楊子輝, 李貝貝, 葉　姣, 胡艾希

(湖南大學化學化工學院, 長沙410082)

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基于呋喃酚構建2-(4-芳氧苯氧基)丙酰胺及除草活性

楊子輝, 李貝貝, 葉姣, 胡艾希

(湖南大學化學化工學院, 長沙410082)

以呋喃酚為原料, 采用2條合成路線制備2種關鍵中間體2-氨基-1-(2,2-二甲基-7-烷氧基-2,3-二氫苯并呋喃-5-基)乙酮鹽酸鹽(2)和n-(2,2-二甲基-2,3-苯并呋喃-7-氧基)烷胺(9), 再經2-(4-芳氧苯氧基)丙?；铣闪?7種基于呋喃酚的2-(4-芳氧苯氧基)丙酰胺, 其化學結構經核磁共振譜、高分辨率質譜和旋光度確證. 除草活性測試結果表明, 在1500 g/hm2劑量下, 大部分化合物對單子葉雜草馬唐(Crabgrass)和稗草(Barnyardgrass)均具有較高的抑制活性. 在化合物4和5中, 有7個化合物對單子葉雜草表現為A級除草活性, 如化合物4a, 4b, 4i, 5a, 5c, 5e和5h對馬唐和稗草的抑制率為100%. 初篩結果顯示, 在375 g/hm2劑量下, 化合物4a, 4b, 4i, 5e和5h對稗草的莖葉處理抑制率達96%以上.

2-(4-芳氧苯氧基)丙酰胺; 呋喃酚; 除草活性

Fig.1　Structures of compounds A—E

2-(4-芳氧苯氧基)丙酸類化合物是一類選擇性抑制植物乙酰輔酶A羧化酶的除草劑[1], 具有高效、低毒、高選擇性、對作物安全及易于降解等特點[2]. 目前, 已商品化的2-(4-芳氧苯氧基)丙酸品種達20余個, 如2010年上市的噁唑酰草胺[3]. 近年來通過對2-(4-芳氧苯氧基)丙酸類化合物的研究, 已發(fā)現一大批高活性化合物[4～7]. 胡宏平[8]將嘌呤環(huán)引入2-(4-芳氧苯氧基)丙酸結構中, 合成的化合物在200 μmol/L濃度下對馬唐(Crabgrass)的抑制率為90%. 鄒小毛等[9]將嗎啉、哌啶和四氫吡咯環(huán)引入2-(4-芳氧苯氧基)丙酰胺結構中, 合成了一類水油兼溶的化合物, 其中化合物A在30 g/hm2劑量下, 對馬唐和稗草(Barnyardgrass)的抑制率達100%. 李斌[10]設計合成了類似喔草酯結構, 并引入乙醇胺和乙二醇等鏈橋連接化合物, 其中化合物B在2000 g/hm2劑量下, 對馬唐、稗草和百日草抑制率達100%. 施娟娟等[11]基于芳氧苯氧丙酸酯和氰基丙烯酸酯的結構特點, 以乙醇胺為鏈接基團, 合成的化合物C在100和50 g/hm2劑量下對馬唐和稗草均有較好的防除效果. 柳愛平等[12]合成了N-吡啶芳氧苯氧羧酸衍生物, 其中(R,R)-N-(3-氯吡啶-2-基)-N-[2-(4-((3-氟-5-氯吡啶-2-基)氧基)苯氧基)]丙?；?[2-(4-(3-氟-5-氯吡啶-2-基氧基)苯氧基)]丙酰胺對馬唐、稗草和狗尾莖葉處理的抑制率均為100%. 劉祈星等[13,14]設計合成的化合物D在2250 g/hm2的劑量下對馬唐及稗草的土壤處理抑制活性均為90%, 其中化合物E活性與炔草酯相當[15]. 化合物A～E的結構如圖1所示. 呋喃酚類化合物在農藥領域特別是在殺蟲和除草方面具有廣泛的應用[16～18].

基于農藥藥效基團呋喃酚, 本文設計合成了(R)-N-[2-(2,2-二甲基-7-烷氧基-2,3-二氫苯并呋喃-5-基)-2-氧代乙基]-2-(4-芳氧苯氧基)丙酰胺(4a～4i). 以呋喃酚為原料, 經醚化、酰化、溴代及氨化得中間體2-氨基-1-(2,2-二甲基-7-烷氧基-2,3-二氫苯并呋喃-5-基)乙酮鹽酸鹽(2), 中間體2經酰化反應得到化合物4a～4i. 同樣基于呋喃酚, 利用中間體衍生化法, 設計合成了(R)-N-[2/3-(2,2-二甲基-2,3-二氫苯并呋喃-7-氧基)乙/丙基]-2-[4-(芳氧苯氧基)]丙酰胺(5a～5h). 以鄰苯二甲酸酐為原料, 經取代及溴代反應得中間體N-(δ-溴烷基)鄰苯二甲酰亞胺(7), 化合物7與呋喃酚醚化、氨解或肼解得中間體n-(2,2-二甲基-2,3-苯并呋喃-7-氧基)烷胺(9), 再經?；没衔?a～5h. 化合物4和5的合成路線見Scheme 1, 并對其進行除草活性測試.

2a: R=Me; 2b: R=Et; 2c: R=n-Pr; 3a: Ar=Ⅰ; 3b: Ar=Ⅱ; 3c: Ar=Ⅲ; 3d: Ar=Ⅳ; 3e: Ar=Ⅴ; 4a:Ar=Ⅰ, R=Me; 4b: Ar=Ⅰ, R=Et; 4c: Ar=Ⅳ, R=Me; 4d: Ar=Ⅳ, R=Et; 4e: Ar=Ⅲ, R=Me; 4f: Ar=Ⅲ, R=Et; 4g: Ar=Ⅱ, R=Me; 4h: Ar=Ⅱ, R=Et; 4i: Ar=Ⅲ, R=n-Pr; 5a: n=2, Ar=Ⅱ; 5b: n=2, Ar=Ⅲ; 5c: n=2, Ar=Ⅰ; 5d: n=2, Ar=Ⅴ; 5e: n=3, Ar=Ⅱ; 5f: n=3, Ar=Ⅲ; 5g: n=3, Ar=Ⅰ; 5h: n=3, Ar=Ⅴ; 6a—9a: n=2; 6b—9b: n=3.

Scheme 1　Synthetic routes of target compounds 4 and 5

1　實驗部分

1.1試劑與儀器

水合肼(質量分數80%); 所用溶劑和試劑均為市售分析純或化學純.

VARIAN INOVA-400型核磁共振儀(以CDCl3為溶劑, TMS為內標, 美國Varian公司); Bruker Avance 500型核磁共振儀(以CDCl3為溶劑, TMS為內標, 瑞士Bruker公司); Nexus智能型傅里葉變換紅外光譜儀(美國Thermo Nicolet公司); MAT 95XP型高分辨質譜儀(美國Thermo公司); RY-1 型熔點儀(天津市天分儀器廠); ZF-2型三用紫外顯色儀(上海市安亭電子儀器廠); 薄層層析用硅膠、柱層析硅膠(青島海洋化工公司).

1.2實驗過程

1.2.1中間體1和2的合成參照文獻[19～21]方法, 分別以2-溴乙?；秽蛹酌选?-溴乙?；秽右颐押?-溴乙?；秽颖褳榈孜锖铣苫衔?a～1c. 化合物1a, m. p. 90～91 ℃(文獻值[20]: 90～91 ℃); 化合物1b, m. p. 99～101 ℃(文獻值[20]: 98～100 ℃); 化合物1c, m.p. 99～100 ℃(文獻值[21]: 99～100 ℃).

化合物2a的合成: 將3.50 g烏洛托品(25 mmol)及40 mL三氯甲烷于45 ℃攪拌溶解, 滴加20 mL溶有化合物1a(6.00 g, 20 mmol)的三氯甲烷溶液, 用TLC監(jiān)測反應. 反應液經過濾、干燥得7.40 g白色固體. 將上述白色固體加入30 mL乙醇及20.00 g濃鹽酸中, 攪拌回流4 h, 趁熱過濾, 將濾液冷卻析出固體, 經過濾、干燥得白色固體2-氨基-1-(2,2-二甲基-7-甲氧基-2,3-二氫苯并呋喃-5-基)乙酮鹽酸鹽(2a) 3.70 g, 收率58.6%, m.p. 157～159 ℃.1H NMR(400 MHz, CDCl3),δ: 1.46(s, 6H, 2×CH3), 3.08(s, 2H, ArCH2), 3.82(s, 3H, OCH3), 4.51(d,J=5.2 Hz, 2H, COCH2), 7.40(s, 1H, C6H2), 7.56(s, 1H, C6H2), 8.17(s, 2H, NH2).

化合物2b的合成: 采用與合成化合物2a相同的方法, 僅以化合物1b代替化合物1a, 反應4.5 h, 得白色固體(2,2-二甲基-7-乙氧基-2,3-二氫苯并呋喃-5-基)乙酮鹽酸鹽(2b) 3.00 g, 收率47.2 %, m. p. 221～223 ℃.1H NMR(500 MHz, CDCl3),δ: 1.34(t, 3H,J=7.0 Hz, CH3), 1.46(s, 6H, 2×CH3), 3.08(s, 2H, ArCH2), 4.12(q, 2H,J=7.0 Hz, OCH2), 4.47(d,J=4.5 Hz, 2H, COCH2), 7.43(s, 1H, C6H2), 7.58(s, 1H, C6H2), 8.51(s, 2H, NH2).

化合物2c的合成: 采用與合成化合物2a相同的方法, 僅以化合物1c代替化合物1a, 反應4.5 h, 得白色固體(2,2-二甲基-7-丙氧基-2,3-二氫苯并呋喃-5-基)乙酮鹽酸鹽(2c) 3.03 g, 收率52.9 %, m. p. 288～290 ℃.1H NMR(500 MHz, CDCl3),δ: 0.97(t, 3H,J=7.0 Hz, CH3), 1.46(s, 6H, 2×CH3), 1.70～1.77(m, 2H, CH2), 3.08(s, 2H, ArCH2), 4.02(t, 2H,J=7.0 Hz, OCH2), 4.48(d,J=5.5 Hz, 2H, COCH2), 7.42(s, 1H, C6H2), 7.58(s, 1H, C6H2), 8.51(s, 2H, NH2).

1.2.3目標化合物4a～4i的合成將中間體2(2.02×103mmol)、25 mL二氯甲烷及1.46 g(14.45 mmol) 三乙胺混合, 冰浴下逐滴加入化合物3(2.42×103mmol)的二氯甲烷溶液. 再在室溫下反應1.0～1.5 h, 將有機層依次用水和飽和食鹽水洗滌, 干燥, 脫溶, 經柱層析分離得固體4a～4i.

1.2.4中間體8和9的合成參考文獻[23]方法合成化合物8a和9a. 化合物8a, m. p. 114～116 ℃, 收率69.7%(文獻值[23]: 113 ℃, 收率71.0%); 化合物9a, m. p. 55～57 ℃, 收率81.4%(文獻值[23]: 56 ℃, 收率88.0%);N-(3-溴丙基)鄰苯二甲酰亞胺(7b)參照文獻[24]方法合成, m. p. 71～73 ℃(文獻值[24]: 71～72 ℃).

化合物8b的合成: 取0.164 g(1.0 mmol)呋喃酚、0.276 g(2.0 mmol)K2CO3、催化量聚乙二醇-200(PEG-200)及20 mLN,N-二甲基甲酰胺(DMF)混合, 攪拌, 滴加溶有化合物7b(0.402 g, 1.5 mmol)的DMF溶液, 于70 ℃反應2 h, 冷卻, 抽濾, 干燥得淡黃色固體8b 0.29 g, 收率82.8%, m. p. 83～85 ℃.1H NMR(400 MHz, CDCl3),δ: 1.45(s, 6H, 2×CH3), 2.15～2.22(m, 2H, CCH2C), 2.98(s, 2H, CH2), 3.87(t,J=6.8 Hz, 2H, NCH2), 4.11(t,J=6.8 Hz, 2H, OCH2), 6.70～6.73(m, 3H, C6H3), 7.68～7.70(m, 2H, C6H4), 7.81～7.84(m, 2H, C6H4);13C NMR(100 MHz, CDCl3),δ: 28.1, 28.6, 35.5, 43.3, 67.0, 87.3, 114.0, 118.0, 120.3, 123.1, 128.6, 132.3, 133.8, 143.6, 148.1, 168.4.

化合物9b的合成: 取3.51 g(10 mmol)化合物8b及32.3 g(0.53 mol)乙醇胺, 室溫下反應9 h后, 傾入冰水中, 二氯甲烷萃取, 再將有機層依次用水和飽和食鹽水洗滌3次, 干燥, 脫溶得淡黃色固體9b 1.64 g, 收率79.4%, m.p. 81～83 ℃.1H NMR(400 MHz, CDCl3),δ: 1.49(s, 6H, 2×CH3), 1.93～1.98(m, 2H, CCH2C), 2.93(t,J=6.0 Hz, 2H, CH2N), 3.01(s, 2H, CH2), 4.14(t,J=6.0 Hz, 2H, OCH2), 6.68～6.75(m, 3H, C6H3);13C NMR(100 MHz, CDCl3),δ: 28.4, 32.7 39.2, 43.4, 67.2, 87.3, 113.2, 117.8, 120.3, 128.43, 143.7, 147.8.

1.2.5目標化合物5a～5h的合成將中間體9(0.48 mmol)、0.053 g(0.53 mmol)三乙胺和催化量4-二甲基氨基吡啶(DMAP)混合, 加入20 mL 二氯甲烷, 攪拌, 滴加溶有化合物3(0.576 mmol)的二氯甲烷溶液, 在室溫下反應2～3 h, 有機層依次用水和飽和食鹽水洗滌, 干燥, 脫溶, 經柱層析[V(石油醚)∶V(乙酸乙酯)=7∶1]得固體化合物5a～5h.

目標化合物4和5的理化數據列于表1. 核磁共振數據列于表2.

Table 1　　　　Reaction time, appearance, yields, melting points, optical rotations and HRMS data for compounds 4 and 5

Table 2　 1H NMR and 13C NMR data for compounds 4 and 5

Continued

Compd.1HNMR(CDCl3),δ*13CNMR(100MHz,CDCl3),δ4e1.55(s,6H,2×CH3),1.64(d,J=6.5Hz,3H,CH3),3.08(s,2H,CH2),3.91(s,3H,OCH3),4.63—4.68(m,1H,CH),4.73—4.78(m,2H,COCH2),6.98(d,J=8.5Hz,1H,C5H3N),7.03(d,J=9.0Hz,2H,C6H4),7.09(d,J=9.0Hz,2H,C6H4),7.41(s,1H,C6H2),7.45(s1H,C6H2),7.60(t,J=4.0Hz,1H,NH),7.87(dd,J1=8.5Hz,J2=2.5Hz,1H,C5H3N),8.42(d,J=2.5Hz,1H,C5H3N)18.7,28.4,42.7,45.5,56.1,75.8,90.1,110.9,111.5,116.7,118.9,122.7,123.1,127.8,128.2,136.7,144.9,145.3,147.6,150.8,152.9,154.7,166.5,172.4,191.84f1.46(t,J=7.0Hz,3H,CH2CH3),1.55(s,6H,2×CH3),1.65(d,J=6.5Hz,3H,CH3),3.07(s,2H,CH2),4.13(q,J=7.0Hz,2H,OCH2),4.63—4.67(m,1H,CH),4.73—4.77(m,2H,COCH2),6.98—7.00(m,1H,C5H3N),6.98(d,J=8.5Hz,1H,C5H3N),7.03(d,J=9.0Hz,2H,C6H4),7.09(d,J=9.0Hz,2H,C6H4),7.41(s,1H,C6H2),7.44(s,1H,C6H2),7.60(t,J=4.0Hz,1H,NH),7.87—7.90(m,1H,C5H3N),8.42(d,J=3.5Hz,1H,C5H3N)14.7,18.8,28.1,42.7,45.5,64.675.8,90.1,111.3,112.5,116.9,118.9,121.4,122.4,122.6,127.7,128.7,136.7,144.0,145.4,147.7,153.1,154.7,165.9,172.4,191.74g1.53(s,6H,2×CH3),1.62(d,J=6.5Hz,3H,CHCH3),3.07(s,2H,CH2),3.90(s,3H,OCH3),4.60—4.65(m,1H,CH),4.71—4.77(m,2H,COCH2),7.00(d,J=9.5Hz,2H,C6H4),7.09(d,J=9.5Hz,2H,C6H4),7.40(s,1H,C6H2),7.44(s,1H,C6H2),7.47(dd,J1=9.0Hz,J2=2.5Hz,1H,C5H2N),7.59(t,J=4.0Hz,1H,NH),7.84(d,J=2.5Hz,1H,C5H2N)18.8,28.1,42.4,45.5,56.1,75.8,89.8,110.8,116.7,118.9,122.5,124.9,125.1,127.8,128.2,140.2,144.7,145.7,147.4,148.3,152.9,154.5,172.3,191.84h1.44(t,J=6.8Hz,3H,CH2CH3),1.53(s,6H,2×CH3),1.62(d,J=6.4Hz,3H,CH3),3.05(s,2H,CH2),4.13(q,J=6.8Hz,2H,OCH2),4.59—4.67(m,1H,CH),4.71—4.77(m,2H,COCH2),7.00(d,J=9.2Hz,2H,C6H4),7.09(d,J=9.2Hz,2H,C6H4),7.40(s,1H,C6H2),7.42(s,1H,C6H26-H),7.47(dd,J1=9.2Hz,J2=2.0Hz,1H,C5H3N),7.61(t,J=4.0Hz,1H,NH),8.42(d,J=2.0Hz,1H,C5H3N)14.7,19.1,28.1,42.7,45.5,64.6,75.8,89.9,112.3,116.7,118.7,122.4,124.9,125.2,127.7,128.5,140.3,144.0,147.4,148.4,151.4,153.2,154.5,172.3,191.74i1.41(t,J=7.5Hz,3H,CH2CH3),1.55(s,6H,2×CH3),1.65(d,J=6.5Hz,3H,CH3),1.82—1.89(m,2H,CH2),3.07(s,2H,ArCH2),4.04(t,J=7.0Hz,2H,OCH2),4.65—4.69(m,1H,CH),4.74—4.79(m,2H,COCH2),6.98(d,J=6.0Hz,1H,C5H3N,6-H),7.04(d,J=8.5Hz,2H,C6H4),7.10(d,J=8.5Hz,2H,C6H4),7.42(s,1H,C6H2),7.45(s,1H,C6H2),7.69(s,1H,NH),7.89(d,J=8.5Hz,1H,C5H3N),8.43(d,J=8.5Hz,1H,C5H3N)10.5,18.5,22.2,28.4,42.4,45.2,70.8,75.6,89.9,105.8,112.6,117.0117.5,118.7,120.1,120.6,121.2,127.5128.2,129.2,143.7,148.7,150.4,151.1,153.3,154.2,171.9,191.75a1.49(s,3H,CH3),1.50(s,3H,CH3),1.58(d,J=6.8Hz,3H,CH3),3.02(s,2H,CH2),3.66—3.72(m,2H,NHCH2),4.08—4.15(m,2H,OCH2),4.66(q,J=6.8Hz,1H,CH),6.69—6.81(m,3H,C6H3),6.94(d,J=8.8Hz,2H,C6H4),7.05(d,J=8.8Hz,2H,C6H4),7.50(dd,J1=8.8Hz,J2=2.0Hz,1H,C5H2N),7.86(d,J=2.0Hz,1H,C5H2N)18.6,28.3,38.9,43.2,68.4,75.8,87.6,114.4,116.6,118.4,120.6,122.2,124.7,125.0,128.7,140.1,143.0,145.6,147.3,148.1,151.1,151.3,172.25b1.48(s,3H,CH3),1.50(s,3H,CH3),1.59(d,J=6.8Hz,3H,CH3),3.02(s,2H,CH2),3.68—3.72(m,2H,NHCH2),4.09—4.15(m,2H,OCH2),4.65—4.70(m,1H,CH),6.71—6.81(m,3H,C6H3),6.89—6.98(m,3H,C6H4,C5H3N),7.04(d,J=8.8Hz,2H,C6H4),7.87(dd,J1=8.8Hz,J2=2.0Hz,1H,C5H2N),8.42(s,1H,C5H2N)18.3,27.7,38.0,42.6,67.9,75.287.0,113.8,116.1,118.0,120.0,121.9,124.4,124.6,128.2,139.5,142.4,145.1,146.7,147.5,147.8,150.6,153.8,171.75c1.49(s,3H,CH3),1.50(s,3H,CH3),1.59(d,J=6.8Hz,3H),3.03(s,2H,CH2),3.65—3.72(m,2H,NHCH2),4.07—4.14(m,2H,OCH2),4.68(q,J=6.8Hz,1H,CH),6.68—6.81(m,3H,C6H3),6.96(d,J=8.8Hz,2H,C6H4),7.05(d,J=8.8Hz,2H,C6H4),7.97(s,1H,C5H2N),8.24(s,1H,C5H2N)18,8,28.1,36.2,43.0,55.7,74.7,88.3,110.1,116.3,116.6,122.5,123.1,124.9,125.3,127.2,128.0,139.8,144.4,146.6,148.2,148.7,154.5,156.0,171.8

Continued

Compd.1HNMR(CDCl3),δ*13CNMR(100MHz,CDCl3),δ5d1.48(s,3H,CH3),1.50(s,3H,CH3),1.61(d,J=6.4Hz,3H,CH3),3.01(s,2H,CH2),3.68—3.72(m,2H,NHCH2),4.10—4.15(m,2H,OCH2),4.67—4.73(m,1H,CH),6.71—6.80(m,3H,C6H3),6.98(d,J=9.2Hz,2H,C6H4),7.15(d,J=9.2Hz,3H,C6H4),7.59(dd,J1=8.8Hz,J2=2.0Hz,1H,quinoxalin-H),7.67(d,J=8.8Hz,1H,quinoxalin-H),8.04(d,J=2.0Hz,1H,quinoxalin-H),8.67(s,1H,quinoxalin-H)19.0.28.0,34.2,43.2,61.2,75.6,87.7,112.7,114.6,116.9,118.7,119.5,120.9,121.0,122.0,122.6,127.9,128.8,130.2,131.1,140.1,144.7,145.7,151.9,157.1,170.05e1.49(s,3H,CH3),1.50(s,3H,CH3),1.58(d,J=6.8Hz,3H,CH3),1.93—2.02(m,2H,CCH2C),3.02(s,2H,CH2),3.48—3.53(m,2H,NHCH2),3.99—4.09(m,2H,OCH2),4.65(q,J=6.8Hz,1H,CH),6.67—6.79(m,3H,C6H3),6.90(d,J=8.8Hz,2H,C6H4),7.06(d,J=8.8Hz,2H,C6H4),7.50(dd,J1=9.2Hz,J2=2.4Hz,1H,C5H2N),7.85(d,J=2.4Hz,1H,C5H2N)13.7,23.0,23.7,31.5,38.0,62.0,70.4,82.1,108.2,111.0,111.8,112.8,115.0,117.2,119.6,119.8,123.3,134.9,138.1,141.8,142.6,143.0,149.1,160.35f1.49(s,3H,CH3),1.50(s,3H,CH3),1.59(d,J=6.8Hz,3H,CH3),1.95—2.04(m,2H,CCH2C),3.02(s,2H,CH2,CH2),3.48—3.53(m,2H,NHCH2),4.00—4.10(m,2H,OCH2),4.63—4.68(m,1H,CH),6.68—6.79(m,3H,C6H3),6.92(d,J=8.4Hz,2H,C6H4),6.99(d,J=8.8Hz,1H,C5H3N),7.05(d,J=8.4Hz,2H,C6H4),7.88(dd,J1=8.8Hz,J2=2.0Hz,1H,C5H3N),8.42(s,1H,C5H3N)18.8,28.2,28.8,35.0,43.4,65.4,73.1,87.3,113.2,115.9,117.8,119.1,120.3,122.7,128.5,133.0,136.3,142.6,143.5,146.8,147.8,149.2,155.3,161.4,172.15g1.49(s,3H,CH3),1.50(s,3H,CH3),1.59(s,J=6.8Hz,3H,CH3),1.94—2.04(m,2H,CCH2C),3.02(s,2H,CH2),3.48—3.53(m,2H,NHCH2),4.00—4.09(m,2H,OCH2),4.65—4.69(m,1H,CH),6.67—6.79(m,3H,C6H3),6.93(d,J=8.8Hz,2H,C6H4),7.06(d,J=8.8Hz,2H,C6H4),7.97(d,J=2.0Hz,1H,C5H2N),8.24(s,1H,C5H2N)19.0,28.3,29.8,36.8,43.4,67.4,75.7,87.5,113.6,116.4,118.1,119.2,120.4,122.8,128.7,136.2,136.3,142.6,142.7,143.4,147.0,147.9,154.8,161.3,172.25h1.49(s,3H,CH3),1.51(s,3H,CH3),1.61(d,J=6.8Hz,3H,CH3),1.97—2.04(m,2H,CCH2C),3.02(s,2H,CH2),3.50—3.55(m,2H,NHCH2),4.03—4.10(m,2H,OCH2),4.66—4.71(m,1H,CH),6.68—6.78(m,3H,C6H3),6.95(d,J=8.8Hz,2H,C6H4),7.17(d,J=8.8Hz,2H,C6H4),7.59(d,J1=8.8Hz,J2=2.0Hz,1H,quinoxa-lin-H),7.67(d,J=8.8Hz,1H,quinoxalin-H),8.06(s,1H,quinoxa-lin-H),8.68(s,1H,quinoxalin-H)19.1,28.5,29.2,39.0,43.4,66.5,75.9,87.4,113.8,114.5,116.5,116.6118.1,120.4,121.2,122.6,127.9,128.8,129.4,131.2,140.2,143.4,146.9,151.0,154.5,158.3,172.2

*1H NMR for compounds 4b—4g and 4i were tested at 500 MHz, others were tested at 400 MHz.

1.3目標化合物的除草活性

采用盆栽法測試了化合物4和5的除草活性. 盆栽法(土壤處理): 在直徑8 cm的塑料小杯中放入一定量的土, 再加入一定量的水, 播種后覆蓋一定厚度的土壤, 置于花房中培養(yǎng), 幼苗出土前以塑料覆蓋. 每天加定量的清水以保持正常生長. 出苗前進行土壤處理, 處理劑量為1500 g/hm2, 30 d后調查結果, 測定地上部鮮重, 以鮮重抑制百分數來表示藥效[25]. 盆栽法(莖葉處理): 在直徑8 cm的塑料小杯中放入一定量的土, 再加入一定量的水, 播種15顆發(fā)芽的種子于泥土下0.5 cm深, 播種后覆蓋一定厚度的土壤, 于花房中培養(yǎng), 幼苗出土前以塑料覆蓋. 出苗后, 每天加定量的清水以保持正常生長. 當幼苗長到一定時期進行莖葉噴灑待測化合物的溶液, 處理劑量為1500 g/hm2, 30 d后調查結果, 測定地上部鮮重, 以鮮重抑制百分數來表示.

2　結果與討論

2.1中間體2的合成

中間體2的制備有Gabrie反應和Delépine反應兩類方法.

Gabrie合成法: 以DMF為溶劑, 將化合物1與鄰苯二甲酰亞胺鉀鹽反應, 得中間體, 再在無水乙醇溶液中用水合肼肼解, 擬得到中間體2, 但由于肼解是堿性條件, 得到的含有氨基和羰基的中間體2可發(fā)生自身縮合, 故得不到中間體2.Delépine合成法: 向烏洛托品中滴加溶有化合物1的三氯甲烷溶液, 于45 ℃下反應, 用TLC監(jiān)測反應. 將反應液過濾, 得到固體; 加入鹽酸在乙醇中回流, 得中間體2的鹽酸鹽, 其穩(wěn)定性較好.

2.2中間體9的合成

中間體9的制備可選擇水合肼或乙醇胺分別進行肼解或氨解2種方法進行(見Scheme 1). 肼解反應速度快, 但與乙醇胺水解法相比, 收率較低, 可能有2種原因: (1) 在肼解過程中生成鄰苯二甲酰肼的同時, 還可能生成另一種副產物, 即中間體胺與鄰苯二甲酰肼形成的鹽難以除去; (2) 肼解反應結束后, 冷卻析出白色絮狀鄰苯二甲酰肼, 在洗滌鄰苯二甲酰肼濾餅過程中, 仍有少量產物胺殘留于鄰苯二甲酰肼固體中.以乙醇胺氨解, 反應溫和, 收率較高且乙醇胺毒性小.

2.3目標化合物譜圖解析

化合物5a～5h的1H NMR譜中, 由于結構中存在雜環(huán)(吡啶和苯并呋喃)的空間位阻, 導致其亞甲基上2個氫原子的化學環(huán)境有所差異, 出現同碳耦合, 亞甲基裂分為多重峰. 以化合物5e為例,δ1.93～2.02, 3.48～3.53和 3.99～4.09處有3種亞甲基均裂分為多重峰.

2.4除草活性評價

以噁唑酰草胺(Metamifop)為陽性對照, 對化合物4和5進行了除草活性篩選, 結果列于表3.

Table 3　Herbicidal activities(%) of compounds 4 and 5(1500 g/hm2)

除草普篩結果表明, 在1500 g/hm2劑量下, 目標化合物4對單子葉雜草(馬唐和稗草)具有更高的抑制活性, 其中, 化合物4a, 4b和4i對馬唐和稗草的莖葉和土壤處理均表現為100%抑制活性, 與對照藥噁唑酰草胺(100%)相當; 對雙子葉油菜和莧菜防治效果一般, 僅化合物4a對莧菜的莖葉處理抑制率為64.2%. 化合物5在1500 g/hm2劑量下, 對單子葉雜草馬唐和稗草具有較強的莖葉和土壤處理防除效果, 且土壤處理活性略優(yōu)于莖葉處理效果, 如化合物5a, 5e和5h對馬唐和稗草的抑制活性(土壤和莖葉處理)與對照藥劑噁唑酰草胺(Metamifop)的抑制活性相當. 當Ar為3-氟-5-氯吡啶或喹喔啉時, 對馬唐和稗草的抑制活性優(yōu)于3-氯-5-三氟甲基吡啶基和5-三氟甲基吡啶基, 如化合物5e和5h對馬唐的土壤和莖葉處理抑制活性為100%, 而化合物5f在相同劑量下對馬唐的土壤和莖葉處理抑制活性分別為77.0%和65.4%; 當側鏈橋長n=3時, 對馬唐和稗草的莖葉處理抑制活性略優(yōu)于n=2時, 如化合物5a和5g;n=2時, 對馬唐和稗草的土壤處理優(yōu)于n=3時, 如化合物5b和5f.

選擇普篩活性最好的5個化合物進行初篩, 結果列于表4. 由表4可見, 在施藥劑量為375 g/hm2時, 化合物4a, 4b, 4i, 5e和5h對稗草的防效較好, 莖葉處理的抑制率>96%.

Table 4　Herbicidal activities(%) of compounds 4a, 4b, 4i, 5e and 5h

2.5構效關系

生物活性數據表明, 化合物結構對除草活性有一定影響, Ar基團的影響較大, 當Ar為3-氯-5-三氟甲基吡啶和3-氟-5-氯吡啶基時, 化合物4中部分化合物的活性優(yōu)于5-三氟甲基吡啶基和4-氰基-2-氟苯基. 但其呋喃酚環(huán)的R基團的影響不大; 對于化合物5, Ar為吡啶環(huán)和喹喔啉時, 活性明顯優(yōu)于苯環(huán); 對于化合物5的吡啶環(huán), Ar為3-氟-5-氯吡啶時, 活性優(yōu)于3-氯-5-三氟甲基吡啶和5-三氟甲基吡啶基. 總體上, Ar基團對活性影響大小順序為吡啶/喹喔啉>苯. 化合物5的橋長n對活性也有影響, 丙酰胺側鏈對活性影響順序為土壤處理:n=2>n=3; 莖葉處理:n=3>n=2.

綜上所述， 基于呋喃酚, 設計合成2個系列共17個2-(4-芳氧苯氧基)丙酰胺衍生物, 其結構經1H NMR,13C NMR, HRMS和旋光度確認. 除草活性測試結果表明, 在1500 g/hm2劑量下, 化合物4和5對單子葉雜草馬唐和稗草均有較高的抑制活性. 其中, 化合物4a, 4b和4i對馬唐和稗草的莖葉和土壤處理均表現為100%的抑制活性; 化合物5a～5h對馬唐和稗草有較好防效, 其中, 化合物5a, 5c, 5e和5h為A級活性, 對馬唐和稗草的抑制率為100%. 初篩結果表明, 375 g/hm2劑量下, 化合物4a, 4b, 4i, 5e和5h對稗草的莖葉處理抑制率>96%.

感謝南開大學元素有機化學研究所李永紅老師在除草活性方面提供的幫助.

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Synthesis and Herbicidal Activity of 2-(4-Arylxoyphenoxy)propionamide Derivatived from Benzofuranol?

YANG Zihui, LI Beibei, YE Jiao, HU Aixi*

(CollegeofChemistryandChemicalEngineering,HunanUniversity,Changsha410082,China)

2-(4-Aryloxyphenoxy) propionamide derivatives were identified as one of the most important herbicides, which inhibited acetyl-CoA carboxylase(ACCase) to restrict fatty acid. Recent years, 2-(4-aryloxyphenoxy) propionamide derivative have developed resistance in varying degrees among weeds. Therefore, resear-ching novel 2-(4-aryloxyphenoxy) propionamide derivatives herbicide is of great importance. Seventeen of 2-(4-aryloxyphenoxy) propionamide derivatives were synthesized by multistep synthetic procedures with two key intermediates 2 and 9, starting from(R)-(+)2-(4-hydroxyphenoxy) propanoic acid and benzofuranol. The intermediate 9 was synthesized fromo-phthalic anhydride and 2-aminoethanolviasubstitution reaction, bromination, etherification and amination. The synthetic reaction condition of intermediates 9 was discussed. The structures of target compounds 4 and 5 were confirmed by1H NMR,13C NMR, HRMS and optical rotation. The bioassay results indicated that most of title compounds possessed a moderate herbicidal activity againstcrabgrassandbarnyardgrassat 1500 g/hm2. The compounds 4a, 4b, 4i, 5e and 5h showed more than 96% activities against thecrabgrassandbarnyardgrassat 375 g/hm2.

? Supported by the National “Twelfth Five-Year” Plan for Science and Technology Support of China(No.2011BAE06B01).

2-(4-Aryloxyphenoxy) propionamide; Benzofuranol; Herbicidal activity

2016-05-12. 網絡出版日期: 2016-07-19.

“十二五”國家科技支撐計劃項目(批準號: 2011BAE06B01)資助.

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聯系人簡介: 胡艾希, 男, 博士, 教授, 博士生導師, 主要從事藥物化學研究. E-mail: axhu@hnu.edu.cn