | — | — | 0 | — | 0 | ||
| 11d | 80 | 0 | — | — | 0 | — | 0 | ||
| 11e | 80 | 30 | — | — | 0 | — | 0 | ||
| 11f | 80 | 70 | 0 | — | 0 | — | 0 | ||
| 11g | 60 | 0 | — | — | 0 | — | 0 | ||
| 11h | 0 | — | — | — | 0 | — | 0 | ||
| 11i | 0 | — | — | — | 0 | — | 0 | ||
| 11j | 85 | 0 | — | — | 0 | — | 0 | ||
| 11k | 90 | 30 | — | — | 0 | — | 0 | ||
| 11l | 100 | 100 | 50 | 0 | 0 | — | 0 | ||
| 11m | 70 | 0 | — | — | 0 | — | 0 | ||
| 11n | 0 | — | — | — | 0 | — | 0 | ||
| 11o | 0 | — | — | — | 0 | — | 0 | ||
| Tolfenpyrad | 100 | 50 | 40 | — | — | — | — | ||
| Imidacloprid | — | — | — | — | 100 | 100 | — | ||
| Fenpyroximate | — | — | — | — | — | — | 100 | ||
| 空白对照 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| a— refers to not tested. | |||||||||
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