馬 媛, 段文貴*, 林桂汕, 劉陸智, 黃正松, 雷福厚
(1.廣西大學 化學化工學院, 廣西 南寧 530004; 2.廣西林產(chǎn)化學與工程重點實驗室, 廣西 南寧 530008)
紫蘇醛基席夫堿-(硫)脲化合物的合成及生物活性
MA Yuan
馬 媛1, 段文貴1*, 林桂汕1, 劉陸智1, 黃正松1, 雷福厚2
(1.廣西大學 化學化工學院, 廣西 南寧 530004; 2.廣西林產(chǎn)化學與工程重點實驗室, 廣西 南寧 530008)
以紫蘇醛為原料,設計合成了13個未見文獻報道的紫蘇醛基席夫堿-(硫)脲化合物(5a~5m),通過FT-IR、1H NMR、13C NMR和ESI-MS對其結(jié)構(gòu)進行了分析和表征,并測試了目標化合物的抑菌和除草活性。生物活性測試表明,在質(zhì)量濃度50 mg/L下,目標化合物5f(R=p-FAr)對蘋果輪紋病菌的抑制率達90.0%(接近陽性對照嘧菌酯),化合物5d(R=Ar)對番茄早疫病菌的抑制率達91.8%(接近陽性對照嘧菌酯)。在質(zhì)量濃度100 mg/L下,目標化合物5c(R=環(huán)己基)、5i(R=p-CH3Ar)和5a(R=CH3)對油菜胚根生長的抑制率分別為77.6%、75.3%和67.4%(高于陽性對照丙炔氟草胺)??傮w上,取代苯基硫脲類目標化合物的抑菌和除草活性優(yōu)于取代苯基脲類目標化合物。
紫蘇醛;席夫堿-(硫)脲;合成;抑菌活性;除草活性
紫蘇醛又稱二氫枯茗醛(perillaldehyde,4-異丙烯基環(huán)己-1-烯-1-醛,C10H14O),是一種具有櫻桃、油脂和枯茗醛香氣的單萜類化合物,天然存在于紫蘇、蓮葉桐和香檸檬中[1],可用于調(diào)制茉莉、水仙等化妝品用花香型香精,也可用于調(diào)制檸檬、留蘭香及香辛料等食品用香型香精。紫蘇醛是一種天然香料,也是一種重要的有機合成中間體。然而由于其天然含量少,不能滿足市場需求,因此,主要來源于以α-蒎烯為原料的人工合成,即先將α-蒎烯經(jīng)烯丙位甲基氧化制備桃金娘烯醛,繼而催化四元環(huán)開環(huán)異構(gòu)得到紫蘇醛。由于紫蘇醛自身具有抗氧化、抗抑郁、抗炎、抑菌、抗癌和殺蟲等多種生物活性[2-7],因此在日化、醫(yī)藥和農(nóng)藥等行業(yè)有著廣泛的應用。此外,紫蘇醛衍生物也表現(xiàn)出抑菌、殺螨、驅(qū)蚊、除草和抗衰老等多種生物活性[8-12]。脲及硫脲類化合物表現(xiàn)出良好的抑菌[13-14]、抗癌[15]、除草[16-17]、殺蟲[18]、抗病毒[19]、抗氧化[20]、抗炎[21]和植物調(diào)節(jié)[22]等生物活性,近年來備受關(guān)注?;谝陨鲜聦嵑徒陙碚n題組對松香松節(jié)油基生物活性化合物的研究成果[14,16-18,23-26],本研究設計將席夫堿、(硫)脲基團引入到紫蘇醛骨架中,合成得到一系列新型的紫蘇醛基席夫堿-(硫)脲化合物,初步探索了合成條件,利用FT-IR、1H NMR、13C NMR和ESI-MS等多種分析方法對目標產(chǎn)物進行了結(jié)構(gòu)表征,并測試了目標產(chǎn)物的抑菌和除草活性,旨在為我國天然優(yōu)勢資源松節(jié)油的深度開發(fā)利用提供新途徑。
1.1 原料、試劑與儀器
紫蘇醛,湖南長沙凱美香精香料股份有限公司,使用前經(jīng)亞硫酸氫鈉法分離純化,質(zhì)量分數(shù)為95.6%;叔丁氧羰基肼和系列胺類均為市售分析純。
Nicolet iS50 FT-IR紅外光譜儀,美國Thermo Scientific公司;AVANCE Ⅲ HD 600 MHz超導核磁共振儀,瑞士Bruker公司;TSQ Quantum Access MAX液相色譜-質(zhì)譜聯(lián)用儀,美國Thermo Scientific公司;Agilent 6890氣相色譜儀,美國Agilent Technologies公司;海能MP420全自動熔點儀,濟南海能儀器股份有限公司。
1.2 合成路線
紫蘇醛基席夫堿-(硫)脲系列化合物的合成路線如下所示:
1.3 中間產(chǎn)物的合成
1.3.1 異硫氰酸酯/異氰酸酯的合成 參考文獻[27]合成系列異硫氰酸酯和異氰酸酯。
1.3.2 化合物(3)的合成 參考文獻[28]合成化合物3。將叔丁氧羰基肼2 (0.66 g,5.0 mmol)溶于25 mL乙腈中,室溫攪拌下通過恒壓滴液漏斗逐滴加入6.0 mmol異硫氰酸酯或異氰酸酯的乙腈稀釋液5 mL。硅膠薄層色譜(TLC)監(jiān)測反應進程,待叔丁氧羰基肼反應完全后停止反應,旋轉(zhuǎn)蒸發(fā)除去溶劑。以石油醚/乙酸乙酯(體積比1 ∶1)為洗脫劑,柱層析提純,得到白色固體3。
1.3.3 系列氨基硫脲和氨基脲類化合物(4)的合成 參考文獻[29]合成化合物4。將5 mmol化合物3溶于10 mL二氯甲烷中,室溫攪拌下,逐滴加入1 mL三氟乙酸(TFA)。硅膠薄層色譜(TLC)監(jiān)測反應進程,待原料反應完全后停止反應,旋蒸除去溶劑。向剩余物質(zhì)中加入適量乙酸乙酯,用飽和碳酸氫鈉溶液洗滌至pH值為7~8。旋轉(zhuǎn)蒸發(fā)除去乙酸乙酯,以石油醚/乙酸乙酯(體積比3 ∶1)為洗脫劑,柱層析提純,得到白色固體4a~4m。
1.4 目標化合物(5a~5m)的合成
將3.0 mmol化合物4溶于10 mL無水乙醇,加入裝有回流冷凝裝置的兩口瓶中,攪拌、加熱至回流。將3.6 mmol紫蘇醛1溶解于5 mL無水乙醇中,通過恒壓滴液漏斗滴加至反應體系中。用TLC監(jiān)測反應進程,待反應完全后,旋轉(zhuǎn)蒸發(fā)除去溶劑。以石油醚/乙酸乙酯(體積比20 ∶1)為洗脫劑,柱層析提純,得到目標產(chǎn)物5a~5m。
1.5 目標化合物的結(jié)構(gòu)表征
采用KBr壓片法測定目標化合物的FT-IR;以CDCl3為溶劑,在600 MHz 核磁共振儀上進行1H NMR和13C NMR分析;采用電噴霧電離源(ESI)在液相色譜-質(zhì)譜聯(lián)用儀(LC-MS)上進行質(zhì)譜分析。
1.6 目標化合物的生物活性測試
采用離體法(也稱瓊脂稀釋法)測試目標化合物的抑菌活性[23];采用油菜平皿法和稗草小杯法測試目標化合物的除草活性[24]。
2.1 目標產(chǎn)物5a~5m的表征
2.2 生物活性測試結(jié)果
2.2.1 抑菌活性 由表1可知,在質(zhì)量濃度50 mg/L下,目標化合物5a~5m對黃瓜枯萎病菌、花生褐斑病菌、蘋果輪紋病菌、番茄早疫病菌和小麥赤霉病菌均具有一定的抑制活性,平均抑制率分別為41.4%、47.2%、69.1%、68.3%和50.2%。目標化合物5a~5m對蘋果輪紋病菌和番茄早疫病菌的抑制效果較好,平均抑制率分別達69.1%和68.3%,其中半數(shù)以上化合物的抑制率在70%~90%之間。化合物5f(R=p-FAr)對蘋果輪紋病菌的抑制率達90.0%(活性級別為A級[23],接近陽性對照嘧菌酯),化合物5b(R=C(CH3)3)、5c(R=環(huán)己基)、5d(R=Ar)、5g(R=o-CH3Ar)、5i(R=p-CH3Ar)、5j(R=m-OCH3Ar)對蘋果輪紋病菌的抑制活性級別均達B級;化合物5d(R=Ar)對番茄早疫病菌的抑制率達91.8%(活性級別為A級,接近陽性對照嘧菌酯),化合物5a(R=CH3)、5b(R=C(CH3)3)、5c(R=環(huán)己基)、5f(R=p-FAr)、5h(R=m-CH3Ar)、5j(R=m-OCH3Ar)對番茄早疫病菌的抑制活性級別均達B級。與原料紫蘇醛相比,大部分紫蘇醛基席夫堿-(硫)脲目標化合物的抑菌活性有明顯提高??傮w上,取代苯基硫脲類目標化合物的抑菌活性優(yōu)于取代苯基脲類目標化合物。
表1 化合物5a~5m的抑菌活性Table 1 Antifungal activity of compounds 5a-5m
1)*:陽性對照positive control 下表同same as in following table
2.2.2 除草活性 由表2可知,在質(zhì)量濃度100 mg/L下,大部分目標化合物對油菜的胚根生長顯示一定的抑制作用,平均抑制率為44.6%,其中,化合物5a(R=CH3)、5c(R=環(huán)己基)和5i(R=p-CH3Ar)的抑制率分別為67.4%、77.6%和75.3%(活性級別為B級[24]),優(yōu)于陽性對照丙炔氟草胺。部分紫蘇醛基席夫堿-(硫)脲目標化合物的除草活性較原料紫蘇醛有明顯的增強作用。總體上,取代苯基硫脲類目標化合物的除草活性優(yōu)于取代苯基脲類目標化合物。
表2 化合物5a~5m的除草活性Table 2 Herbicidal activity of compounds 5a-5m
3.1 以紫蘇醛為原料,經(jīng)3步反應,合成得到13個未見文獻報道的紫蘇醛基席夫堿-(硫)脲化合物(5a~5m),并利用FT-IR、1H NMR、13C NMR 和ESI-MS等多種手段對目標產(chǎn)物進行了分析和表征。
3.2 初步的生物活性測試表明,50 mg/L的目標化合物對5種供試植物病原菌均有一定的抑制作用,其中化合物5f(R=p-FAr)對蘋果輪紋病菌的抑制率達90.0%(接近陽性對照嘧菌酯),化合物5d(R=Ar)對番茄早疫病菌的抑制率達91.8%(接近陽性對照嘧菌酯)。目標化合物對油菜的胚根生長具有一定的抑制作用,在質(zhì)量濃度100 mg/L條件下,其中化合物5c(R=環(huán)己基)、5i(R=p-CH3Ar)和5a(R=CH3)的抑制率分別為77.6%、75.3%和67.4%(優(yōu)于陽性對照丙炔氟草胺)??傮w上,取代苯基硫脲類目標化合物的抑菌和除草活性優(yōu)于取代苯基脲類目標化合物。
致謝:抑菌和除草活性測試由南開大學元素有機化學研究所生物活性測試室測定,謹表謝意。
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Synthesis and Biological Activities of Perillaldehyde-based Schiff Base-(thio)urea Compounds
MA Yuan1, DUAN Wengui1, LIN Guishan1, LIU Luzhi1, HUANG Zhengsong1, LEI Fuhou2
(1.College of Chemistry and Chemical Engineering,Guangxi University, Nanning 530004, China; 2.Guangxi KeyLaboratory of Chemistry and Engineering of Forest Products, Nanning 530008, China)
Thirteen novel perillaldehyde-based Schiff base-(thio)urea compounds (5a-5m) were designed and synthesized by using perillaldehyde as starting material. Their structures were analyzed and characterized by FT-IR,1H NMR,13C NMR, and ESI-MS. The results of preliminary bioassay showed that, at the mass concentration of 50 mg/L, the inhibition rate of target compound 5f (R=p-FAr) againstPhysalosporapiricolawas 90.0% (close to that of the positive control azoxystrobin), and the inhibition rate of target compound 5d (R=Ar) againstAlternariasolaniwas 91.8% (close to that of the positive control azoxystrobin). Besides, at the mass concentration of 100 mg/L, the target compounds 5c (R=cyclopentyl), 5i (R=p-CH3Ar) and 5a (R=CH3) exhibited 77.6%, 75.3% and 67.4% inhibition against the growth of rape (Brassicacampestris) root, respectively (greater than positive control flumioxazin). Furthermore, substituted phenyl thioureas showed better antifungal and herbicidal activities than substituted phenyl ureas.
perillaldehyde;Schiff base-(thio)urea;synthesis;antifungal activity;herbicidal activity
10.3969/j.issn.0253-2417.2017.01.007
2016- 04- 05
國家自然科學基金資助項目(31460173);廣西林產(chǎn)化學與工程重點實驗室開放基金資助項目(GXFC15- 01);廣西大學“大學生創(chuàng)新創(chuàng)業(yè)訓練計劃”資助項目(201510593002)
馬 媛(1990— ),女,寧夏中衛(wèi)人,碩士生,從事天然產(chǎn)物改性及有機合成的研究
*通訊作者:段文貴,教授,博士生導師,主要從事天然資源化學和有機合成的研究;E-mail:wgduan@gxu.edu.cn。
TQ351
A
0253-2417(2017)01- 0054- 09
馬媛,段文貴,林桂汕,等.紫蘇醛基席夫堿-(硫)脲化合物的合成及生物活性[J].林產(chǎn)化學與工業(yè),2017,37(1):54-62.