氰胺类化合物的合成及其应用研究进展

黎吉辉 李正章 张玉苍 许文茸 徐树英

引用本文: 黎吉辉, 李正章, 张玉苍, 许文茸, 徐树英. 氰胺类化合物的合成及其应用研究进展[J]. 有机化学, 2017, 37(8): 1903-1915. doi: 10.6023/cjoc201706003 shu
Citation:  Li Jihui, Li Zhengzhang, Zhang Yucang, Xu Wenrong, Xu Shuying. Progress on the Synthesis and Applications of Cyanamides[J]. Chinese Journal of Organic Chemistry, 2017, 37(8): 1903-1915. doi: 10.6023/cjoc201706003 shu

氰胺类化合物的合成及其应用研究进展

    通讯作者: 黎吉辉, lijihui@hainu.edu.cn
  • 基金项目:

    海南省自然科学基金(Nos.20162015,217008)资助项目

摘要: 氰胺类化合物(R1R2NCN)是一种带有氨基和氰基双官能团的重要精细化工原料,广泛应用于医药、农药、化肥、保健产品和材料等领域,受到合成化学家和药物化学家们的广泛关注.近年来对于氰胺合成方法和其反应的研究发展迅速,不断有新的氰胺合成方法和以其为原料合成各种含氮化合物的反应涌现.本文主要综述了近二十年来发展的氰胺合成方法及氰胺在有机合成中的应用,全面介绍氰胺的各种合成方法和反应,归纳总结他们的特点、规律和优劣势,为氰胺的合成方法和反应性的研究提供帮助.

English

  • 近年来, 含氮杂环化合物因其多样化的结构形式及广谱的生物活性而成为新药创制研究的一个热点[1~4]. 1, 3, 4-噁二唑类化合物作为含氮杂环体系中的重要一员, 以其独特的生物活性和光学活性[5]被广泛用于杀虫[6]、除草[7]、杀菌[8]及抗癌[9]等方面.如Zheng等[10]合成的含双苯基结构的噁二唑类化合物A(图 1)具有较好的杀虫活性, 在测试浓度为125 mg/L时, 化合物A对粘虫的防治效果为100%, Shi等[11]报道的含氰基丙烯酸酯结构单元的噁二唑化合物B(图 1)对人肝癌(HepG2) 细胞株显示出较好的体外抗肿瘤活性, 其IC50值为5.9 μmol/L.吡唑类衍生物亦为一类重要的含氮杂环化合物, 因其良好的杀虫、杀螨及抗病毒等活性而倍受药物学家们的关注[12~15].目前, 具有多种生物活性的吡唑类衍生物相继被开发出来, 如美国Du Pont公司研制的氯虫苯甲酰胺对鳞翅目和半翅目类害虫表现出优异的杀虫效果[16], 日本三菱化学公司开发的吡螨胺(Tebufenpyrad, 图 1)和唑虫酰胺(Tolfenpyrad, 图 1)具有良好的杀虫杀螨作用[17, 18].另外, 酰胺基团在药物分子中也是一种常见的结构单元[19~22], 酰胺基常被作为良好的药效团引入到化合物分子中, 以改善其生物活性.鉴于此, 本工作以吡螨胺为先导, 将重要的1, 3, 4-噁二唑环引入吡螨胺分子结构中, 设计合成了一系列新型含1, 3, 4-噁二唑单元结构的吡唑酰胺类衍生物(Eq. 1), 并对其进行了生物活性测试研究.初步的生物活性测试结果表明, 部分目标化合物显示出较好的杀虫活性.利用1H NMR, 13C NMR和元素分析等方法对目标化合物的结构进行了表征.目标化合物的合成路线如Scheme 1所示.

    图 1  化合物AB、吡螨胺和唑虫酰胺的化学结构式 Figure 1.  Chemical structures of compounds A, B, tebufenpyrad and tolfenpyrad
    图式1  目标化合物9的合成路线 图式1.  Synthetic route of the title compounds 9

    1   结果与讨论

    1.1   目标化合物的合成

    我们以目标化合物9c为研究对象, 研究了不同的反应条件对化合物9c收率的影响.由表 1可以看出, 采用三乙胺作缚酸剂, THF为溶剂, 室温反应10 h, 是制备目标物的较佳方法, 化合物9c的收率为55%, 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, 并通过1H NMR, 13C NMR和元素分析等手段对其结构进行了表征.

    表 1  不同反应条件对目标化合物9c合成收率的影响 Table 1.  Effects of reaction conditions on the synthesis of the title compound 9c
    Entry Base Solvent Reaction condition Yield/%
    1 Pyridine CH3COCH3 Reflux for 10 h 32
    2 Pyridine CH3CN Reflux for 10 h 25
    3 Pyridine THF Reflux for 10 h 15
    4 Pyridine Toluene Reflux for 10 h 0
    5 Et3N CH3CN Room temperature for 10 h 20
    6 Et3N THF Room temperature for 10 h 55
    7 Et3N CH3CN Reflux for 10 h 26
    8 Et3N THF Reflux for 10 h 50
    9 Et3N CH3COCH3 Reflux for 10 h 40
    10 K2CO3 THF Room temperature for 10 h 32
    11 K2CO3   DMF Room temperature for 10 h 0

    1.2   化合物的图谱分析

    以目标化合物9b的核磁氢谱与碳谱数据为例进行解析. δ在9.19处的单峰为酰胺基上氢的吸收峰; δ 7.96~7.93间的多重峰为苯环上两个氢的吸收峰; δ 7.73~7.63间的多重峰为苯环上另外两个氢的吸收峰; δ 4.84处的双重峰为与噁二唑环相连的CH2上两个氢的吸收峰; δ 3.89处的单峰为吡唑环1-位甲基上三个氢的吸收峰; δ 2.57处的四重峰为与吡唑环相连的亚甲基上两个氢的吸收峰; δ 1.18处的三重峰为甲基上三个氢的吸收峰; δ在40.9处的峰为与噁二唑环相连的CH2碳原子的信号峰; δ 34.5处的峰为吡唑环1-位甲基碳原子的信号峰; δ 19.2处的峰为与吡唑环相连的亚甲基碳原子的信号峰; δ 12.8处的峰对应于甲基碳原子的信号峰.

    1.3   化合物的杀虫活性

    目标化合物9a~9q对粘虫(Oriental armyworm)、蚜虫(Aphis medicaginis)和褐飞虱(Nilaparvata lugens)的杀虫活性测试结果见表 2.初步的生测结果表明, 部分目标化合物具有一定的杀虫活性.在测试浓度为500 μg/mL时, 化合物9b, 9k, 9m, 9n, 9o9p对粘虫的杀灭效果分别为90%, 90%, 90%, 50%, 80%和100%, 其中化合物9b, 9k, 9m9p对粘虫的防效与对照药唑虫酰胺相当; 当测试剂量降至100 μg/mL时, 化合物9b9p对粘虫仍呈现出一定的杀虫效果, 其抑制率分别为30%和40%.另外, 化合物9g在测试浓度为500 μg/mL时对蚜虫的抑制率为100%, 与其对照药吡虫啉接近.这为今后进一步从事吡唑酰胺类衍生物的结构优化与研究提供了重要的实验数据.

    表 2  目标化合物9a~9q的杀虫活性(死亡率/%)a Table 2.  Insecticidal activities (mortality/%) of target compounds 9a~9q
    Compd. Oriental armyworm Aphis medicaginis Nilaparvata lugens
    500 μg/mL 100 μg/mL 500 μg/mL 100 μg/mL 500 μg/mL
    9a 0 0 0
    9b 90 30 0 0
    9c 0 0 0
    9d 0 0 0
    9e 0 0 0
    9f 0 0 0
    9g 10 100 0 0
    9h 0 0 0
    9i 0 0 0
    9j 0 0 0
    9k 90 0 0 0
    9l 0 0 0
    9m 90 0 0 0
    9n 50 20 0
    9o 80 0 0 0
    9p 100 40 0 0
    9q 0 0 0
    Tolfenpyrad 100 50
    Imidacloprid 100 100 100
    a—refers to “not tested”.

    2   结论

    采用活性基团拼接原理, 设计并制备了17个新型含1, 3, 4-噁二唑杂环结构的吡唑酰胺类化合物.初步的生物活性测试结果表明, 部分目标化合物显示出较好的杀虫活性.在测试浓度为500 μg/mL时, 化合物9b, 9k, 9m, 9o9p对粘虫的抑制率分别为90%, 90%, 90%, 80%和100%;当测试浓度降为100 μg/mL时, 化合物9b9p对粘虫的杀死率分别为30%和40%.此外, 化合物9g测试浓度为500 μg/mL时对蚜虫表现出良好的杀灭效果, 其杀死率为100%.具有进一步研究的价值.

    3   实验部分

    3.1   仪器与试剂

    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DMSO-d6或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.

    3.2   中间体47的合成

    中间体4参照文献[11]方法制备,

    中间体7参照文献[23, 24]方法制备.

    3.3   1-甲基-3-取代基-4-氯吡唑-5-甲酰基氯(8) 的合成

    在100 mL反应瓶中, 加入0.03 mol中间体7及0.18 mol二氯亚砜, 室温搅拌下, 向其中加入几滴N, N-二甲基甲酰胺(DMF), 加热回流6 h, 冷却至室温, 减压蒸除过量的二氯亚砜, 得到相应的中间体8, 不经纯化直接用于下一步反应.

    3.4   目标化合物9的合成

    在一100 mL圆底烧瓶中, 加入5 mmol中间体4、5 mmol三乙胺及30 mL THF, 冰浴下搅拌, 向其中慢慢滴加5 mmol 1-甲基-3-取代基-4-氯吡唑-5-甲酰氯(8)的THF溶液(10 mL).滴毕, 室温搅拌8~18 h.减压蒸去溶剂, 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, 脱溶, 残余物经柱层析[V(石油醚):V(乙酸乙酯)=4:1]分离得到目标化合物9a~9q.

    1-甲基-3-乙基-4-氯-N-{[5-(3-氟苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9a):白色固体, 产率48%. m.p. 138~140 ℃; 1H NMR (400 MHz, DMSO-d6) δ: 9.21 (s, 1H, NH), 7.83 (d, J=7.6 Hz, 1H, ArH), 7.77~7.66 (m, 2H, ArH), 7.54~7.49 (m, 1H, ArH), 4.83 (d, J=6.0 Hz, 2H, CH2), 3.88 (s, 3H, N-CH3), 2.57 (q, J=7.6 Hz, 2H, CH2), 1.17 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 164.5, 163.2, 161.6, 158.7, 149.8, 131.0, 130.1, 125.3, 122.7, 119.2, 113.9, 108.4, 40.9, 34.5, 19.2, 12.8. Anal. calcd for C16H15ClFN5O2: C 52.83, H 4.16, N 19.25; found C 52.95, H 4.06, N 19.12.

    1-甲基-3-乙基-4-氯-N-{[5-(3-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9b):白色固体, 产率50%. m.p. 135~137 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.19 (s, 1H, NH), 7.96~7.93 (m, 2H, ArH), 7.73~7.63 (m, 2H, ArH), 4.84 (d, J=6.0 Hz, 2H, CH2), 3.89 (s, 3H, N-CH3), 2.57 (q, J=7.6 Hz, 2H, CH2), 1.18 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 164.4, 163.2, 158.7, 149.8, 135.3, 132.1, 130.5, 130.1, 127.0, 125.1, 125.0, 108.4, 40.9, 34.5, 19.2, 12.8. Anal. calcd for C16H15-Cl2N5O2: C 50.54, H 3.98, N 18.42; found C 50.67, H 3.86, N 18.29.

    1-甲基-3-乙基-4-氯-N-{[5-(4-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9c):白色固体, 产率55%. m.p. 156~158 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.21 (s, 1H, NH), 7.99 (d, J=8.8 Hz, 2H, ArH), 7.70 (d, J=8.8 Hz, 2H, ArH), 4.82 (d, J=5.6 Hz, 2H, CH2), 3.88 (s, 3H, N-CH3), 2.55 (q, J=7.6 Hz, 2H, CH2), 1.17 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 164.7, 163.0, 158.7, 154.9, 149.8, 138.4, 130.1, 129.5, 128.3, 121.9, 108.4, 40.9, 34.5, 19.2, 12.8. Anal. calcd for C16H15-Cl2N5O2: C 50.54, H 3.98, N 18.42; found C 50.45, H 4.06, N 18.31.

    1-甲基-3-乙基-4-氯-N-{[5-(3-溴苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9d):白色固体, 产率47%. m.p. 135~136 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.20 (s, 1H, ArH), 7.99 (d, J=8.0 Hz, 1H, ArH), 7.68 (d, J=8.8 Hz, 1H, ArH), 7.43~7.37 (m, 1H, ArH), 4.96 (d, J=5.2 Hz, 2H, CH2), 4.15 (s, 3H, NCH3), 2.66 (q, J=7.6 Hz, 2H, CH2), 1.25 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 164.3, 163.3, 158.7, 149.8, 135.0, 130.7, 130.2, 129.9, 125.5, 125.3, 123.2, 108.4, 40.9, 34.6, 19.2, 12.8. Anal. calcd for C16H15BrClN5O2: C 45.25, H 3.56, N 16.49; found C 45.13, H 3.69, N 16.60.

    1-甲基-3-乙基-4-氯-N-{[5-(3-三氟甲基苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9e):白色固体, 产率45%. m.p. 125~127 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.29 (s, 1H, NH), 8.35 (d, J=7.6 Hz, 1H, ArH), 8.27 (s, 1H, ArH), 8.09 (d, J=7.6 Hz, 1H, ArH), 7.96~7.92 (m, 1H, ArH), 4.90 (d, J=5.6 Hz, 2H, CH2), 3.94 (s, 3H, N-CH3), 2.62 (q, J=7.6 Hz, 2H, CH2), 1.23 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 164.3, 163.4, 158.7, 149.8, 132.0, 131.7, 130.1, 129.9, 128.6, 124.3, 123.9, 122.1, 108.4, 40.9, 34.5, 19.2, 12.8. Anal. calcd for C17H15ClF3N5O2: C 49.35, H 3.65, N 16.93; found C 49.48, H 3.74, N 16.81.

    1-甲基-3-乙基-4-氯-N-{[5-(4-氰基苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9f):白色固体, 产率51%, m.p. 175~177 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.20 (s, 1H, NH), 8.16~8.09 (m, 4H, ArH), 4.85 (d, J=5.6 Hz, 2H, CH2), 3.89 (s, 3H, NCH3), 2.57 (q, J=7.6 Hz, 2H, CH2), 1.18 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 164.0, 163.8, 158.7, 149.8, 132.9, 130.0, 127.5, 127.3, 117.8, 115.5, 108.4, 40.9, 34.5, 19.2, 12.8. Anal. calcd for C17H15ClN6O2: C 55.07, H 4.08, N 22.66; found: C 55.20, H 3.99, N 22.58.

    1-甲基-3-乙基-4-氯-N-{[5-(4-甲基苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9g):白色固体, 产率58%. m.p. 144~146 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.21 (s, 1H, NH), 7.86 (d, J=8.0 Hz, 2H, ArH), 7.14 (d, J=8.0 Hz, 2H, ArH), 4.81 (d, J=5.6 Hz, 2H, CH2), 3.87 (s, 3H, N-CH3), 2.56 (q, J=8.0 Hz, 2H, CH2), 2.40 (s, 3H, Ar-CH3), 1.17 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 165.7, 162.5, 158.6, 149.8, 142.6, 130.2, 129.8, 126.9, 120.6, 108.4, 40.8, 34.6, 21.7, 19.2, 12.8. Anal. calcd for C17H18ClN5O2: C 56.75, H 5.04, N 19.46; found C 56.62, H 5.15, N 19.59.

    1-甲基-3-乙基-4-氯-N-{[5-(2, 4-二氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9h):白色固体, 产率50%. m.p. 150~152 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.20 (s, 1H, NH), 7.99~7.94 (m, 2H, ArH), 7.71~7.68 (m, 1H, ArH), 4.83 (d, J=5.6 Hz, 2H, CH2), 3.87 (s, 3H, NCH3), 2.56 (q, J=7.6 Hz, 2H, CH2), 1.17 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 163.4, 163.2, 158.7, 149.8, 138.4, 134.0, 131.9, 131.2, 130.1, 127.7, 121.3, 108.4, 40.8, 34.6, 19.2, 12.8. Anal. calcd for C16H14Cl3N5O2: C 46.34, H 3.40, N 16.89; found C 46.22, H 3.53, N 16.80.

    1-甲基-3-乙基-4-氯-N-{[5-(3, 5-二氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9i):白色固体, 产率48%. m.p. 173~175 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.21 (s, 1H, NH), 7.96 (s, 3H, ArH), 4.83 (d, J=5.6 Hz, 2H, CH2), 3.88 (s, 3H, N-CH3), 2.57 (q, J=7.6 Hz, 2H, CH2), 1.18 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ: 163.6, 163.4, 158.7, 149.8, 136.1, 131.9, 130.0, 126.0, 125.2, 108.4, 40.9, 34.5, 19.2, 12.8. Anal. calcd for C16H14Cl3N5O2: C 46.34, H 3.40, N 16.89; found C 46.45, H 3.28, N 16.80.

    1-甲基-3-乙基-4-氯-N-{[5-(3-甲基-4-硝基苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9j):白色固体, 产率43%. m.p. 145~147 ℃; 1H NMR (400 MHz, DMSO-d6)δ: 9.20 (s, 1H, NH), 8.20 (d, J=8.4 Hz, 1H, ArH), 8.12 (s, 1H, ArH), 8.02 (d, J=8.4 Hz, 1H, ArH), 4.85 (d, J=5.6 Hz, 2H, CH2), 3.89 (s, 3H, N-CH3), 2.61 (s, 3H, Ar-CH3), 2.57 (q, J=7.6 Hz, 2H, CH2), 1.18 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 163.8, 158.7, 150.9, 149.8, 134.7, 131.2, 130.0, 127.3, 125.6, 125.4, 108.4, 40.9, 34.5, 20.4, 19.2, 12.8. Anal. calcd for C17H17ClN6O4: C 50.44, H 4.23, N 20.76; found C 50.54, H 4.12, N 20.65.

    1-甲基-3-正丙基-4-氯-N-{[5-(4-氟苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9k):白色固体, 产率54%. m.p. 156~157 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.00~7.97 (m, 2H, ArH), 7.37 (s, 1H, NH), 7.20~7.11 (m, 2H, ArH), 4.88 (d, J=5.6 Hz, 2H, CH2), 4.08 (s, 3H, N-CH3), 2.53 (t, J=7.6 Hz, 2H, CH2), 1.64~1.58 (m, 2H, CH2), 0.90 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 165.2, 163.7, 162.7, 161.9, 157.6, 147.6, 129.0, 128.3, 118.7, 115.6, 115.4, 107.7, 39.9, 33.5, 26.6, 20.8, 12.8. Anal. calcd for C17H17ClFN5O2: C 54.04, H 4.54, N 18.54; found C 53.93, H 4.66, N 18.63.

    1-甲基-3-正丙基-4-氯-N-{[5-(4-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9l):白色固体, 产率60%. m.p. 134~135 ℃; 1H NMR (400 MHz, CDCl3)δ: 7.98 (d, J=8.8 Hz, 2H, ArH), 7.50~7.45 (m, 3H, ArH and NH), 4.94 (d, J=5.6 Hz, 2H, CH2), 4.14 (s, 3H, N-CH3), 2.59 (t, J=7.6 Hz, 2H, CH2), 1.70~1.64 (m, 2H, CH2), 0.96 (t, J=7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3)δ: 164.7, 163.0, 158.7, 148.6, 138.4, 130.1, 129.5, 128.3, 121.9, 108.8, 40.9, 34.5, 27.7, 21.9, 13.8. Anal. calcd for C17H17Cl2N5O2: C 51.79, H 4.35, N 17.76; found: C 51.89, H 4.46, N 17.64.

    1-甲基-3-(3-氟苯基)-4-氯-N-{[5-(4-氟苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9m):灰白色固体, 产率42%. m.p. 145~147 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.08~8.04 (m, 2H, ArH), 7.65~7.50 (m, 3H, ArH and NH), 7.44~7.39 (m, 1H, ArH), 7.23~7.07 (m, 3H, ArH), 4.99 (d, J=5.6 Hz, 2H, CH2), 4.25 (s, 3H, N-CH3); 13C NMR (100 MHz, CDCl3)δ: 166.3, 164.8, 164.0, 163.7, 162.8, 161.6, 158.5, 145.2, 132.8, 131.7, 130.1, 129.3, 123.1, 119.8, 116.7, 115.7, 114.4, 107.8, 41.4, 34.7. Anal. calcd for C20H14ClF2N5O2: C 55.89, H 3.28, N 16.29; found C 55.77, H 3.37, N 16.36.

    1-甲基-3-(3-氟苯基)-4-氯-N-{[5-(4-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9n):白色固体, 产率46%. m.p. 158~159 ℃; 1H NMR (400 MHz, CDCl3)δ: 7.99 (d, J=8.8 Hz, 2H, ArH), 7.65~7.39 (m, 6H, ArH and NH), 7.12~7.07 (m, 1H, ArH), 4.99 (d, J=5.6 Hz, 2H, CH2), 4.25 (s, 3H, N-CH3); 13C NMR (100 MHz, CDCl3)δ: 164.8, 164.1, 162.9, 161.6, 158.5, 145.2, 138.4, 132.7, 131.6, 130.2, 129.6, 128.3, 123.2, 121.9, 115.7, 114.4, 107.8, 41.4, 34.7. Anal. calcd for C20H14Cl2FN5O2: C 53.83, H 3.16, N 15.69; found C 53.72, H 3.25, N 15.58.

    1-甲基-3-(4-氟苯基)-4-氯-N-{[5-(4-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9o):白色固体, 产率49%. m.p. 200~201 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.01 (d, J=8.8 Hz, 2H, ArH), 7.84~7.80 (m, 2H, ArH), 7.55~7.51 (m, 3H, ArH and NH), 7.19~7.14 (m, 2H, ArH), 5.01 (d, J=5.6 Hz, 2H, CH2), 4.26 (s, 3H, N-CH3); 13C NMR (100 MHz, CDCl3)δ: 164.8, 164.2, 162.9, 161.7, 158.5, 145.6, 138.4, 131.4, 129.6, 129.5, 129.4, 128.3, 126.8, 121.9, 115.7, 115.5, 107.5, 41.4, 34.7. Anal. calcd for C20H14Cl2FN5O2: C 53.83, H 3.16, N 15.69; found C 53.95, H 3.07, N 15.80.

    1-甲基-3-(4-氯苯基)-4-氯-N-{[5-(4-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9p):灰白色固体, 产率52%. m.p. 223~224 ℃; 1H NMR (400 MHz, CDCl3)δ: 8.00 (d, J=8.8 Hz, 2H, ArH), 7.78 (d, J=8.4 Hz, 2H, ArH), 7.51~7.42 (m, 5H, ArH and NH), 4.98 (d, J=5.6 Hz, 2H, CH2), 4.24 (s, 3H, N-CH3); 13C NMR (100 MHz, CDCl3)δ: 164.9, 163.4, 159.7, 148.7, 138.6, 135.5, 133.9, 130.9, 129.6, 129.0, 128.3, 126.8, 121.7, 103.9, 39.6, 34.6. Anal. calcd for C20H14Cl3N5O2: C 51.91, H 3.05, N 15.14; found C 51.80, H 3.13, N 15.05.

    1-甲基-3-(2, 4-二氟苯基)-4-氯-N-{[5-(4-氯苯基)-1, 3, 4-噁二唑-2-基]甲基}-1H-吡唑-5-甲酰胺(9q):白色固体, 产率43%. m.p. 157~158 ℃; 1H NMR (400 MHz, CDCl3)δ: 7.99 (d, J=8.8 Hz, 2H, ArH), 7.51~7.46 (m, 4H, ArH and NH), 7.01~6.92 (m, 2H, ArH), 4.98 (d, J=5.6 Hz, 2H, CH2), 4.26 (s, 3H, N-CH3); 13C NMR (100 MHz, CDCl3)δ: 164.8, 162.9, 158.4, 142.5, 138.4, 132.4, 132.3, 131.1, 129.6, 128.3, 121.9, 114.8, 111.8, 111.6, 109.8, 104.6, 41.5, 34.7. Anal. calcd for C20H13Cl2F2N5O2: C 51.74, H 2.82, N 15.09; found C 51.65, H 2.93, N 15.21.

    3.5   生物活性测试

    杀虫试验方法分别如下: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.杀虫活性测试所选昆虫分别为粘虫(Oriental armyworm)、蚜虫(Aphis medicaginis)和褐飞虱(Nilaparvata lugens).对照药剂分别为啶虫丙醚(Pyridalyl)和吡虫啉(Imidacloprid).蚜虫和褐飞虱:采用喷雾法.首先, 分别将接有蚜虫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, 褐飞虱置于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9a~9q1H 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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  • 图式1  铜催化2-卤代芳基硫脲串联反应合成芳基氰胺

    Scheme 1  Copper-catalyzed cascade reaction of 2-haloarylth-ioureas for the synthesis of arylcyanamides

    图式2  胺和TMSCN偶联反应合成氰胺

    Scheme 2  Coupling reaction of amines and TMSCN for the synthesis of cyanamides

    图式3  钯催化异氰、三甲基硅叠氮三组分反应合成氰胺

    Scheme 3  Palladium-catalyzed three-component reaction of isocyanides, allyl carbonate and trimethylsilyl azide for the synthesis of cyanamides

    图式4  钯催化邻炔基芳基异氰、烯丙醇酯和三甲基硅叠氮三组分反应合成N-氰基吲哚

    Scheme 4  Palladium-catalyzed three-component reaction of 2-alkynylaryl isocyanides, allyl carbonate and trimethylsilyl azide for the synthesis of N-cyanoindoles

    图式5  钯催化异氰和三甲基硅叠氮反应合成氰胺

    Scheme 5  Palladium-catalyzed reaction of isocyanides and trimethylsilyl azide for the synthesis of cyanamides

    图式6  氰胺和二芳基碘盐偶联反应合成氰胺和脲

    Scheme 6  Cross coupling of NH-cyanamides and diaryliodoniums for the synthesis of cyanamides and ureas

    图式7  氰胺和吡啶N-氧多米诺反应合成脲类化合物

    Scheme 7  Domino reaction of cyanamides and pyridine N-oxides for the synthesis of ureas

    图式8  N-酰基氰胺自由基串联反应合成稠环胍

    Scheme 8  Radical cascade reaction of N-acyl cyanamides for the synthesis of fused cyclic guanidines

    图式9  N-酰基氰胺和二硫化合物自由基串联反应合成异脲类化合物

    Scheme 9  Radical cascade reaction of N-acyl cyanamides and diaryldisulfides for the synthesis of isothioureas.

    图式10  铜催化氰胺、胺和硼酸三组分反应合成胍

    Scheme 10  Copper-catalyzed three-component reaction of cyanamides, amines and boronic acides for the synthesis of guanidines

    图式11  钴促进二炔和氰胺[2+2+2]环加成反应合成稠环2-氨基吡啶

    Scheme 11  Cobalt-promoted [2+2+2] cycloaddition of bis-alkynes and cyanamides for the synthesis of fused 2-aminopyridines

    图式12  铑催化硼酸和NCTS氰基化反应合成氰

    Scheme 12  Rhodium catalyzed cyanation of boronic acids with NCTS for the synthesis of nitriles

    图式13  铜催化邻炔基芳香氰胺环化反应合成3-氰基吲哚

    Scheme 13  Copper-catalyzed cyclization of o-alkynyl arylcyanamides for the synthesis of 3-cyanoindoles

    图式14  CsF促进2-(三甲基硅基)苯酚三氟甲磺酸酯和氰胺串联反应合成2-氨基苯甲氰类化合物

    Scheme 14  CsF-promoted cascade reaction of cyanamides and (trimethylsilyl)aryl trifluoromethanesulfonate for the synthesis of 2-aminobenzonitriles

    图式15  B(C6F5)3促进分子内烯烃氨基氰基化反应合成吲哚啉

    Scheme 15  B(C6F5)3-promoted intramolecular aminocyanation of alkenes by cyanamides for the synthesis of indolines

    图式16  钯催化分子内氨基氰基化反应合成吲哚啉

    Scheme 16  Palladium-catalyzed intramolecular aminocyanation of alkenes for the synthesis of indolines

    图式17  N-酰基氰胺自由基串联反应合成四环稠合喹唑啉

    Scheme 17  Radical cascade reaction of N-acyl cyanamides for the synthesis of tetracycle-fused quinazolines

    图式18  N-酰基氰胺自由基串联反应合成三环喹唑啉

    Scheme 18  Radical cascade reaction of N-acyl cyanamides for the synthesis of tricycle-fused quinazolines

    图式19  钯催化氰胺和芳基三氟硼酸钾加成反应合成芳基脒

    Scheme 19  Palladium-catalyzed addition of cyanamides and potassium arlyltrifluoroborates for the synthesis of arylamidines

    图式20  钯催化氰胺和α-羰基羧酸脱羧加成反应合成α-酮酰胺

    Scheme 20  Palladium-catalyzed decarboxylative addition of cyanamides and α-oxocarboxylic acids for the synthesis of α-ketoamides

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  • 发布日期:  2017-08-25
  • 收稿日期:  2017-06-02
  • 修回日期:  2017-06-26
  • 网络出版日期:  2017-08-14
通讯作者: 陈斌, bchen63@163.com
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