吳小盛, 湯 君, 陳樸青, 王 濤*, 羅 勁,*
(1.江西師范大學(xué) a. 化學(xué)化工學(xué)院 江西省化學(xué)生物學(xué)重點(diǎn)實驗室; b. 分析測試中心,江西 南昌 330022)
·研究論文·
新型含氟1,2,4-三唑[3,4-b]-1,3,4-噻二唑衍生物的合成及其除草活性
吳小盛1a, 湯 君1a, 陳樸青1b, 王 濤1a*, 羅 勁1a,1b*
(1.江西師范大學(xué) a. 化學(xué)化工學(xué)院 江西省化學(xué)生物學(xué)重點(diǎn)實驗室; b. 分析測試中心,江西 南昌 330022)
以對氟苯甲酰肼為初始原料,經(jīng)成鹽、環(huán)化和一鍋法反應(yīng)制得中間體5-對氟苯基-2,4-二氫-1,2,4-三唑-3-硫酮磷亞胺(4); 4與芳基異氰酸酯發(fā)生氮雜Wittig反應(yīng),后經(jīng)成環(huán)反應(yīng)合成了11個新型的含氟6-芳氨基-1,2,4-三唑[3,4-b]-1,3,4-噻二唑衍生物(6a~6k),其結(jié)構(gòu)經(jīng)1H NMR,13C NMR, IR和HR-MS表征。對單、雙子葉植物的除草活性測試結(jié)果表明:濃度為100 mg·L-1時,6c和6f對稗草和蘿卜的莖和根的生長表現(xiàn)出優(yōu)異的抑制活性,抑制率高達(dá)100%。
氮雜Wittig反應(yīng); 1,2,4-三唑[3,4-b]-1,3,4-噻二唑; 合成; 除草活性
1,2,4-三唑[3,4-b]-1,3,4-噻二唑類衍生物自1956年首次被Kanaoka[1]合成以來,因其具有抗真菌[2]、抗炎[3]、抗病毒[4-5]、鎮(zhèn)痛劑[6]、殺蟲[7]、殺菌[8]、抗結(jié)核[9-10]、抗氧化[11]、降壓[12]、膽堿酯酶抑制劑[13]和抗腫瘤[14-15]等生物活性和藥理活性,在過去幾十年中引起了科學(xué)家廣泛的興趣。從文獻(xiàn)報道來看,此類衍生物有關(guān)農(nóng)藥學(xué)的報道相對較少,其除草活性有待進(jìn)一步研究。
Scheme 1
氟原子是一種非常獨(dú)特的元素,它不僅電負(fù)性強(qiáng),而且具有很好的熱穩(wěn)定性和親油性。因此將氟原子引入有機(jī)小分子中可以提高其物理化學(xué)性質(zhì)以及生物活性[16],如含氟雜環(huán)化合物往往具有較好的除草[17]、殺菌[18]和殺蟲[19]活性。為了進(jìn)一步研究含氟雜環(huán)化合物在農(nóng)藥上的除草活性,本文以對氟苯甲酰肼(1)為初始原料,經(jīng)成鹽、環(huán)化和一鍋法反應(yīng)制得中間體5-對氟苯基-2,4-二氫-1,2,4-三唑-3-硫酮磷亞胺(4); 4與芳基異氰酸酯經(jīng)氮雜Wittig反應(yīng),后經(jīng)成環(huán)反應(yīng)合成了11個新型的含氟6-芳氨基-1,2,4-三唑[3,4-b]-1,3,4-噻二唑(6a~6k, Scheme 1),其結(jié)構(gòu)經(jīng)1H NMR,13C NMR, IR和HR-MS確證。對單、雙子葉植物的除草活性測試結(jié)果表明:用藥量為100 mg·L-1時,6c和6f對稗草和蘿卜的莖和根的生長表現(xiàn)優(yōu)異的抑制活性,抑制率高達(dá)100%。
1.1 儀器與試劑
XT-4型熔點(diǎn)儀; AVANCE 400型核磁共振儀(DMSO-d6為溶劑, TMS為內(nèi)標(biāo)); Nicolet 6700型傅里葉紅外光譜儀(KBr壓片); FinniganMAT8430型質(zhì)譜儀。
1[20]、中間體對氟苯甲酰肼基二硫代甲酸鹽(2)[21]和4-氨基-5-對氟苯基-2,4-二氫-1,2,4-三唑-3-硫酮(3)[21]參照文獻(xiàn)方法合成;其余所用試劑均為分析純,其中乙醇、三乙胺和二氯甲烷按標(biāo)準(zhǔn)方法除水。
1.2 合成
(1) 4的合成
在三口燒瓶中依次加入3 0.84 g(4 mmol), PPh31.57 g (6 mmol), C2Cl61.42 g(6 mmol)和CH2Cl220 mL,冷卻至0 ℃,緩慢滴加Et3N 1.21 g (12 mmol),滴畢,于室溫反應(yīng)10 h。過濾,濾液蒸除溶劑得粗品,粗品經(jīng)混合溶劑(CH2Cl2/石油醚=1/6,V/V)重結(jié)晶得白色固體4 1.53 g, 收率81%, m.p.201~203 ℃;1H NMRδ: 12.62(s, 1H, NH), 7.79~6.94(m, 19H, ArH)。
(2) 6的合成通法
氮?dú)獗Wo(hù)下,向燒瓶中依次加入4 4.0 mmol和CH2Cl240 mL,待固體溶解后,快速加入取代苯基異氰酸酯4.6 mmol,加畢,待4反應(yīng)完全(TLC檢測)。抽濾,濾餅用(3×100 mL)工業(yè)酒精洗滌,經(jīng)混合溶劑(DMSO/EtOH=1/8,V/V)重結(jié)晶得化合物6。
6a: 淡黃色固體,收率74%, m.p.>300 ℃;1H NMRδ: 10.81(s, 1H, NH), 8.29~8.26(m, 2H, ArH), 7.61~7.59(d,J=7.6 Hz, 2H, ArH), 7.50~7.43(t,J=8.8 Hz, 4H, ArH), 7.16~7.12(t,J=7.6 Hz, 1H, ArH);13C NMRδ: 116.0(d,JCF=23.0 Hz), 120.3(d,JCF=8.0 Hz), 125.5, 129.1, 129.8, 135.5, 144.8, 150.3, 156.9(d,JCF=238.0 Hz), 160.9, 162.5; IRν: 3 410(NH), 3 016, 1 608, 1 237(N—N=C), 689(C—S—C) cm-1;HR-MS(ESI)m/z: Calcd for C15H10N5SF{[M+H]+} 312.064 1, found 312.063 8。
6b: 黃色固體,收率68%, m.p.279~281 ℃;1H NMRδ: 10.78(s, 1H, NH), 8.29~8.26 (m, 2H, ArH), 7.49~7.45(t,J=8.8 Hz, 2H, ArH), 7.40~7.38(d,J=8.8 Hz, 1H, ArH), 7.34~7.30(t,J=7.6 Hz, 1H, ArH), 6.96~6.94(d,J=7.2 Hz, 1H, ArH), 2.36(s, 3H, CH3);13C NMRδ: 17.83, 115.5, 116.2(d,JCF=23.0 Hz), 119.0, 122.7, 124.1, 127.9(d,JCF=9.0 Hz), 129.2, 138.7, 139.0, 144.0, 150.3, 160.9, 162.8(d,JCF=246.0 Hz); IRν: 3 432(NH), 3 012, 1 577, 1 231(N—N=C), 688(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C16H12N5SF{[M+H]+} 326.079 7, found 326.079 2。
6c: 黃色固體,收率70%, m.p.>300 ℃;1H NMRδ: 11.35(s, 1H, NH), 8.18(s, 1H, ArH), 7.95(s, 1H, ArH), 7.63~7.60(d,J=6.8 Hz, 2H, ArH), 7.42~7.40(d,J=8.0 Hz, 2H, ArH);13C NMRδ: 116.0(d,JCF=23.0 Hz), 119.2, 125.7, 126.3, 126.6, 127.8(d,JCF=9.0 Hz), 129.2, 131.2, 134.4, 151.1, 152.8, 162.5(d,JCF=245.0 Hz), 164.5; IRν: 3 419(NH), 3 031, 1 580, 1 230(N—N =C), 684(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C15H8N5SFCl2{[M+H]+} 379.986 1, found 379.985 5。
6d: 黃色固體,收率75%, m.p.>300 ℃;1H NMRδ: 10.94(s, 1H, NH), 8.26~8.22(d,J=8.8 Hz, 2H, ArH), 7.63~7.61(d,J=8.0 Hz, 2H, ArH), 7.51~7.44(m, 4H, ArH);13C NMRδ: 116.2(d,JCF=22.0 Hz), 120.0, 122.5, 126.8, 128.0(d,JCF=8.0 Hz), 129.3, 138.1, 144.1, 150.3, 152.7, 161.8(d,JCF=228.0 Hz), 163.9; IRν: 3 433(NH), 3 044, 1 579, 1 236(N—N=C), 678(C—S—C) cm-1;HR-MS(ESI)m/z: Calcd for C15H9N5SFCl{[M+H]+} 346.025 1, found 346.024 8。
6e: 黃色固體,收率68%, m.p.>300 ℃;1H NMRδ: 11.26(s, 1H, NH), 8.22(s, 1H, ArH), 7.93(s, 1H, ArH), 7.65~7.63(d,J=6.8 Hz, 2H, ArH), 7.45~7.43(d,J=8.0 Hz, 2H, ArH);13C NMRδ: 116.1(d,JCF=22.0 Hz), 116.2, 118.3, 119.5, 122.5, 124.6, 127.8(d,JCF=8.0 Hz), 129.0, 131.1, 131.4, 138.9, 144.1, 150.2, 160.4, 163.1(d,JCF=181.0 Hz); IRν: 3 419(NH), 3 027, 1 583, 1 229(N—N=C), 682(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C15H8N5SFCl2{[M+H]+} 379.986 1, found 379.985 5。
“簡單來說,就是一個前體mRNA分子可以經(jīng)過不同的加工方式,形成不同的成熟mRNA產(chǎn)物?!痹撜撐牡谝蛔髡摺⒅袊r(nóng)業(yè)大學(xué)玉米改良中心陳秋月博士解釋,這就像用剪刀去剪繩子,再把剪下來的繩段重新打結(jié)一樣,剪哪里、剪幾刀、留下哪些繩段、以什么順序打結(jié),這些都會產(chǎn)生不同的新繩。
6f: 淡黃色固體,收率62%, m.p.>300 ℃;1H NMRδ: 10.86(s, 1H, NH), 8.28~8.27(d,J=5.6 Hz, 2H, ArH), 7.51~7.43(m, 4H, ArH), 7.25~7.20(m, 2H, ArH), 2.31(s, 3H, CH3);13C NMRδ: 21.2, 115.5, 116.2(d,JCF=20.0 Hz), 118.9, 122.7, 124.1, 127.9(d,JCF=9.0 Hz), 129.2, 138.7, 139.0, 144.0, 150.3, 160.9, 162.8(d,JCF=246.0 Hz); IRν: 3 418(NH), 3 009, 1 570, 1 236(N—N=C), 678(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C16H12N5SF{[M+H]+} 326.079 7, found 326.079 3。
6g: 黃色固體,收率66%, m.p.274~275 ℃;1H NMRδ: 10.04(s, 1H, NH), 8.22~8.19(m,J=5.6 Hz, 2H, ArH), 7.79~7.77(d,J=7.6 Hz, 1H, ArH), 7.45~7.40(t,J=8.8 Hz, 2H, ArH), 7.33~7.29(t,J=7.2 Hz, 2H, ArH), 7.17~7.16(t,J=6.8 Hz, 1H, ArH), 2.32(s, 3H, CH3);13C NMRδ: 18.52, 116.1(d,JCF=22.0 Hz), 116.2, 122.6(d,JCF=4.0 Hz), 122.9, 125.6, 126.9, 127.8(d,JCF=8.0 Hz), 130.8, 131.0, 137.0, 143.8, 150.7, 162.5(d,JCF=198.0 Hz), 164.0; IRν: 3 428(NH), 3 034, 1 565, 1 238(N—N=C), 682(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C16H12N5SF{[M+H]+} 326.079 7, found 326.079 3。
6h: 黃色固體,收率60%, m.p.297~298 ℃;1H NMRδ: 10.61(s, 1H, NH), 8.28~8.24(m,J=5.6 Hz, 4H, ArH), 7.51~7.43(m, 4H, ArH), 7.01~6.99(d,J=8.8 Hz, 2H, ArH), 4.04~4.02(m, 2H, OCH2CH3), 1.35~1.32(m, 3H, OCH2CH3);13C NMRδ: 14.6, 63.2, 115.1, 116.2(d,JCF=22.0 Hz), 120.4, 122.6(d,JCF=4.0 Hz), 127.9(d,JCF=9.0 Hz), 132.1, 144.0, 150.2, 154.8, 161.3, 162.8(d,JCF=246.0 Hz); IRν: 3 441(NH), 3 036, 1 234(N—N=C), 678(C—S—C) cm-1;HR-MS(ESI)m/z: Calcd for C17H14N5OSF{[M+H]+} 356.098 1, found 356. 097 7。
6i: 淡黃色固體,收率65%, m.p.>300 ℃;1H NMRδ: 10.65(s, 1H, NH), 8.41(s, 1H, ArH), 8.28~8.27(d,J=5.2 Hz, 2H, ArH), 7.63~7.44(m, 2H, ArH), 7.35~7.32(d,J=8.8 Hz, 2H, ArH), 7.04~7.01(d,J=8.8 Hz, 1H, ArH), 6.86~6.84(d,J=8.8 Hz, 2H, ArH), 3.71(s, 3H, OCH3);13C NMRδ: 115.3, 116.3(d,JCF=23.0 Hz), 120.4, 122.6(d,JCF=4.0 Hz), 127.5(d,JCF=9.0 Hz), 132.1, 143.8, 150.4, 154.9, 161.5, 162.8(d,JCF=246.0 Hz); IRν: 3 440(NH), 3 029, 1 583, 1 230(N—N=C), 679(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C16H12N5OSF{[M+H]+} 342.074 7, found 342.075 4。
6j: 黃色固體,收率75%, m.p.>300 ℃;1H NMRδ: 11.08(s, 1H, NH), 8.22(s, 2H, ArH), 7.93(s, 1H, ArH), 7.59~7.40(d,J=6.8Hz, 2H, ArH), 7.30~6.89(m, 3H, ArH);13C NMRδ: 111.5, 116.1(d,JCF=22.0 Hz), 119.7, 123.5, 125.3, 127.8(d,JCF=9.0 Hz), 129.0, 137.3, 140.5, 144.7, 150.4, 161.4, 162.9(d,JCF=245.0 Hz); IRν: 3 428(NH), 3 031, 1 580, 1 239(N—N=C), 694(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C15H9N6O2SF{[M+H]+} 357.049 2, found 357.048 8。
6k: 淡黃色固體,收率72%, m.p.278~279 ℃;1H NMRδ: 11.28(s, 1H, NH), 8.28~8.25(t,J=6.4 Hz, 1H, ArH), 7.68~7.65(t,J=6.4 Hz, 2H, ArH), 7.49~7.45(t,J=8.8 Hz, 2H, ArH), 7.37~7.27(m, 3H, ArH);13C NMRδ: 116.0(d,JCF=22.0 Hz), 116.4(d,JCF=22.0 Hz), 119.9, 121.5(d,JCF=9.0 Hz), 126.8, 127.9(d,JCF=8.0 Hz), 138.2, 144.2, 150.4, 152.4, 157.4(d,JCF=218.0 Hz), 161.7(d,JCF=245 Hz); IRν: 3 437(NH), 3 018, 1 567, 1 234(N—N=C), 687(C—S—C) cm-1; HR-MS(ESI)m/z: Calcd for C15H9N5SF2{[M+H]+} 330.054 7, found 330.055 2。
2.1 合成
4對水敏感,極容易吸水分解,需保存于干燥器中。芳基異氰酸酯也容易吸水變質(zhì),因此在合成6時,二氯甲烷等溶劑要除水干燥,且整個反應(yīng)需氮?dú)獗Wo(hù)。
由6的1H NMR可以看出,由于受不同取代基的影響,NH活潑氫的吸收峰位于δ10.04~11.28,均為單寬峰,苯環(huán)上的氫吸收峰位于δ7.12~8.26,δ2.32處的單峰為苯環(huán)相連的甲基吸收峰,δ3.71處的單峰是甲氧基的吸收峰,乙氧基中的亞甲基的吸收峰在δ4.02~4.04,其甲基吸收峰在δ1.32~1.35;由6的IR圖譜可見,N—H的吸收峰在3 436 cm-1處,N=N—C的振動吸收峰在1 228 cm-1處,C—S—C的振動吸收峰在680 cm-1處;HR-MS測試分子量和理論分子量誤差也很小(<0.000 7)。
2.3 除草活性
供試植物為稗草(代表單子葉植物)和蘿卜(代表雙子葉植物),依據(jù)文獻(xiàn)[22]方法測試了6在濃度為10 mg·L-1和100 mg·L-1時對它們的莖長和根長的抑制率,其結(jié)果見表1。表1中的測試數(shù)據(jù)結(jié)果表明:當(dāng)濃度為100 mg·L-1時,當(dāng)濃度為100 mg·L-1時,6a~6k對稗草的莖和根的抑制率非常優(yōu)異,有9個達(dá)到A級,尤其是6c、 6e、 6f和6g抑制率均為100%。當(dāng)濃度為10 mg·L-1時,6a~6k對稗草的莖和根的抑制率都在C級以下,說明隨著濃度從100 mg·L-1降為10 mg·L-1,對稗草的莖和根的抑制率也大幅度降低。
表1 6對單、雙子葉植物(稗草、蘿卜)的抑制活性aTable 1 The inhibition percentage of 6 to barnyard grass and radish
a負(fù)抑制率表示促進(jìn)植物生長,活性標(biāo)準(zhǔn):A級:≥90%; B級:≥70%; C級:≥50%; D級:<50%。
6a~6k對蘿卜的莖和根的抑制率有9個達(dá)到A級,其中6a、 6c和6f抑制率達(dá)到了100%。當(dāng)濃度為10 mg·L-1時,對蘿卜的莖和根的抑制率只有2個C級,多數(shù)化合物如6a和6c為負(fù)值,說明具有一定的促進(jìn)作用,隨著濃度的降低對蘿卜的莖和根的抑制率也減小。
總之隨著濃度降低,6a~6k對稗草和蘿卜的莖和根的抑制率也下降。當(dāng)濃度為100 mg·L-1時,6c和6f對稗草和蘿卜的除草活性非常好,抑制率都是100%。隨著Ar基團(tuán)的變化,對稗草和蘿卜莖和根的抑制率并不是很有規(guī)律的變化,在隨后的工作中還需適當(dāng)引入更多的吸電子和供電子基團(tuán),進(jìn)一步研究其除草活性。
本文以對氟苯甲酰肼為初始原料,設(shè)計合成了11種新型的含氟6-芳氨基-1,2,4-三唑[3,4-b]-1,3,4-噻二唑(6a~6k)。對單、雙子葉植物的除草活性測試結(jié)果表明:濃度為100 mg·L-1時, 6c和6f對稗草、蘿卜的莖和根的抑制率非常優(yōu)異,均達(dá)到了100%。該研究結(jié)果為尋找合成含氟雜環(huán)化合物農(nóng)藥提供了一種較好的思路。
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Synthesis and Herbicidal Activities of Novel Fluorine-Containing 1,2,4-Triazolo[3,4-b]-1,3,4-thiadiazole Derivatives
WU Xiao-sheng1a, TANG Jun1a, CHEN Pu-qing1b, WANG Tao1a*, LUO Jin1a,1b*
(a. Jiangxi Province Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering;b. Analytical & Testing Center, 1. Jiangxi Normal University, Nanchang 330022, China)
5-(4-Fluorophenyl)-2,4-2H- 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole iminophosphorane (4) was prepared by salt forming, cyclization and one pot reaction, using benzoyl hydraziono as starting material. Eleven novel fluorine-containing 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives(6a~6k) were successfully synthesized by the aza-Wittig reaction with 4 with arylisocyanates, and then annulation reaction. The structures were characterized by1H NMR,13C NMR, IR and HR-MS. The results of preliminary bioassay demonstrated that 6c and 6f showed 100% inhibitory activities on barnyard grass and radish at the dosage of 100 mg·L-1.
aza-Wittig reaction; 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole; synthesis; herbicidal activity
2017-03-01
國家自然科學(xué)基金資助項目(21262018, 21562026); 江西省自然科學(xué)基金資助項目(20161BAB203085); 江西省自然科學(xué)青年基金資助項目(20161BAB213072)
吳小盛(1963-),男,漢族,江西撫州人,碩士研究生,主要從事新型雜環(huán)化合物的合成與除草活性的研究。 E-mail: 1340125160@qq.com
羅勁,實驗師, Tel. 0791-88122739, E-mail: jinluo@jxnu.edu.cn; 王濤,教授, E-mail: wangtao@jxnu.edu.cn
O626.2
A
10.15952/j.cnki.cjsc.1005-1511.2017.06.17041