含取代噁唑结构的新型吡唑肟衍生物的合成与生物活性

朱玥 郑丹丹 倪亚丹 李金峰 周环宇 胡兰萍 李玲 鞠剑峰 陈家正 李宏 石玉军 戴红

引用本文: 朱玥, 郑丹丹, 倪亚丹, 李金峰, 周环宇, 胡兰萍, 李玲, 鞠剑峰, 陈家正, 李宏, 石玉军, 戴红. 含取代噁唑结构的新型吡唑肟衍生物的合成与生物活性[J]. 有机化学, 2020, 40(3): 774-781. doi: 10.6023/cjoc201910013 shu
Citation:  Zhu Yue, Zheng Dandan, Ni Yadan, Li Jinfeng, Zhou Huanyu, Hu Lanping, Li Ling, Ju Jianfeng, Chen Jiazheng, Li Hong, Shi Yujun, Dai Hong. Synthesis and Biological Activities of Novel Pyrazole Oxime Derivatives Bearing an Oxazole Moiety[J]. Chinese Journal of Organic Chemistry, 2020, 40(3): 774-781. doi: 10.6023/cjoc201910013 shu

含取代噁唑结构的新型吡唑肟衍生物的合成与生物活性

    通讯作者: 胡兰萍, hlp@ntu.edu.cn; 鞠剑峰, ju.jf@ntu.edu.cn; 戴红, daihong_2015@aliyun.com
  • 基金项目:

    国家自然科学基金(Nos.21372135,21802075)、江苏省自然科学基金(No.BK20160413)、南通市科技计划(Nos.MS12017022-4,JC2018118,MS12019060)资助项目

摘要: 为了发现具有良好生物活性的吡唑肟化合物,以唑螨酯为先导化合物,在吡唑肟中引入取代噁唑结构,设计并制备了20个未见文献报道的新型吡唑肟衍生物,利用1H NMR,13C NMR和元素分析确证了目标产物的结构.生物活性测试结果显示,部分目标化合物在500和100 μg/mL浓度下对粘虫或蚜虫表现出优良的杀虫活性,其中5-(3-氟苯氧基)-1,3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9j)、5-(4-氟苯氧基)-1,3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9k)、5-(4-叔丁基苯氧基)-1,3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9r)和5-(4-甲氧基苯氧基)-1,3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9s)在浓度为100 μg/mL时对粘虫的防治效果均达100%,5-(4-溴苯氧基)-1,3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9g)和9s在浓度为100 μg/mL时对蚜虫的杀灭活性均为100%.此外,化合物9s在500 μg/mL时对朱砂叶螨的防治效果为70%.

English

  • 噁唑是含有一个氮原子、一个氧原子的五元芳香杂环.噁唑结构在农业生产和医疗保健领域多用于杀菌[1]、杀虫[2]、除草[3]、抗癌[4]、抗炎[5]等活性化合物的研发.如Xu等开发的化合物A在浓度为50 mg/L时对粘虫的杀灭效果达100%[6], Li课题组等开发的化合物B在200 mg/L浓度下对粘虫具有中等水平的杀虫效果[7], Ye课题组通过研究发现化合物C在20 mg/kg浓度下对玉米根部鲜重恢复活性达91.87%[8](图 1).吡唑环也是一类重要的五元芳香杂环, 在新药创制研究中, 许多含吡唑结构单元的药物分子构成了杀虫剂、杀菌剂、除草剂和抗肿瘤药[9~11].目前已商品化的杀虫剂有吡螨胺(Tebufenpyrad)和氯虫苯甲酰胺(Chlorantraniliprole)等(图 1)[12].吡唑肟作为吡唑类化合物中的重要一员, 在农药与医药领域发挥着举足轻重的作用, 被广泛应用于杀菌、杀虫及抗肿瘤等分支[13~15], 其中典型性代表为杀螨剂唑螨酯(Fenpyroximate, 图 1), 该化合物一直被用来防治多种植食性螨[16, 17].近年来, 一些科研工作者在唑螨酯结构基础上衍生制备出不少具有新颖结构的吡唑肟衍生物, 如Fu等研发的化合物D在浓度为100 mg/L时对蚜虫和螨虫的杀灭活性分别为90%和100%[18]; He课题组研究发现化合物E在浓度为200 μg/mL时对小菜蛾、蚜虫和螨虫均有100%的防效[19]; Shi等合成的化合物F在浓度为500 μg/mL时对粘虫的杀灭活性为100%, 同时化合物F对人肝癌细胞HepG2还表现出较好的抗肿瘤活性, 其IC50值为2.6 μmol/L(图 1)[20].因此, 本课题组基于商品化的杀螨剂唑螨酯的结构, 将取代的噁唑单元通过亚甲基桥引入吡唑肟化合物中, 设计制备了一系列新颖的吡唑肟类衍生物(图 2), 同时筛选目标化合物对粘虫、蚜虫和螨虫的杀虫活性, 为新型农用杀虫剂的研究与开发提供重要参考.目标化合物的合成路线见Scheme 1.

    图 1

    图 1.  吡螨胺、氯虫苯甲酰胺、唑螨酯和化合物A~F的化学结构
    Figure 1.  Chemical structures of tebufenpyrad, chlorantraniliprole, fenpyroximate, and compounds A~F

    图 2

    图 2.  目标化合物9的设计
    Figure 2.  Design of the target compounds 9

    图式 1

    图式 1.  目标化合物9的合成路线
    Scheme 1.  Synthetic route of target compounds 9

    在合成目标化合物9时, 以9e为例, 尝试了不同的溶剂如丙酮、乙腈和N, N-二甲基甲酰胺(DMF), 不同的缚酸剂如碳酸氢钠、碳酸钠、碳酸钾、碳酸铯和氢氧化钠对化合物9e收率的影响(如表 1所示).在试验过程中发现当选用碳酸铯为缚酸剂, 乙腈为溶剂, 加热回流反应12 h, 化合物9e的收率相对较高(76%).所以, 最终选用该方法顺利合成出目标化合物9.

    表 1

    表 1  不同反应条件对目标化合物9e收率的影响
    Table 1.  Effect of various reaction conditions on the yield of target compound 9e
    下载: 导出CSV
    Entry Base Solvent Reaction condition Yield/%
    1 NaHCO3 CH3COCH3 Reflux for 12 h 0
    2 Na2CO3 CH3COCH3 Reflux for 12 h 0
    3 K2CO3 CH3COCH3 Reflux for 12 h 20
    4 Cs2CO3 CH3COCH3 Reflux for 12 h 33
    5 NaOH CH3 COCH3 Reflux for 12 h 0
    6 Na2CO3 CH3CN Reflux for 12 h 43
    7 K2CO3 CH3CN Reflux for 12 h 65
    8 Cs2CO3 CH3CN Reflux for 12 h 76
    9 NaOH CH3CN Reflux for 12 h 0
    10 Na2CO3 DMF 90 ℃ for 12 h 41
    11 K2CO3 DMF 90 ℃ for 12 h 49
    12 Cs2CO3 DMF 90 ℃ for 12 h 58
    13 NaOH DMF 90 ℃ for 12 h 0

    以化合物9g为例, 对其核磁共振氢谱及碳谱数据进行分析.从9g的核磁共振氢谱数据可看出, 与吡唑环相连的CH=N氢的化学位移在δ 7.85, 与噁唑环相连的苯环上四个氢分别在δ 7.59~7.62和7.09~7.14以多重峰出现, 4-溴取代的苯环上四个氢分别在δ 7.37和6.75以双重峰出现, 噁唑环4-位上氢在δ 7.24以单峰出现, 与噁唑环相连的亚甲基两个氢在δ 5.08以单峰出现, 吡唑环上的1-位甲基三个氢在δ 3.58以单峰出现, 吡唑环上的3-位甲基三个氢在δ 2.34以单峰出现; 从9g的核磁共振碳谱数据可知, 与噁唑环相连的亚甲基碳原子的δ值为67.58, 吡唑环上的1-位甲基碳原子的δ值为34.24, 吡唑环上的3-位甲基碳原子的δ值为14.59.

    通过浸叶法[21]对粘虫(Oriental armyworm)进行了生物活性评价, 另外通过喷雾法[22]对蚜虫(Aphis medicaginis)和朱砂叶螨(Tetranychus cinnabarinus)进行了生物活性测定, 化合物9a~9t的杀虫活性数据列于表 2中.从表 2可看出, 该系列化合物在500 μg/mL浓度下对粘虫均有不错的杀虫作用.化合物9a~9t对粘虫具有90%~100%的杀死率, 与对照药唑虫酰胺的杀虫效果相近.从构效关系分析可得出, 当R1=4-Cl时, R2为3-F (9j)、4-F (9k)、4-Br (9o)、4-t-C4H9 (9r)、4-OCH3 (9s)的化合物在浓度降到100 μg/mL时, 对粘虫还表现出杀虫作用, 其杀灭效果分别为100%, 100%, 40%, 100%和100%, 其中9j9k9r9s对粘虫的杀虫活性明显高于对照药唑虫酰胺的防效, 9j9k9s在20μg/mL浓度下对粘虫仍表现出30%, 40%和70%的杀灭效果.部分目标产物在500 μg/mL浓度下对蚜虫呈现出优异的防治效果, 当R1=4-F时, R2为4-F (9b)、3-Cl (9d)、4-Cl (9e)和4-Br (9g)的化合物对蚜虫的防效均达100%, 与对照药剂吡虫啉接近, 当R1=4-Cl时, R2为4-OCH3 (9s)的化合物对蚜虫的杀死率为100%, 与对照药剂吡虫啉相当; 当浓度为100 μg/mL时, 部分化合物对蚜虫还表现出杀虫活性, 当R1=4-F时, R2为4-Cl (9e)和4-Br (9g)的化合物对蚜虫的杀死率分别为20%和100%, 其中化合物9g与对照药剂吡虫啉相近, 当R1=4-Cl时, R2为4-OCH3 (9s)的化合物对蚜虫的防效为100%, 与对照药剂吡虫啉相当; 化合物9g (R1=4-F, R2=4-Br)和9s (R1=4-Cl, R2=4-OCH3)在浓度为20 μg/mL时对蚜虫仍表现出20%和40%的杀虫作用, 要高于其它目标化合物的杀虫效果.另外, 化合物9s (R1=4-Cl, R2=4-OCH3)在浓度为500 μg/mL时对朱砂叶螨具有70%的杀灭效果, 明显优于其它化合物的杀虫作用.通过构效关系分析也能看出, 目标化合物9s (R1=4-Cl, R2=4-OCH3)的杀虫谱相对较广, 对所测试的三种虫都展现出了优良的杀虫作用, 可选为先导化合物作衍生合成与生物活性研究.

    表 2

    表 2  目标化合物9a~9t的杀虫活性(死亡率/%)a
    Table 2.  Insecticidal activities of the target compounds 9a~9t (mortality/%)
    下载: 导出CSV
    Compd. Oriental armyworm Aphis medicaginis Tetranychus cinnabarinus
    500 μg/mL 100 μg/mL 20 μg/mL 500 μg/mL 100 μg/mL 20 μg/mL 500 μg/mL 100 μg/mL
    9a 100 0 0 0
    9b 100 0 100 0 0
    9c 100 0 0 0
    9d 90 0 100 0 0
    9e 100 0 100 20 0 0
    9f 100 0 0 0
    9g 100 0 100 100 20 0
    9h 90 0 0 0
    9i 100 0 0 0
    9j 100 100 30 0 0
    9k 100 100 40 0 0
    9l 100 0 0 0
    9m 100 0 0 0
    9n 100 0 0 0
    9o 100 40 0 0 0
    9p 100 0 0 0
    9q 100 0 0 0
    9r 100 100 0 0 0
    9s 100 100 70 100 100 40 70 0
    9t 100 0 0 0
    Tolfenpyrad 100 50 40
    Imidacloprid 100 100 100
    Fenpyroximate 100 100
    a — refers to “not tested”.

    本研究以唑螨酯为先导结构, 设计合成了20个含取代噁唑结构的新型吡唑肟化合物.生物活性数据显示, 所有化合物在500 μg/mL浓度下对粘虫呈现出90%以上的杀死率, 9j9k9r9s在100 μg/mL浓度下对粘虫具有100%杀灭效果, 9s在20 μg/mL浓度下对粘虫仍表现出70%的杀虫作用; 化合物9b9d9e9g9s在500 μg/mL时对蚜虫的杀灭效果都达100%, 9g9s在100 μg/mL下对蚜虫的杀死率仍为100%;另外, 9s在500 μg/mL时对朱砂叶螨表现出70%的杀虫作用.这为今后继续从事吡唑肟类杀虫剂的研究提供了重要的试验数据.

    通过Bruker AM-400型核磁共振波谱仪(TMS为内标)测定其化合物的核磁共振氢谱与核磁共振碳谱数据; 通过X-4型数字显示显微熔点测定仪(温度计未经校正)测试了化合物的熔点; 由Yanaco-CHN CORDER MT-3自动元素分析仪测试其化合物的元素分析; 实验用200~300目硅胶购于青岛海洋化工厂.本研究中所用试剂都为分析纯.

    化合物1~3的合成参照文献[23].化合物6~8的合成参照文献[24]和[25].

    将中间体3 (0.05 mol)、50 mL二氯甲烷加入100 mL圆底烧瓶中, 搅拌下加入三乙胺(0.15 mol).冰浴条件下向其中滴加氯乙酰氯(0.07 mol), 滴加完后, 冰浴条件继续搅拌2 h, 然后室温搅拌8~10 h, 薄层色谱(TLC)检测反应进程, 完全结束后, 将混合物倒入水中, 有机相通过盐洗、干燥后处理, 浓缩溶剂后得到粗品, 通过乙醇重结晶后得化合物4a4b.

    2-氯-N-[2-(4-氟苯基)-2-氧代乙基]乙酰胺(4a):白色固体, 产率58%. m.p. 115~117 ℃; 1H NMR (400 MHz, CDCl3) δ:4.14 (s, 2H), 4.77 (d, J=4.40 Hz, 2H), 7.18~7.22 (m, 2H), 7.63 (s, 1H), 8.01~8.05 (m, 2H); 13C NMR (CDCl3, 101 MHz) δ:42.47, 46.37, 116.21, 116.43, 130.67, 130.76, 165.15, 166.27, 167.70, 191.68. Anal. calcd for C10H9ClFNO2: C 52.30, H 3.95, N 6.10; found C 52.13, H 3.80, N 6.26.

    2-氯-N-[2-(4-氯苯基)-2-氧代乙基]乙酰胺(4b):白色固体, 产率65%. m.p. 124~126 ℃; 1H NMR (CDCl3, 400 MHz) δ:4.14 (s, 2H), 4.77 (d, J=4.42 Hz, 2H), 7.50 (d, J=8.80 Hz, 2H), 7.62 (s, 1H), 7.93 (d, J=8.40 Hz, 2H); 13C NMR (CDCl3, 101 MHz) δ:42.46, 46.45, 129.34, 129.43, 132.46, 140.97, 166.28, 192.11. Anal. calcd for C10H9Cl2NO2: C 48.81, H 3.69, N 5.69; found C 48.92, H 3.53, N 5.84.

    将中间体4 (20 mmol)、30 mL乙腈加入100 mL圆底烧瓶中, 冰浴条件下向其中滴加三氯氧磷(40 mmol), 滴加结束后, 升温回流反应8~10 h, TLC检测反应进程, 完全结束后, 将混合物倒入水中, 用二氯甲烷萃取, 有机相通过盐洗、干燥后处理, 浓缩溶剂, 粗品经过硅胶快速柱层析(以石油醚/乙酸乙酯为洗脱剂, V:V=8:1)分离形成化合物5a5b.

    2-氯甲基-5-(4-氟苯基)噁唑(5a):黄色油状物, 产率52%. 1H NMR (400 MHz, CDCl3) δ:4.68 (s, 2H), 7.11~7.16 (m, 2H), 7.27 (s, 1H), 7.62~7.66 (m, 2H); 13C NMR (101 MHz, DMSO-d6)δ: 36.68, 116.67, 116.89, 123.54, 124.13, 126.98, 151.47, 159.10, 161.45, 163.91. Anal. calcd for C10H7ClFNO: C 56.76, H 3.33, N 6.62; found C 56.60, H 3.48, N 6.50.

    2-氯甲基-5-(4-氯苯基)噁唑(5b):黄色油状物, 产率56%. 1H NMR (CDCl3, 400 MHz) δ:4.67 (s, 2H), 7.31 (s, 1H), 7.41 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.80 Hz, 2H); 13C NMR (CDCl3, 101 MHz) δ:35.95, 122.80, 125.67, 125.86, 129.27, 134.79, 151.83, 158.63. Anal. calcd for C10H7Cl2- NO: C 52.66, H 3.09, N 6.14; found C 52.83, H 3.23, N 6.01.

    将吡唑甲酰基肟8 (2 mmol)、化合物5 (2.5 mmol)及25 mL乙腈加入一50 mL圆底烧瓶中, 室温搅拌下, 向其中加入4 mmol碳酸铯.加完后升温至回流, 反应10~20 h, TLC跟踪反应的进程.反应完成后, 趁热过滤, 母液浓缩至干, 所得粗品通过硅胶快速柱层析[石油醚/乙酸乙酯(V:V=4:1)为洗脱剂]分离得到目标产物9a~9t.

    5-(3-氟苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9a):黄色固体, 产率62%. m.p. 63~65 ℃; 1H NMR (400 MHz, CDCl3) δ:2.28 (s, 3H), 3.52 (s, 3H), 5.02 (s, 2H), 6.53~6.72 (m, 3H), 7.02~7.06 (m, 2H), 7.12~7.17 (m, 2H), 7.51~7.55 (m, 2H), 7.79 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.69, 34.26, 67.61, 99.93, 103.45, 110.88, 115.94, 116.16, 121.80, 124.18, 126.18, 126.26, 130.92, 141.61, 147.24, 151.23, 157.65, 160.02, 161.50, 162.25, 163.97, 164.71. Anal. calcd for C22H18F2N4O3: C 62.26, H 4.28, N 13.20; found C 62.13, H 4.43, N 13.37.

    5-(4-氟苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9b):黄色固体, 产率65%. m.p. 73~75 ℃; 1H NMR (400 MHz, CDCl3) δ:2.34 (s, 3H), 3.60 (s, 3H), 5.09 (s, 2H), 6.82~6.85 (m, 2H), 6.94~6.98 (m, 2H), 7.09~7.13 (m, 2H), 7.24 (s, 1H), 7.58~7.62 (m, 2H), 7.84 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.65, 34.21, 67.57, 99.60, 115.94, 116.16, 116.62, 121.75, 124.14, 126.18, 141.68, 147.19, 148.05, 151.20, 152.53, 157.56, 160.04, 161.49, 163.97. Anal. calcd for C22H18F2N4O3: C 62.26, H 4.28, N 13.20; found C 62.43, H 4.15, N 13.06.

    5-(2-氯苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9c):黄色油状物, 产率63%. 1H NMR (400 MHz, CDCl3) δ:2.35 (s, 3H), 3.64 (s, 3H), 5.08 (s, 2H), 6.67~6.92 (m, 1H), 7.00~7.13 (m, 4H), 7.24 (s, 1H), 7.41~7.43 (m, 1H), 7.59~7.62 (m, 2H), 7.82 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.65, 34.24, 67.58, 99.69, 115.94, 116.16, 121.74, 122.82, 124.14, 124.72, 126.18, 126.26, 128.01, 130.97, 141.46, 147.18, 147.59, 151.20, 152.04, 160.01, 161.48. Anal. calcd for C22H18ClFN4O3: C 59.94, H 4.12, N 12.71; found C 59.78, H 4.25, N 12.54.

    5-(3-氯苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9d):黄色油状物, 产率69%. 1H NMR (400 MHz, CDCl3) δ:2.38 (s, 3H), 3.63 (s, 3H), 5.10 (s, 2H), 6.75~6.78 (m, 1H), 6.90 (s, 1H), 7.04~7.23 (m, 4H), 7.25 (s, 1H), 7.59~7.62 (m, 2H), 7.85 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.60, 34.28, 67.62, 99.98, 113.56, 115.94, 116.16, 121.77, 124.09, 126.18, 126.26, 130.78, 135.48, 141.48, 147.21, 151.22, 157.04, 159.97, 161.50, 163.97. Anal. calcd for C22H18Cl- FN4O3: C 59.94, H 4.12, N 12.71; found C 60.12, H 4.01, N 12.86.

    5-(4-氯苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9e):黄色固体, 产率76%. m.p. 91~93 ℃; 1H NMR (400 MHz, CDCl3) δ:2.34 (s, 3H), 3.59 (s, 3H), 5.09 (s, 2H), 6.81 (d, J=9.22 Hz, 2H), 7.09~7.13 (m, 2H), 7.21~7.24 (m, 3H), 7.59~7.62 (m, 2H), 7.85 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.60, 34.24, 67.59, 99.81, 115.96, 116.18, 116.64, 121.76, 124.16, 126.19, 128.84, 129.92, 141.60, 147.25, 147.52, 151.20, 155.12, 160.03, 161.50, 163.98. Anal. calcd for C22H18ClFN4O3: C 59.94, H 4.12, N 12.71; found C 59.80, H 4.03, N 12.80.

    5-(3-溴苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9f):黄色油状物, 产率70%. 1H NMR (400 MHz, CDCl3) δ:2.35 (s, 3H), 3.59 (s, 3H), 5.09 (s, 2H), 6.79~7.20 (m, 6H), 7.25 (s, 1H), 7.59~7.62 (m, 2H), 7.86 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.62, 34.27, 67.59, 99.92, 114.00, 115.93, 116.15, 118.80, 121.77, 123.18, 124.15, 126.18, 126.26, 126.95, 131.04, 141.54, 147.27, 151.20, 157.08, 160.00, 161.48, 163.95. Anal. calcd for C22H18BrFN4O3: C 54.45, H 3.74, N 11.54; found C 54.28, H 3.90, N 11.65.

    5-(4-溴苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9g):黄色固体, 产率73%. m.p. 89~91 ℃; 1H NMR (400 MHz, CDCl3) δ:2.34 (s, 3H), 3.58 (s, 3H), 5.08 (s, 2H), 6.75 (d, J=9.20 Hz, 2H), 7.09~7.14 (m, 2H), 7.24 (s, 1H), 7.37 (d, J=8.82 Hz, 2H), 7.59~7.62 (m, 2H), 7.85 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.59, 34.24, 67.58, 99.81, 115.94, 116.16, 117.06, 121.78, 124.15, 126.17, 126.26, 132.85, 141.57, 147.24, 147.38, 151.17, 155.67, 160.01, 161.48, 163.96. Anal. calcd for C22H18BrFN4O3: C 54.45, H 3.74, N 11.54; found C 54.61, H 3.58, N 11.39.

    5-(4-甲基苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9h):黄色油状物, 产率80%. 1H NMR (400 MHz, CDCl3) δ:2.29 (s, 3H), 2.36 (s, 3H), 3.60 (s, 3H), 5.11 (s, 2H), 6.76 (d, J=8.80 Hz, 2H), 7.06~7.13 (m, 4H), 7.25 (s, 1H), 7.59~7.62 (m, 2H), 7.82 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.89, 20.57, 34.18, 67.54, 99.69, 115.19, 115.93, 116.15, 121.70, 124.15, 126.18, 126.26, 130.43, 132.65, 133.39, 141.94, 147.00, 148.59, 151.24, 154.58, 160.13, 161.49, 163.97. Anal. calcd for C23H21FN4O3: C 65.71, H 5.03, N 13.33; found C 65.53, H 5.19, N 13.20.

    5-(4-叔丁基苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氟苯基)噁唑-2-基]甲基}肟(9i):黄色油状物, 产率70%. 1H NMR (400 MHz, CDCl3) δ:1.29 (s, 9H), 2.37 (s, 3H), 3.60 (s, 3H), 5.11 (s, 2H), 6.79 (d, J=8.82 Hz, 2H), 7.09~7.13 (m, 2H), 7.26 (s, 1H), 7.30 (d, J=8.80 Hz, 2H), 7.59~7.63 (m, 2H), 7.84 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:15.02, 31.40, 34.21, 34.30, 67.55, 99.74, 114.75, 115.94, 116.16, 121.75, 124.15, 126.19, 126.27, 126.83, 132.66, 142.00, 146.72, 146.98, 148.58, 151.26, 154.48, 160.09, 161.49, 163.97. Anal. calcd for C26H27FN4O3: C 67.52, H 5.88, N 12.11; found C 67.68, H 5.73, N 12.07.

    5-(3-氟苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基-O- {[5-(4-氯苯基)噁唑-2-基]甲基}肟(9j):黄色固体, 产率67%. m.p. 95~97 ℃; 1H NMR (400 MHz, CDCl3) δ:2.35 (s, 3H), 3.60 (s, 3H), 5.09 (s, 2H), 6.60~6.69 (m, 3H), 7.20~7.25 (m, 1H), 7.29 (s, 1H), 7.38 (d, J=8.80 Hz, 2H), 7.55 (d, J=8.82 Hz, 2H), 7.86 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.66, 34.25, 67.58, 99.90, 103.43, 110.86, 122.50, 125.53, 126.29, 129.15, 130.81, 134.33, 141.63, 147.22, 151.02, 157.51, 160.27, 162.22, 164.69. Anal. calcd for C22H18ClFN4O3: C 59.94, H 4.12, N 12.71; found C 60.06, H 4.28, N 12.88.

    5-(4-氟苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9k):黄色固体, 产率72%. m.p. 101~103 ℃; 1H NMR (400 MHz, CDCl3) δ:2.27 (s, 3H), 3.53 (s, 3H), 5.02 (s, 2H), 6.74~6.90 (m, 4H), 7.21 (s, 1H), 7.31 (d, J=8.42 Hz, 2H), 7.48 (d, J=8.82 Hz, 2H), 7.76 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.66, 34.24, 67.57, 99.59, 116.34, 116.63, 122.50, 125.54, 126.29, 129.18, 134.27, 141.74, 147.21, 148.06, 151.03, 152.54, 157.57, 159.98, 160.32. Anal. calcd for C22H18ClFN4O3: C 59.94, H 4.12, N 12.71; found C 59.76, H 4.03, N 12.79.

    5-(2-氯苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9l):黄色固体, 产率65%. m.p. 70~72 ℃; 1H NMR (400 MHz, CDCl3) δ:2.27 (s, 3H), 3.56 (s, 3H), 5.01 (s, 2H), 6.59~6.61 (m, 1H), 6.92~7.07 (m, 2H), 7.21 (s, 1H), 7.30~7.35 (m, 3H), 7.48 (d, J=8.82 Hz, 2H), 7.75 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.66, 34.25, 67.58, 99.68, 115.67, 122.49, 122.82, 124.70, 125.55, 126.30, 128.01, 129.17, 130.98, 134.36, 141.54, 147.21, 147.58, 151.02, 152.07, 160.29. Anal. calcd for C22H18Cl2N4O3: C 57.78, H 3.97, N 12.25; found C 57.95, H 3.83, N 12.09.

    5-(3-氯苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9m):黄色固体, 产率70%. m.p. 92~94 ℃; 1H NMR (400 MHz, CDCl3) δ:2.28 (s, 3H), 3.53 (s, 3H), 5.02 (s, 2H), 6.67~6.98 (m, 3H), 7.10~7.14 (m, 1H), 7.22 (s, 1H), 7.32 (d, J=8.82 Hz, 2H), 7.49 (d, J=8.80 Hz, 2H), 7.79 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:13.58, 33.25, 66.57, 98.90, 112.51, 114.94, 121.47, 123.03, 124.51, 125.26, 128.14, 129.72, 133.32, 134.44, 140.53, 146.21, 150.00, 156.03, 159.22. Anal. calcd for C22H18Cl2N4O3: C 57.78, H 3.97, N 12.25; found C 57.63, H 4.11, N 12.42.

    5-(3-溴苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9n):黄色固体, 产率73%. m.p. 100~102 ℃; 1H NMR (400 MHz, CDCl3) δ:2.36 (s, 3H), 3.60 (s, 3H), 5.09 (s, 2H), 6.79~6.81 (m, 1H), 7.04~7.20 (m, 3H), 7.30 (s, 1H), 7.39 (d, J=8.42 Hz, 2H), 7.50 (d, J=8.80 Hz, 2H), 7.86 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.57, 34.28, 67.58, 99.93, 114.01, 118.81, 122.48, 123.18, 125.54, 126.27, 126.98, 129.16, 131.04, 134.34, 141.52, 147.20, 147.23, 151.02, 157.03, 160.24. Anal. calcd for C22H18BrClN4O3: C 52.66, H 3.62, N 11.17; found C 52.50, H 3.49, N 11.32.

    5-(4-溴苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9o):黄色固体, 产率78%. m.p. 96~98 ℃; 1H NMR (400 MHz, CDCl3) δ:2.34 (s, 3H), 3.58 (s, 3H), 5.08 (s, 2H), 6.75 (d, J=9.20 Hz, 2H), 7.29 (s, 1H), 7.35~7.40 (m, 4H), 7.56 (d, J=8.80 Hz, 2H), 7.85 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.57, 34.24, 67.56, 99.79, 116.21, 117.05, 122.50, 125.53, 126.28, 129.16, 132.85, 134.34, 141.61, 147.24, 147.37, 150.99, 155.66, 160.27. Anal. calcd for C22H18BrClN4O3: C 52.66, H 3.62, N 11.17; found C 52.56, H 3.78, N 11.02.

    5-苯氧基-1, 3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9p):黄色油状物, 产率75%. 1H NMR (400 MHz, CDCl3) δ:2.29 (s, 3H), 3.52 (s, 3H), 5.02 (s, 2H), 6.80 (d, J=8.02 Hz, 2H), 6. 98~7.23 (m, 4H), 7.31 (d, J=8.40 Hz, 2H), 7.48 (d, J=8.80 Hz, 2H), 7.77 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.88, 34.24, 67.56, 99.78, 115.34, 122.50, 123.80, 125.56, 126.32, 129.17, 130.02, 134.35, 141.95, 147.09, 148.17, 151.05, 156.65, 160.37. Anal. calcd for C22H19ClN4O3: C 62.49, H 4.53, N 13.25; found C 62.60, H 4.38, N 13.07.

    5-(4-甲基苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9q):黄色固体, 产率80%. m.p. 63~65 ℃; 1H NMR (400 MHz, CDCl3) δ:2.21 (s, 3H), 2.28 (s, 3H), 3.51 (s, 3H), 5.04 (s, 2H), 6.69 (d, J=8.80 Hz, 2H), 6.99 (d, J=8.00 Hz, 2H), 7.22 (s, 1H), 7.31 (d, J=8.40 Hz, 2H), 7.48 (d, J=8.42 Hz, 2H), 7.76 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.96, 20.58, 34.21, 67.54, 99.65, 115.17, 122.47, 125.55, 126.31, 129.17, 130.43, 133.34, 134.35, 142.08, 147.03, 148.56, 151.06, 154.64, 160.42. Anal. calcd for C23H21ClN4O3: C 63.23, H 4.85, N 12.82; found C 63.40, H 4.98, N 12.68.

    5-(4-叔丁基苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9r):黄色油状物, 产率71%. 1H NMR (400 MHz, CDCl3) δ:1.29 (s, 9H), 2.36 (s, 3H), 3.60 (s, 3H), 5.11 (s, 2H), 6.79 (d, J=8.82 Hz, 2H), 7.29 (d, J=8.80 Hz, 3H), 7.38 (d, J=8.42 Hz, 2H), 7.56 (d, J=8.40 Hz, 2H), 7.84 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:15.04, 31.42, 34.23, 34.31, 67.54, 99.73, 114.76, 122.48, 125.57, 126.30, 126.84, 128.73, 129.18, 131.40, 134.38, 142.10, 146.72, 147.02, 148.58, 151.10, 154.52, 160.39. Anal. calcd for C26H27ClN4O3: C 65.20, H 5.68, N 11.70; found C 65.05, H 5.81, N 11.86.

    5-(4-甲氧基苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基- O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9s):黄色油状物, 产率82%. 1H NMR (400 MHz, CDCl3) δ:2.28 (s, 3H), 3.53 (s, 3H), 3.68 (s, 3H), 5.04 (s, 2H), 6.74 (s, 4H), 7.22 (s, 1H), 7.31 (d, J=8.38 Hz, 2H), 7.49 (d, J=8.80 Hz, 2H), 7.74 (s, 1H); 13C NMR (101 MHz, CDCl3) δ:14.90, 34.20, 55.68, 67.55, 99.41, 114.96, 116.47, 122.50, 125.56, 126.31, 129.17, 131.40, 134.35, 142.02, 147.03, 148.91, 150.54, 151.05, 155.87, 160.40. Anal. calcd for C23H21Cl- N4O4: C 61.00, H 4.67, N 12.37; found C 61.16, H 4.55, N 12.22.

    5-(4-三氟甲氧基苯氧基)-1, 3-二甲基-1H-吡唑-4-甲酰基-O-{[5-(4-氯苯基)噁唑-2-基]甲基}肟(9t):黄色固体, 产率75%. m.p. 113~115 ℃; 1H NMR (400 MHz, CDCl3) δ:2.27 (s, 3H), 3.53 (s, 3H), 5.00 (s, 2H), 6.81 (d, J=9.18 Hz, 2H), 7.06 (d, J=8.82 Hz, 2H), 7.21 (s, 1H), 7.31 (d, J=8.80 Hz, 2H), 7.48 (d, J=8.82 Hz, 2H), 7.78 (s, 1H); 13C NMR (101 MHz, CDCl3)δ:14.59, 34.28, 67.58, 99.82, 116.38, 119.13, 122.49, 122.85, 125.53, 126.27, 129.18, 134.40, 141.56, 144.81, 147.28, 147.46, 151.05, 154.84, 160.24. Anal. calcd for C23H18ClF3N4O4: C 54.50, H 3.58, N 11.05; found C 54.32, H 3.73, N 11.19.

    辅助材料(Supporting Information)   目标化合物9a~9t的核磁共振氢谱和碳谱图谱.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.


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  • 图 1  吡螨胺、氯虫苯甲酰胺、唑螨酯和化合物A~F的化学结构

    Figure 1  Chemical structures of tebufenpyrad, chlorantraniliprole, fenpyroximate, and compounds A~F

    图 2  目标化合物9的设计

    Figure 2  Design of the target compounds 9

    图式 1  目标化合物9的合成路线

    Scheme 1  Synthetic route of target compounds 9

    表 1  不同反应条件对目标化合物9e收率的影响

    Table 1.  Effect of various reaction conditions on the yield of target compound 9e

    Entry Base Solvent Reaction condition Yield/%
    1 NaHCO3 CH3COCH3 Reflux for 12 h 0
    2 Na2CO3 CH3COCH3 Reflux for 12 h 0
    3 K2CO3 CH3COCH3 Reflux for 12 h 20
    4 Cs2CO3 CH3COCH3 Reflux for 12 h 33
    5 NaOH CH3 COCH3 Reflux for 12 h 0
    6 Na2CO3 CH3CN Reflux for 12 h 43
    7 K2CO3 CH3CN Reflux for 12 h 65
    8 Cs2CO3 CH3CN Reflux for 12 h 76
    9 NaOH CH3CN Reflux for 12 h 0
    10 Na2CO3 DMF 90 ℃ for 12 h 41
    11 K2CO3 DMF 90 ℃ for 12 h 49
    12 Cs2CO3 DMF 90 ℃ for 12 h 58
    13 NaOH DMF 90 ℃ for 12 h 0
    下载: 导出CSV

    表 2  目标化合物9a~9t的杀虫活性(死亡率/%)a

    Table 2.  Insecticidal activities of the target compounds 9a~9t (mortality/%)

    Compd. Oriental armyworm Aphis medicaginis Tetranychus cinnabarinus
    500 μg/mL 100 μg/mL 20 μg/mL 500 μg/mL 100 μg/mL 20 μg/mL 500 μg/mL 100 μg/mL
    9a 100 0 0 0
    9b 100 0 100 0 0
    9c 100 0 0 0
    9d 90 0 100 0 0
    9e 100 0 100 20 0 0
    9f 100 0 0 0
    9g 100 0 100 100 20 0
    9h 90 0 0 0
    9i 100 0 0 0
    9j 100 100 30 0 0
    9k 100 100 40 0 0
    9l 100 0 0 0
    9m 100 0 0 0
    9n 100 0 0 0
    9o 100 40 0 0 0
    9p 100 0 0 0
    9q 100 0 0 0
    9r 100 100 0 0 0
    9s 100 100 70 100 100 40 70 0
    9t 100 0 0 0
    Tolfenpyrad 100 50 40
    Imidacloprid 100 100 100
    Fenpyroximate 100 100
    a — refers to “not tested”.
    下载: 导出CSV
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  • 发布日期:  2020-03-25
  • 收稿日期:  2019-10-11
  • 修回日期:  2019-10-29
  • 网络出版日期:  2019-11-13
通讯作者: 陈斌, bchen63@163.com
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