徐高飛, 劉艷紅, 楊新玲, 王道全, 袁德凱

(中國(guó)農(nóng)業(yè)大學(xué)理學(xué)院應(yīng)用化學(xué)系, 北京 100193)

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含有雙氰基環(huán)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(guó)農(nóng)業(yè)大學(xué)理學(xué)院應(yīng)用化學(xué)系, 北京 100193)

以含氰基及環(huán)丙烷的酰胺類殺菌劑為先導(dǎo), 設(shè)計(jì)合成了結(jié)構(gòu)全新的雙氰基環(huán)丙烷甲酰胺類化合物. 通過(guò)Strecker反應(yīng)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(huán)經(jīng)環(huán)化、 水解得到1-氰基環(huán)丙烷-1-甲酸(3), 由化合物3和1經(jīng)縮合反應(yīng)得到目標(biāo)化合物4a～4n, 其結(jié)構(gòu)均經(jīng)NMR和HRMS表征. 生物活性測(cè)試結(jié)果表明, 在離體條件下, 50 μg/mL的化合物4f對(duì)瓜果腐霉和稻瘟菌的抑制活性分別為55.3%和67.1%; 盆栽實(shí)驗(yàn)中, 400 μg/mL的化合物4f對(duì)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(duì)玉米銹病的抑制活性達(dá)100%; 5 μg/mL的化合物4c, 4d, 4g, 4j和4m對(duì)蚊幼蟲(chóng)的致死率均>60%, 600 μg/mL的化合物 4h和4j對(duì)粘蟲(chóng)的致死率分別為66.7%和50%.

雙氰基環(huán)丙烷甲酰胺; Strecker反應(yīng); 縮合; 生物活性

環(huán)丙烷結(jié)構(gòu)廣泛存在于天然產(chǎn)物和農(nóng)藥分子中[1], 可作為抗腫瘤活性雜環(huán)化合物的重要藥效團(tuán)[2]. 菊酯類、 腐霉利、 嘧環(huán)菌胺、 環(huán)丙酰菌胺和環(huán)丙嘧啶醇等都是含有環(huán)丙烷的農(nóng)藥活性分子[3～7]. 氰基能改善分子的理化性質(zhì), 提高其生物活性, 在農(nóng)藥及醫(yī)藥領(lǐng)域中含氰基化合物的合成及生物活性研究受到廣泛關(guān)注[8,9]. 在商品化農(nóng)藥中, 約10%的分子中含有氰基[10], 這些農(nóng)藥包括氰菊酯、 辛硫磷、 氟蟲(chóng)腈、 氰氟蟲(chóng)腙、 氰蟲(chóng)酰胺、 噻蟲(chóng)啉、 啶蟲(chóng)脒、 氟啶蟲(chóng)胺腈和氟啶蟲(chóng)酰胺等殺蟲(chóng)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(kāi)發(fā)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(huán)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(guò)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(jié)構(gòu), 能抑制菌絲生長(zhǎng)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(jié)構(gòu), 通過(guò)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(huán)合反應(yīng)制備1-氰基環(huán)丙烷甲酸乙酯, 水解得到1-氰基環(huán)丙烷甲酸; 以(取代)苯甲醛(酮)的氰氨化反應(yīng)得到2-氨基-2-(取代)苯乙腈或2-氨基-2-(取代)苯丙腈, 在二環(huán)己基碳二亞胺(DCC)/4-二甲氨基吡啶(DMAP)作用下縮合得14個(gè)全新目標(biāo)化合物(設(shè)計(jì)思路如Scheme 1所示), 經(jīng)1H NMR,13C NMR及HRMS確證了其結(jié)構(gòu). 以平皿法和盆栽法[37]測(cè)定了目標(biāo)化合物的殺菌活性, 以浸葉法和浸液法測(cè)定了其殺蟲(chóng)活性.

1 實(shí)驗(yàn)部分

1.1 試劑與儀器

氰基三甲基硅烷(TMSCN)、 二環(huán)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(gòu)自北京偶合科技有限公司; 其它試劑均為分析純, 購(gòu)自北京化工廠; 乙腈經(jīng)CaH2進(jìn)行無(wú)水處理.

Yanaco-300型熔點(diǎn)儀(日本芝山制造所); Bruker DPX 300 MHz核磁共振儀(TMS為內(nèi)標(biāo), 德國(guó)Bruker公司); Agilent 1100 Series HPLC/MSD Trap液相色譜-質(zhì)譜聯(lián)用儀(ESI, 美國(guó)Agilent公司); Varian 7.0T FT-ICR MS HRMS質(zhì)譜儀(MALDI, 美國(guó)Varian公司).

1.2 實(shí)驗(yàn)部分

中間體及目標(biāo)化合物的合成路線見(jiàn)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(xiàn)[33]方法合成化合物1a～1h, 用乙酸乙酯/石油醚重結(jié)晶, 經(jīng)真空干燥后直接用于合成目標(biāo)化合物. 化合物1a: m.p. 52～54 ℃(文獻(xiàn)值[34]: 55 ℃); 化合物1b: m.p.72～74 ℃(文獻(xiàn)值[34]: 73～74 ℃); 化合物1c: MS(C8H7ClN2計(jì)算值), m/z: 167.0(166.0); 化合物1d: MS(C8H7BrN2計(jì)算值), m/z: 211.0(210.0); 化合物1e: MS(C9H10N2計(jì)算值), m/z: 147.1(146.1); 化合物1f: MS(C12H16N2計(jì)算值), m/z: 189.1(188.1); 化合物1g: m.p. 35～37 ℃(文獻(xiàn)值[35]: 37～38 ℃); 化合物1h: MS(C12H16N2計(jì)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(xiàn)[36]方法合成. 將經(jīng)無(wú)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(nèi)通入干燥HCl氣體, 生成產(chǎn)物1i～1n. 于0 ℃靜置1 h, 抽濾, 真空干燥, 用于合成目標(biāo)化合物. 化合物1i: m.p. 109～111 ℃(文獻(xiàn)值[37]: 110～112 ℃); 化合物1j: MS(C9H9ClN2計(jì)算值), m/z: 181.0(180.0); 化合物1k: MS(C9H9BrN2計(jì)算值), m/z: 225.0(224.0); 化合物1l: MS(C9H9BrN2計(jì)算值), m/z: 225.0(224.0); 化合物1m: MS(C10H12N2計(jì)算值), m/z: 161.1(160.1); 化合物1n: MS(C10H12N2O計(jì)算值), m/z: 177.1(176.1).

1.2.3 1-氰基環(huán)丙烷-1-甲酸(3)的合成 1-氰基環(huán)丙烷-1-甲酸乙酯(2)參照文獻(xiàn)[38]方法合成, 減壓蒸餾, 收集72～77 ℃/6.65 kPa的餾分, 得無(wú)色液體, 產(chǎn)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(huán)丙烷-1-甲酸乙酯(2, 5 g, 0.036 mol)溶于20 mL無(wú)水乙醇, 0 ℃下滴入含KOH粉末(2.62 g, 0.038 mol)的25 mL無(wú)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(huán)丙烷-1-甲酸(3), 白色固體, 產(chǎn)率41.1%;1H NMR(CDCl3, 300 MHz), δ: 1.72～1.82(m, 4H), 10.64(s, 1H).

1.2.4 目標(biāo)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(zhì)量分?jǐn)?shù)為10%的NaOH溶液, 滴加完畢后攪拌10 min, 靜置分液, 有機(jī)相用無(wú)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(huán)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(huán)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(yīng)5 h[39]， 過(guò)濾, 減壓除去溶劑, 加入15 mL乙酸乙酯, 于4 ℃靜置12 h, 過(guò)濾, 經(jīng)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(biāo)化合物的理化數(shù)據(jù)見(jiàn)表1和表2, 核磁共振氫譜、 碳譜及高分辨質(zhì)譜見(jiàn)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(biāo)化合物的生物活性測(cè)定

采用菌絲生長(zhǎng)法[40]測(cè)試了目標(biāo)化合物對(duì)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(jié)果見(jiàn)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(yáng)性對(duì)照測(cè)定了目標(biāo)化合物對(duì)黃瓜霜霉病(Pseudoperonospora cubensis)、 小麥白粉病(Erysiphe graminis)和玉米銹病(Puccinia sorghi)的保護(hù)活性, 結(jié)果見(jiàn)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(cè)定了目標(biāo)化合物對(duì)東方粘蟲(chóng)(Mythimma separata Walker)的殺蟲(chóng)活性, 采用浸液法[43]測(cè)定了目標(biāo)化合物對(duì)尖音庫(kù)蚊淡色亞種(Culex pipiens pallens) 的殺蟲(chóng)活性, 結(jié)果見(jiàn)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(jié)果與討論

2.1 中間體及目標(biāo)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(chǎn)物可通過(guò)重結(jié)晶或柱層析純化; 中間體1i～1n使用氰化鈉制備, 為便于后續(xù)反應(yīng)的準(zhǔn)確計(jì)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(jīng)真空干燥后, 低溫保存.

在1-氰基環(huán)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(zhuǎn)移催化劑, 發(fā)現(xiàn)[BMIM]PF6催化的產(chǎn)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(huán)丙烷-1-甲酸乙酯(2)無(wú)法得到1-氰基環(huán)丙烷-1-甲酸(3), 需在低溫下于無(wú)水乙醇中用KOH水解后酸化才能獲得產(chǎn)物.

2.2 目標(biāo)化合物的生物活性

在離體活性測(cè)試中, 化合物4j, 4l和4n對(duì)油菜菌核菌的抑制率接近50%; 化合物4i, 4j, 4k, 4l和4m對(duì)黃瓜灰霉菌的抑制率為45.9%～65.6%; 化合物4f對(duì)瓜果腐霉菌的抑制率為55.3%; 化合物4b和4f對(duì)稻瘟菌的抑制率為44.3%和67.1%, 與對(duì)照藥劑百菌清相當(dāng); 化合物4c和4f對(duì)蘆筍莖枯菌的抑制率約40%. 在盆栽實(shí)驗(yàn)中, 化合物4f, 4j和4m對(duì)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(duì)白粉病的抑制率(85%)和化合物4m對(duì)玉米銹病的抑制率(100%)較突出. 由以上結(jié)果可知: (1) 目標(biāo)化合物對(duì)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(biāo)化合物(4i～4m)對(duì)油菜菌核菌和黃瓜灰霉病的抑制活性較好, 無(wú)甲基取代的化合物(4a～4j)對(duì)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(duì)化合物的抑制活性具有重要影響; (3) 化合物4f對(duì)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(huán)的C4位有叔丁基取代, 表明苯環(huán)上的C4空間體積較大的取代基對(duì)活性有利;(4) 活體活性測(cè)試結(jié)果表明, 化合物4f和4m具有確切的殺菌活性, 與離體測(cè)試中化合物4f和4m的殺菌活性特征一致, 另外二者苯環(huán)C4位均有較大的給電子取代基.

此外, 目標(biāo)化合物具有一定的殺蟲(chóng)活性, 化合物4h和4m對(duì)粘蟲(chóng)的致死率分別為66.7%和50%; 化合物4c, 4d, 4g, 4j和4m等對(duì)蚊幼蟲(chóng)有一定的殺蟲(chóng)活性, 可歸因于其與菊酯的結(jié)構(gòu)相似性.

3 結(jié) 論

合成了14個(gè)全新化合物, 通過(guò)1H NMR,13C NMR和HRMS確證了其結(jié)構(gòu). 制備了2-氨基-2-(取代)苯丙腈鹽酸鹽以對(duì)其提純和準(zhǔn)確計(jì)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(huán)丙烷-1-甲酸乙酯的收率. 研究發(fā)現(xiàn), 目標(biāo)化合物對(duì)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(duì)小麥白粉病和玉米銹病具有活體保護(hù)活性; 此外, 目標(biāo)化合物還具有一定的殺蟲(chóng)活性. 該工作對(duì)殺菌劑的創(chuàng)制研究具有一定的指導(dǎo)意義.

感謝中國(guó)農(nóng)業(yè)科學(xué)院植保所閆曉靜副研究員和南開(kāi)大學(xué)元素所趙衛(wèi)光研究員在活性測(cè)試工作中的大力支持.

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

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(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(guó)家自然科學(xué)基金(批準(zhǔn)號(hào): 20902107)資助.

O624.5; O625.4

A

聯(lián)系人簡(jiǎn)介: 袁德凱, 男, 博士, 副教授, 主要從事有機(jī)合成及新農(nóng)藥創(chuàng)制研究. E-mail: yuandekai@aliyun.com

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