含有雙氰基環丙烷甲酰胺類化合物的合成及生物活性

徐高飛, 劉艷紅, 楊新玲, 王道全, 袁德凱

(中國農業大學理學院應用化學系, 北京 100193)

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含有雙氰基環丙烷甲酰胺類化合物的合成及生物活性

徐高飛, 劉艷紅, 楊新玲, 王道全, 袁德凱

(中國農業大學理學院應用化學系, 北京 100193)

以含氰基及環丙烷的酰胺類殺菌劑為先導, 設計合成了結構全新的雙氰基環丙烷甲酰胺類化合物. 通過Strecker反應獲得中間體2-氨基-2-(取代)苯基乙(丙)腈(1a～1n), 以氰乙酸乙酯和1,2-二溴乙烷環經環化、 水解得到1-氰基環丙烷-1-甲酸(3), 由化合物3和1經縮合反應得到目標化合物4a～4n, 其結構均經NMR和HRMS表征. 生物活性測試結果表明, 在離體條件下, 50 μg/mL的化合物4f對瓜果腐霉和稻瘟菌的抑制活性分別為55.3%和67.1%; 盆栽實驗中, 400 μg/mL的化合物4f對黃瓜霜霉病和小麥白粉病的抑制活性分別為50%和85%, 化合物4m對玉米銹病的抑制活性達100%; 5 μg/mL的化合物4c, 4d, 4g, 4j和4m對蚊幼蟲的致死率均>60%, 600 μg/mL的化合物 4h和4j對粘蟲的致死率分別為66.7%和50%.

雙氰基環丙烷甲酰胺; Strecker反應; 縮合; 生物活性

環丙烷結構廣泛存在于天然產物和農藥分子中[1], 可作為抗腫瘤活性雜環化合物的重要藥效團[2]. 菊酯類、 腐霉利、 嘧環菌胺、 環丙酰菌胺和環丙嘧啶醇等都是含有環丙烷的農藥活性分子[3～7]. 氰基能改善分子的理化性質, 提高其生物活性, 在農藥及醫藥領域中含氰基化合物的合成及生物活性研究受到廣泛關注[8,9]. 在商品化農藥中, 約10%的分子中含有氰基[10], 這些農藥包括氰菊酯、 辛硫磷、 氟蟲腈、 氰氟蟲腙、 氰蟲酰胺、 噻蟲啉、 啶蟲脒、 氟啶蟲胺腈和氟啶蟲酰胺等殺蟲劑[11～18], 早期的溴菌腈、 百菌清、 霜脲氰和二氰蒽醌[19～22]以及近期開發的嘧菌酯、 氰霜唑、 噻唑菌胺、 氰菌唑、 唑菌腈、 氰菌胺和雙氯氰菌胺等殺菌劑[23～29]. 環丙酰菌胺、 氰菌胺和雙氯氰菌胺為黑色素生物合成抑制劑(MBIs)[6,28,29], 可通過抑制真菌黑色素合成而降低孢子的侵染性, 用于防治稻瘟病、 霜霉病和晚疫病[28,30]. 噻唑菌胺為噻唑甲酰胺結構, 能抑制菌絲生長和孢子形成, 可防治霜霉病和晚疫病[25,31].

Scheme 1 Design strategy of title compounds

本文參照上述高活性化合物的結構, 通過活性中間體衍生化策略[32], 以氰基乙酸乙酯和1,2-二溴乙烷的環合反應制備1-氰基環丙烷甲酸乙酯, 水解得到1-氰基環丙烷甲酸; 以(取代)苯甲醛(酮)的氰氨化反應得到2-氨基-2-(取代)苯乙腈或2-氨基-2-(取代)苯丙腈, 在二環己基碳二亞胺(DCC)/4-二甲氨基吡啶(DMAP)作用下縮合得14個全新目標化合物(設計思路如Scheme 1所示), 經1H NMR,13C NMR及HRMS確證了其結構. 以平皿法和盆栽法[37]測定了目標化合物的殺菌活性, 以浸葉法和浸液法測定了其殺蟲活性.

1 實驗部分

1.1 試劑與儀器

氰基三甲基硅烷(TMSCN)、 二環己基碳二亞胺(DCC)、 4-(N,N-二甲氨基)吡啶(DMAP)、 氯化三乙基芐基銨(TEBA)、 聚乙二醇400(PEG400)和1-丁基-3-甲基咪唑六氟磷鹽([BMIM]PF6)等試劑均為分析純, 購自北京偶合科技有限公司; 其它試劑均為分析純, 購自北京化工廠; 乙腈經CaH2進行無水處理.

Yanaco-300型熔點儀(日本芝山制造所); Bruker DPX 300 MHz核磁共振儀(TMS為內標, 德國Bruker公司); Agilent 1100 Series HPLC/MSD Trap液相色譜-質譜聯用儀(ESI, 美國Agilent公司); Varian 7.0T FT-ICR MS HRMS質譜儀(MALDI, 美國Varian公司).

1.2 實驗部分

中間體及目標化合物的合成路線見Scheme 2.

a: R1=H, R2=H; b: R1=4-F, R2=H; c: R1=3-Cl, R2=H; d: R1=4-Br, R2=H; e: R1=4-Me, R2=H; f: R1=4-t-Bu, R2=H; g: R1=4-OMe, R2=H; h: R1=3,4-dioxomethylene, R2=H; i: R1=H, R2=Me; j: R1=4-Cl, R2=Me; k: R1=3-Br, R2=Me; l: R1=4-Br, R2=Me; m: R1=4-Me, R2=Me; n: R1=4-OMe, R2=Me.Scheme 2 General synthetic routes for title compounds 4a—4h

1.2.1 2-氨基-2-(取代)苯乙腈(1a～1h)的合成 參照文獻[33]方法合成化合物1a～1h, 用乙酸乙酯/石油醚重結晶, 經真空干燥后直接用于合成目標化合物. 化合物1a: m.p. 52～54 ℃(文獻值[34]: 55 ℃); 化合物1b: m.p.72～74 ℃(文獻值[34]: 73～74 ℃); 化合物1c: MS(C8H7ClN2計算值), m/z: 167.0(166.0); 化合物1d: MS(C8H7BrN2計算值), m/z: 211.0(210.0); 化合物1e: MS(C9H10N2計算值), m/z: 147.1(146.1); 化合物1f: MS(C12H16N2計算值), m/z: 189.1(188.1); 化合物1g: m.p. 35～37 ℃(文獻值[35]: 37～38 ℃); 化合物1h: MS(C12H16N2計算值), m/z: 177.1(176.1).

1.2.2 2-氨基-2-(取代)苯丙腈鹽酸鹽(1i～1n)的合成 2-氨基-2-(取代)苯丙腈參照文獻[36]方法合成. 將經無水Na2SO4干燥后的2-氨基-2-(取代)苯丙腈的乙醚溶液冷卻至0 ℃, 攪拌下于0.5 h內通入干燥HCl氣體, 生成產物1i～1n. 于0 ℃靜置1 h, 抽濾, 真空干燥, 用于合成目標化合物. 化合物1i: m.p. 109～111 ℃(文獻值[37]: 110～112 ℃); 化合物1j: MS(C9H9ClN2計算值), m/z: 181.0(180.0); 化合物1k: MS(C9H9BrN2計算值), m/z: 225.0(224.0); 化合物1l: MS(C9H9BrN2計算值), m/z: 225.0(224.0); 化合物1m: MS(C10H12N2計算值), m/z: 161.1(160.1); 化合物1n: MS(C10H12N2O計算值), m/z: 177.1(176.1).

1.2.3 1-氰基環丙烷-1-甲酸(3)的合成 1-氰基環丙烷-1-甲酸乙酯(2)參照文獻[38]方法合成, 減壓蒸餾, 收集72～77 ℃/6.65 kPa的餾分, 得無色液體, 產率77.2%;1H NMR(CDCl3, 300 MHz), δ: 1.71～1.60(m, 4H), 1.34(t, 3H), 4.27(q, 2H). 將1-氰基環丙烷-1-甲酸乙酯(2, 5 g, 0.036 mol)溶于20 mL無水乙醇, 0 ℃下滴入含KOH粉末(2.62 g, 0.038 mol)的25 mL無水乙醇中, 室溫下攪拌2 h, 減壓除去溶劑, 加入20 mL水, 用20 mL CHCl3萃取, 將水相酸化至pH=2, 用氯仿萃取(60 mL×3), 減壓除去溶劑, 得到1-氰基環丙烷-1-甲酸(3), 白色固體, 產率41.1%;1H NMR(CDCl3, 300 MHz), δ: 1.72～1.82(m, 4H), 10.64(s, 1H).

1.2.4 目標化合物4a～4n的合成 將0.005 mol 2-氨基-2-(取代)苯丙腈鹽酸鹽溶于15 mL CH2Cl2中, 緩慢滴加15 mL質量分數為10%的NaOH溶液, 滴加完畢后攪拌10 min, 靜置分液, 有機相用無水Na2SO4干燥3 h, 得到2-氨基-2-(取代)苯丙腈CH2Cl2溶液, 備用.

冰浴下, 將二環己基碳二亞胺(DCC, 1.02 g, 0.0050 mol)、 4-二甲氨基吡啶(DMAP, 0.60 g, 0.0050 mol)以及2-氨基-2-(取代)苯乙腈或2-氨基-2-(取代)苯丙腈(0.0050 mol)加入到含1-氰基環丙烷-1-甲酸(3, 0.5 g, 0.0045 mol)的20 mL CH2Cl2中后, 于常溫下攪拌反應5 h[39]， 過濾, 減壓除去溶劑, 加入15 mL乙酸乙酯, 于4 ℃靜置12 h, 過濾, 經柱層析[V(乙酸乙酯)∶V(石油醚)=5∶1]分離得到白或黃色固體化合物4a～4n. 目標化合物的理化數據見表1和表2, 核磁共振氫譜、 碳譜及高分辨質譜見支持信息圖S1～圖S21.

Table 1 Appearance, yield, melting points and HRMS data of compounds 4a—4h

Table 2 1H NMR data of compounds 4a—4h

Continued

Compd.1HNMR(300MHz,CDCl3),δ13CNMR(100MHz,CDCl3),δ4g1.58—1.63,1.77—1.83(dm,4H,CH2CH2),3.85(s,3H,OCH3),5.94,5.96[d,1H,(CN)CH],6.78,6.80(d,1H,CONH),6.95—7.44(m,4H,Ar—H)13.61,18.64,18.90,44.59,55.47,114.79,116.98,119.24,124.29,128.73,160.66,165.144h1.56—1.64,1.75—1.82(dm,4H,CH2CH2),5.90,5.93[d,1H,(CN)CH],6.04(s,2H,OCH2O),6.85—7.02(m,4H,Ar—H)13.63,18.66,18.96,44.80,101.93,107.58,108.88,116.60,119.17,121.24,125.63,148.73,149.11,164.984i1.55—1.68,1.70—1.80(dm,4H,CH2CH2),2.03[s,3H,(CN)C(CH3)],6.82(s,1H,CONH),7.25—7.58(m,5H,Ar—H) 13.58,18.48,18.56,29.33,54.76,118.86,119.61,124.50,129.14,129.33,138.45,164.554j1.55—1.78(dm,4H,CH2CH2),1.99[s,3H,(CN)C(CH3)],6.91(s,1H,CONH),7.26—7.50(m,4H,Ar—H)13.53,18.59,18.74,29.51,54.30,118.53,119.52,125.98,129.46,135.03,137.15,164.644k1.57—1.80(dm,4H,CH2CH2),1.99[s,3H,(CN)C(CH3)],6.91(s,1H,CONH),7.26—7.66(m,4H,Ar—H)13.54,18.70,18.82,29.61,54.26,118.39,119.51,123.29,127.57,130.80,132.21,140.84,164.684l1.54—1.79(dm,4H,CH2CH2),1.99[s,3H,(CN)C(CH3)],6.85(s,1H,CONH),7.40—7.58(m,4H,Ar—H)13.52,18.60,18.75,29.49,54.36,118.47,119.51,123.15,126.24,132.41,137.71,164.634m1.54—1.58,1.67—1.75(dm,4H,CH2CH2),2.01[s,3H,(CN)C(CH3)],2.37(s,3H,Ar—CH3),5.79(s,1H,CONH),7.23—7.45(m,4H,Ar—H)19.26,22.04,22.09,25.74,34.78,59.01,124.90,125.14,129.23,134.49,142.50,142.64,170.294n1.54—1.57,1.71—1.76(dm,4H,CH2CH2),2.05[s,3H,(CN)C(CH3)],3.83(s,3H,OCH3),6.74(s,1H,CONH),6.94—7.50(m,4H,Ar—H)13.62,18.41,18.48,28.84,54.23,55.43,114.63,118.98,119.63,126.08,130.20,160.09,164.47

1.3 目標化合物的生物活性測定

采用菌絲生長法[40]測試了目標化合物對油菜菌核菌(Sclerotinia sclerotiorum)、 黃瓜灰霉菌(Botrytis cinerea)、 瓜果腐霉菌(Pythium aphanidermatum)、 稻瘟梨孢菌(Pyricularia oryzae)、 蘆筍莖枯菌(Phomopsis asparagi)和棉花立枯菌(Rhizoctonia solani)的離體殺菌活性, 結果見表3.

Table 3 In vitro fungicidal activity of title compounds

a. Test concentration was 50 μg/mL; b. SS: Sclerotinia sclerotiorum; BC: Botrytiscinerea; PA: Pythium aphanidermatum; PO: Pyricularia oryzae; PAS: Phomopsis asparagi; RS: Rhizoctonia solani.

采用盆栽法[41], 以烯肟菌胺(SYP-1620)為陽性對照測定了目標化合物對黃瓜霜霉病(Pseudoperonospora cubensis)、 小麥白粉病(Erysiphe graminis)和玉米銹病(Puccinia sorghi)的保護活性, 結果見表4.

Table 4 In vivo fungicidal activity of some title compounds

a. Test concentration was 400 μg/mL, compounds 4i, 4k, 4l and 4n showed no activity against the above fungi; b. PC: Pseudoperonospora cubensis; EG: Erysiphe graminis; PS: Puccinia sorghi; c. positive control.

采用浸葉法[42]測定了目標化合物對東方粘蟲(Mythimma separata Walker)的殺蟲活性, 采用浸液法[43]測定了目標化合物對尖音庫蚊淡色亞種(Culex pipiens pallens) 的殺蟲活性, 結果見表5.

Table 5 Larvicidal activity of title compounds

a. Test concentration was 600 μg/mL; b. test concentration was 5 μg/mL.

2 結果與討論

2.1 中間體及目標化合物的合成

在化合物1a～1h的合成中使用低毒的氰基三甲基硅烷(TMSCN)代替金屬氰化物, 產物可通過重結晶或柱層析純化; 中間體1i～1n使用氰化鈉制備, 為便于后續反應的準確計量, 于0 ℃下向其干燥后的乙醚粗提溶液中通入干燥的氯化氫氣體, 制得其鹽酸鹽沉淀. 將該沉淀經真空干燥后, 低溫保存.

在1-氰基環丙烷-1-甲酸乙酯(2)的合成中嘗試使用氯化三乙基芐基銨(TEBA)、 PEG400和1-丁基-3-甲基咪唑六氟磷鹽([BMIM]PF6)分別作為相轉移催化劑, 發現[BMIM]PF6催化的產物收率接近80%, 高于TEBA和PEG400催化的收率(約60%); 使用NaOH水溶液水解1-氰基環丙烷-1-甲酸乙酯(2)無法得到1-氰基環丙烷-1-甲酸(3), 需在低溫下于無水乙醇中用KOH水解后酸化才能獲得產物.

2.2 目標化合物的生物活性

在離體活性測試中, 化合物4j, 4l和4n對油菜菌核菌的抑制率接近50%; 化合物4i, 4j, 4k, 4l和4m對黃瓜灰霉菌的抑制率為45.9%～65.6%; 化合物4f對瓜果腐霉菌的抑制率為55.3%; 化合物4b和4f對稻瘟菌的抑制率為44.3%和67.1%, 與對照藥劑百菌清相當; 化合物4c和4f對蘆筍莖枯菌的抑制率約40%. 在盆栽實驗中, 化合物4f, 4j和4m對黃瓜霜霉病、 小麥白粉病及玉米銹病有較好的抑制活性, 其中以化合物4f對白粉病的抑制率(85%)和化合物4m對玉米銹病的抑制率(100%)較突出. 由以上結果可知: (1) 目標化合物對油菜菌核菌、 黃瓜灰霉菌、 瓜果腐霉菌和稻瘟菌具有一定的抑制活性; (2) 酰胺α位有甲基取代的目標化合物(4i～4m)對油菜菌核菌和黃瓜灰霉病的抑制活性較好, 無甲基取代的化合物(4a～4j)對稻瘟菌、 蘆筍莖枯菌和棉花立枯菌的抑制活性較好, 表明酰胺α位的甲基對化合物的抑制活性具有重要影響; (3) 化合物4f對黃瓜灰霉菌、 瓜果腐霉菌、 稻瘟菌和蘆筍莖枯菌均具有顯著抑制活性, 其典型特征為苯環的C4位有叔丁基取代, 表明苯環上的C4空間體積較大的取代基對活性有利;(4) 活體活性測試結果表明, 化合物4f和4m具有確切的殺菌活性, 與離體測試中化合物4f和4m的殺菌活性特征一致, 另外二者苯環C4位均有較大的給電子取代基.

此外, 目標化合物具有一定的殺蟲活性, 化合物4h和4m對粘蟲的致死率分別為66.7%和50%; 化合物4c, 4d, 4g, 4j和4m等對蚊幼蟲有一定的殺蟲活性, 可歸因于其與菊酯的結構相似性.

3 結 論

合成了14個全新化合物, 通過1H NMR,13C NMR和HRMS確證了其結構. 制備了2-氨基-2-(取代)苯丙腈鹽酸鹽以對其提純和準確計量; 使用1-丁基-3-甲基咪唑六氟磷鹽([BMIM]PF6)催化提高了1-氰基環丙烷-1-甲酸乙酯的收率. 研究發現, 目標化合物對稻瘟菌和黃瓜霜霉菌具有一定的抑制活性, 化合物4f和4m對小麥白粉病和玉米銹病具有活體保護活性; 此外, 目標化合物還具有一定的殺蟲活性. 該工作對殺菌劑的創制研究具有一定的指導意義.

感謝中國農業科學院植保所閆曉靜副研究員和南開大學元素所趙衛光研究員在活性測試工作中的大力支持.

支持信息見http://www.cjcu.jlu.edu.cn/CN/10.7503/cjcu20150729.

[1] Zhu L.T., A Collection of Fine Chemicals, Agrichemicals, Zhejiang Science and Technology Press, Hangzhou, 2000, 10, 11, 22, 23, 163—239(朱良天. 精細化學品大全—農藥卷, 杭州: 浙江科學技術出版社, 2000, 10, 11, 22, 23, 163—239)

[2] Zhai X., Wang L. M., Shi J.Y., Gong P., Chem. Res. Chinese Universities, 2015, 31(3), 372—380

[3] Zhao S. H., Plant Chemical Protection, China Agricultural Press, Beijing, 2000, 83—90(趙善歡. 植物化學保護, 北京: 中國農業出版社, 2000, 83—90)

[4] Fujinami A., Ozaki T., Ooba S., Yamamoto S., Nodera K., Tanaka K., Akiba K., Ooishi T., Kameda N., Antimicrobial N-(3,5-dihalophenyl)imide Compounds, ZA 7001624, 1970-10-05

[5] Baettig W., Hanreich R. G., Crystal Modification of (4-Cyclopropyl-6-methyl-pyrimidin-2-yl)-phenyl-amine, Process for Its Preparation and Its Use as Fungicide, EP 655441, 1995-05-31

[6] Kurahashi Y., Shiokawa K., Kagabu S., Sakawa S., Moriya K., N-Benzylcyclopropane-carboxamide Derivatives, Intermediates for Their Preparation, and Fungicides for Agriculture and Horticulture, EP 170842, 1986-02-12

[7] Snel M., Gramlich J. V., Med. van de Facult. Landbouw., Univ. Gent., 1973, 38(3), 1033—1041

[8] Wang D. J., Zhang E. S., Xu T. L., Li J., Huang T. K., Zou Y., Chem. J. Chinese Universities, 2015, 36(2), 267—273(王德建, 張恩生, 徐田龍, 李軍, 黃桐堃, 鄒永. 高等學?；瘜W學報, 2015, 36(2), 267—273)

[9] Liao H. M., Chong L. E., Tan L., Chen X. D., You R., Gong P., Chem. Res. Chinese Universities, 2014, 30(5), 759—763

[10] Zhang Y. B., World Pesticides, 2013, 35(Supplement), 38—42(張一賓. 世界農藥, 2013, 35(增刊), 38—42)

[11] Walter L., Wilheim S., Ingeborg H., Christa F., Manfred F., Winfride F., Phosphorus Containing Alpha Oximino Acetic Acid Nitriles, US 3591662, 1966-05-26

[12] Moffat A. S., Science, 1993, 261, 550—551

[13] Takagi K., Ohtani T., Nishida T., Hamaguchi H., Nishimatsu T., Kanaoka A., Hydrazinecarboxamide Derivatives, A Process for Production Thereof, and Uses Thereof, EP 462456, 1991-12-27

[14] Hughes K. A., Lahm G. P., Selby T. P., Stevenson T. M., Preparation of Cyano Anthranilamide Insecticides, WO 2004067528, 2004-08-12

[15] Shiokawa K., Tsuboi S., Kagabu S., Sasaki S., Moriya K., Hattori Y., Heterocyclic Compounds, EP 235725, 1987-09-09

[16] Ishimitsu K., Suzuki J., Ohishi H., Yamada T., Hatano R., Takakusa N., Mitsui J., Amine Derivatives, WO 9104965, 1991-04-18

[17] Loso M. R., Nugent B. M., Huang J. X., Rogers R. B., Zhu Y., Renga J. M., Hegde V. B., Demark J. J., Inseticidal N-Substituted(6-Haloalkylpyridin-3-yl)Alkyl Sulfoximines, WO 2007095229, 2007-08-23

[18] Toki T., Koyanagi T., Morita M., Yoneda T., Kagimoto C., Okada H., Pyridine Amides and Their Salts, Processes for Their Production and Pesticidal Compositions Containing Them, EP 580374, 1994-01-26

[19] Grier N., Lederer S. J., Dihalomethylglutaronitriles Used as Antibacterical and Antifungal Agents, US 3833731, 1974-09-03

[20] Ugi I., Polyisonitriles and A Process for Their Production, DE 1158500B, 1963-12-05

[21] Klopping H. L., Delp C. J., J. Agric. Food Chem., 1980, 28(2), 467—468

[22] Van Schoor A., Mohr G., 2,3-Dicyano-1,4-dithiaanthrahydroquinone and Anthraquinone, DE 1156821, 1963-11-07

[23] Clough J. M., Godfrey C. R. A., Streeting I. T., Cheetham R., Fungicides, EP 382375, 1990-08-16

[24] Nasu R., Komyoji T., Suzuki K., Nakajima T., Ito K., Ohshima T., Yoshimura H., Imidazole Compounds and Biocidal Compositions Comprising the Same, BR 8801098, 1988-10-18

[25] Rew Y. S., Cho J. H., Ra C. S., Ahn S. C., Kim S. K., Lee Y. H., Jung B. Y., Choi W. B., Rhee Y. H., Yoon M. Y., Chun S. W., 2-Aminothiazolecarboxamide Derivatives, Processes for Their Preparation and Their Use for Controlling Phytopathogenic Organisms, EP 639574, 1995-02-22

[26] Fujimoto T. T., Substituted Triazoles, Processes for Making Them, Their Use as Fungicides and Fungicidal Compositions Containing Them, EP 145294, 1985-06-19

[27] Shaber S. H., Flynn K. E., Weinstein B., Alpha-aryl-alpha-phenylethyl-1H-1,2,4- triazole-1-propanenitriles, DE 3721786, 1988-01-07

[28] Sieverding E., Hirooka T., Nishiguchi T., Yamamoto Y., Spadafora V. J., Hasui H., Brighton Crop Protection Conference Pests and Diseases, 1998, 2, 359—366

[29] Enomoto M., Magara O., Yamada Y., Production of Lower Alkyl 2-Cyano-3-metyl-2-butenoate, JP H08143528, 1996-06-04

[30] Manabe A., Enomoto M., Yamada Y., Oguri Y., Sasaki M., Pesticide Science, 1999, 55(6), 649—650

[31] Ra C. S., Rew Y. S., Choi W. B., Korean J. Med. Chem., 1995, 5(2), 72—75

[32] Guan A.Y., Liu C. L., Yang X. P., Dekeyser M., Chem. Rev., 2014, 114, 7079—7107

[33] Khuong M., Ghanshyam P., Tetrahedron Lett., 1984, 25(41), 4583—4586

[34] Sakulsombat M., Vongvilai P., Amstrom O., Chemistry—A European Journal, 2014, 20(36), 11322—11325

[35] Morris G. F., Hauser C. R., J. Org. Chem., 1961, 26(11), 4741—4743

[36] Wang B. Y., Zhang W., Zhang L. L., Du D. M., Liu G., Xu J. X., Eur. J. Org., 2008, (2), 350—355

[37] Allen D. J., Ruso E. R., Frankel S. A., α-Caboxamidomethylaminocarboxamides, US 3293294, 1966-12-20

[38] Muthusamy S., Gnanaprakasam B., Tetrahedron Lett., 2005, 46(4), 635—638

[39] Li Q. R., Gu C. Z., Yin H., Zhang Y., Chin J. Org. Chem., 2005, 25(11), 1416—1419 (李前榮, 顧承志, 尹浩, 張毅. 有機化學, 2005, 25(11), 1416—1419)

[40] Xiao Y. S., Zhang J. J., Yan X. J., Dong Y. H., Yuan H. Z., Liang X. M., Wang D. Q., Chin. J. Org. Chem., 2014, 34(12), 2493—2498(肖炎雙, 張建軍, 閆曉靜, 董燕紅, 袁會珠, 梁曉梅, 王道全. 有機化學, 2014, 34(12), 2493—2498)

[41] Wang L. Z., Sun X. F., Li Z. N., Guan A. Y., Proceedings of the 16th Annual Meeting of CIESC, Pesticide Professional Committee, Guiyang, 2014, 49—51(王立增, 孫旭峰, 李志念, 關愛瑩. 中國化工學會農藥專業委員會第十六屆年會論文集, 貴陽, 2014年9月, 49—51)

[42] Mao C. H., Zhao Y., Li Y. Q., Huang R. Q., Bi F. C., Wang Q. M., Chin. J. Org. Chem., 2009, 29(6), 929—935(毛春暉, 趙毓, 李永強, 黃潤秋, 畢富春, 汪清民. 有機化學, 2009, 29(6), 929—935)

[43] Raymond M., Marquine M., J. Evol. Biol., 1994, 7(3), 315—337

(Ed.: P， H， S， K)

Synthesis and Biological Activity of Novel Dicyano-containning Cyclopropane-1-carboxamides?

XU Gaofei, LIU Yanhong, YANG Xinling, WANG Daoquan, YUAN Dekai*

(Department of Applied Chemistry, Science College, China Agricultural University, Beijing 100193, China)

A series of novel dicyano-contained cyclopropanecarboxamide derivatives were designed and synthesized using fungicides containing cyano or cyclopropyl as leading structures. Intermediates 2-amino-2-(substituted) phenylacetonitriles or propionitriles 1a—1n were prepared via Strecker reaction. 1-Cyano-cyclopro-pyl-1-carboxylic(3) was obtained from ethyl cyanacetate and 1,2-dibrimoethane via cyclization and hydrolysis. 14 title compounds were obtained via the condensation of intermediates 1 and 3. The structures of all title compounds were confirmed by1H NMR and HRMS. Compound 4f showed good fungicidal activity against Pythium aphanidermatum and Pyricularia oryzae with inhibiton rates of 55.3% and 67.1% at 50 μg/mL in vitro and against Pseudoperonospora cubensis and Erysiphe graminis with inhibiton rates of 50% and 85% at 400 μg/mL in vivo. Compound 4m could give total control against Puccinia sorghi at 400 μg/mL in vivo. In addition, compounds 4c, 4d, 4g, 4j and 4m showed good larvicidal activity against mosquitoes(Culex pipiens pallens) at 5 μg/mL with the lethal rate above 60%; compounds 4h and 4j possessed larvicidal activity against armyworms(Mythimna separata) at 600 μg/mL with the lethal rate of 66.7% and 50%.

Dicyano-containning cyclopropane-1-carboxamide; Strecker reaction; Condensation; Biological activity

10.7503/cjcu20150729

2015-09-17.

日期: 2016-01-24.

國家自然科學基金(批準號: 20902107)資助.

O624.5; O625.4

A

聯系人簡介: 袁德凱, 男, 博士, 副教授, 主要從事有機合成及新農藥創制研究. E-mail: yuandekai@aliyun.com

? Supported by the National Natural Science Foundation of China(No.20902107).