CN116768916A - 一种含螺吡喃结构的香豆素类化合物及其合成方法与应用 - Google Patents
一种含螺吡喃结构的香豆素类化合物及其合成方法与应用 Download PDFInfo
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Abstract
本发明属于有机合成化学的技术领域,尤其涉及一种含螺吡喃结构的香豆素类化合物及其合成方法与应用。所述含螺吡喃结构的香豆素类化合物合成方法,是在惰性氛围下将噁嗪类化合物、香豆素类化合物和铑催化剂、添加剂一起加入到溶剂中进行加热反应,反应结束后经萃取和提纯分离得到含螺吡喃结构的香豆素类化合物。本发明方法具有反应条件温和、操作简单、反应溶剂绿色、经济效益高以及官能团耐受性强等特点,并对所得部分化合物进行了生物活性测试,展现出良好的抑菌效果。
Description
技术领域
本发明属于有机合成化学的技术领域,尤其涉及一种含螺吡喃结构的香豆素类化合物及其合成方法与应用。
背景技术
吡喃环是一类重要的化合物,是许多具有生物活性的天然化合物的重要组成成分,如花青素、生物碱、黄酮类等,吡喃环的衍生物具有广泛的生物和药理活性(北华大学学报,2001,2,489)。
香豆素类化合物可看作是邻羟基肉桂酸的内酯,是一类广泛存在于芸香科、伞形科、菊科、豆科、茄科、藤黄科等植物中的内源性物质,香豆素类化合物及其衍生物因其良好的生物活性,引起了医药、农药领域科学家们的广泛关注。在医药方面,香豆素类化合物展现出抗肿瘤、抗凝血、抗骨质疏松、抗病毒等多种生物活性(中国药理学通报,2012,28:165-168;J Pharm Pharmacol,2010,62:205-213),临床上常见的香豆素类药物有抗凝药物醋硝香豆素和华法林,治疗银屑病的药物补骨脂内酯(补骨脂素)。在农业方面,作为植物体内的次生代谢产物,香豆素类物质因广泛参与到植物体防御病虫害的过程中,利用香豆素类化合物实现昆虫、病原菌的防治,成为一个重要的研究方向(天然产物研究与开发,2018,30,332-338;江西农业学报,2006,97-100)。尽管,天然香豆素具有种类繁多、生物活性多样、作用机制独特、易降解、环境友好等特点,但其往往存在着提取成本高,结构稳定性差,生物活性尚达不到高效农药的标准等问题。
南开大学的汪清民等人采用水杨酸衍生物与芳基乙酸缩合合成了一系列3位、5位、6位、8位取代的香豆素,这些化合物对番茄早疫病菌、禾谷镰刀菌、辣椒疫霉菌等多种病原菌展现出良好的抑菌效果(J.Agric.Food Chem.2021,69,151235)。河南农业大学的徐翠莲等人制备的3-酰基水杨酸香豆素以及香豆素壳聚糖席夫碱衍生物对串珠镰刀菌、禾谷镰刀菌具有较高的抑菌活性(Arab.J.Chem.2021,14,102880)。尽管以香豆素为先导化合物的合成取得了一些进展,但受限于目前的合成方法的匮乏,如何引入复杂多样的杂环或药效基团仍然是开发香豆素类农药面临的主要挑战。
发明内容
本发明的目的在于提供一种含螺吡喃结构的香豆素类化合物及其合成方法与应用。本发明方法具有反应条件温和、操作简单、溶剂绿色环保、经济效益高以及官能团耐受性强等特点。
本发明的实现过程如下:
一种含螺吡喃结构的香豆素类化合物,化学结构式如下所示:
其中,R1为氢基、碳原子数为1-8的烷基或卤素基;R2为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基或卤素基;R3为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基、卤素基、硝基或苯基。
上述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:在惰性氛围下将噁嗪类化合物、香豆素类化合物和铑催化剂、添加剂一起加入到溶剂中进行加热反应,反应结束后经萃取和提纯分离得到含螺吡喃结构的香豆素类化合物;反应方程式如下所示:
进一步,所述噁嗪类化合物的化学结构式如下所示:
其中,R2为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基或卤素基;R3为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基、卤素基、硝基或苯基;
所述香豆素类化合物的化学结构式如下所示:
其中,R1为氢基、碳原子数为1-8的烷基或卤素基。
进一步,所述铑催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体。
进一步,添加剂包括碘苯二乙酸和第二添加剂,所述第二添加剂为醋酸钠、碳酸钠、碳酸氢钠或特戊酸中的任意一种。
进一步,所述溶剂为六氟异丙醇、碳酸乙烯酯或碳酸丙烯酯中任意一种或两种。
进一步,所述噁嗪类化合物、香豆素类化合物和铑催化剂、添加剂的摩尔比为1:(1.0~2.2):(0.001~0.04):(1.2~3.1)。
进一步,碘苯二乙酸和第二添加剂的摩尔比为(1~1.1):(0.2~2)。
进一步,所述加热反应的反应温度为30℃~80℃,反应时间为1~12h,所述惰性氛围为氮气氛围;噁嗪类化合物在溶剂中的浓度为0.1~0.2mol·L-1。
上述含螺吡喃结构的香豆素类化合物在农药中作为抑菌剂的应用。
本发明方法的反应机理如下:
苯并噁嗪在铑催化剂的作用下生成环金属中间体A,4-羟基香豆素与碘苯二乙酸的产物B***生成中间体C,随后发生金属的脱除得到中间体D,羟基进攻生成螺环化合物E,该反应简单高效地合成含螺吡喃结构的香豆素类化合物。
本发明的有益效果:本发明开创性地选取简单易得的噁嗪类化合物和香豆素类化合物作为反应物,在金属铑催化剂的作用下,通过[3+3]一步实现了新型含螺吡喃结构的香豆素类化合物骨架的构建,为复杂含螺吡喃结构的香豆素类化合物的构建提供了一种简单有效的合成方法,并且该方法具有反应条件温和、操作简单、反应溶剂绿色、经济效益高以及官能团耐受性强等特点,并对所得部分化合物进行了生物活性测试,展现出良好的抑菌效果。
附图说明
图1是化合物3aa的核磁1H谱图;
图2是化合物3aa的核磁13C谱图;
图3是化合物3ba的核磁1H谱图;
图4是化合物3ba的核磁13C谱图;
图5是化合物3ca的核磁1H谱图;
图6是化合物3ca的核磁13C谱图;
图7是化合物3da的核磁1H谱图;
图8是化合物3da的核磁13C谱图;
图9是化合物3ea的核磁1H谱图;
图10是化合物3ea的核磁13C谱图;
图11是化合物3fa的核磁1H谱图;
图12是化合物3fa的核磁13C谱图;
图13是化合物3ga的核磁1H谱图;
图14是化合物3ga的核磁13C谱图;
图15是化合物3ha的核磁1H谱图;
图16是化合物3ha的核磁13C谱图;
图17是化合物3ia的核磁1H谱图;
图18是化合物3ia的核磁13C谱图;
图19是化合物3ja的核磁1H谱图;
图20是化合物3ja的核磁13C谱图;
图21是化合物3ka的核磁1H谱图;
图22是化合物3ka的核磁13C谱图;
图23是化合物3la的核磁1H谱图;
图24是化合物3la的核磁13C谱图;
图25是化合物3ma的核磁1H谱图;
图26是化合物3ma的核磁13C谱图;
图27是化合物3ab的核磁1H谱图;
图28是化合物3ab的核磁13C谱图;
图29是化合物3ac的核磁1H谱图;
图30是化合物3ac的核磁13C谱图;
图31是化合物3ad的核磁1H谱图;
图32是化合物3ad的核磁13C谱图;
图33是化合物3aa对油菜菌核(St)的抑菌效果;
图34是化合物3aa对喙角担菌(Rc)的抑菌效果;
图35是化合物3ea对油菜菌核(St)的抑菌效果;
图36是化合物3fa对油菜菌核(St)的抑菌效果;
图37是化合物3ha对油菜菌核(St)的抑菌效果;
图38是化合物3ia对油菜菌核(St)的抑菌效果。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有付出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
氮气条件下,噁嗪化合物1a(10mmol),4-羟基香豆素化合物2a(11mmol),[Cp*RhCl2]2(0.01mmol),PhI(OAc)2(10mmol),NaOAc(20mmol),溶剂EC(碳酸乙烯酯)(40mL)和HFIP(六氟异丙醇)(10mL)加入到200mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA(乙酸乙酯)和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3aa),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,59%的产率,熔程:212–213℃.核磁谱图如图1和2所示,1H NMR(400MHz,Chloroform-d)δ8.8(dd,J=8.1,1.2Hz,1H),7.7(dd,J=8.0,1.6Hz,1H),7.6–7.5(m,3H),7.4(td,J=7.6,1.3Hz,1H),7.3(dd,J=8.4,1.0Hz,1H),7.2–7.2(m,1H),7.0(ddd,J=13.3,7.6,1.6Hz,2H),6.9(td,J=7.6,1.7Hz,1H),6.8(dd,J=7.6,1.6Hz,1H),5.1(d,J=2.4Hz,1H),4.5(dd,J=11.5,2.3Hz,1H),3.9(d,J=11.6Hz,1H).13C NMR(101MHz,CDCl3)δ160.21,159.02,153.04,143.18,132.85,130.48,130.09,128.87,128.27,127.49,125.74,124.77,124.36,123.75,122.33,120.81,116.85,116.40,115.95,115.44,100.74,87.56,68.47.HRMS:[M+Na]+calculated for C23H15NNaO4 +:392.0893,found:392.0889.
实施例2
氮气条件下,噁嗪化合物1b(0.20mmol),4-羟基香豆素化合物2a(0.44mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(1.0mL)加入到10mL密封管中,在40℃的反应模块中反应1h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物8-溴-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ba),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,87%的产率,熔程:247–248℃.核磁谱图如图3和4所示,1H NMR(400MHz,DMSO-d6)δ8.6(d,J=7.8Hz,1H),8.3(s,1H),7.7–7.6(m,1H),7.6–7.5(m,3H),7.5–7.4(m,2H),7.4(t,J=7.5Hz,1H),7.0(dd,J=7.6,1.9Hz,1H),6.9–6.7(m,2H),4.8(dd,J=11.5,2.0Hz,1H),4.1(d,J=11.6Hz,1H).13C NMR(101MHz,DMSO)δ159.39,158.43,152.69,139.50,133.37,132.70,130.15,128.91,128.28,127.30,125.61,124.83,124.80,123.11,122.94,122.58,116.54,115.35,114.95,109.55,100.96,87.45,68.39.HRMS:[M+H]+calculated for C23H15BrNO4 +:448.0179,found:448.0184.
实施例3
氮气条件下,噁嗪化合物1c(0.20mmol),4-羟基香豆素化合物2a(0.3mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物7-苯基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ca),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,82%的产率,熔程:201–202℃.核磁谱图如图5和6所示,1H NMR(400MHz,Chloroform-d)δ8.8(dd,J=8.1,1.2Hz,1H),7.7(dd,J=8.0,1.6Hz,1H),7.6–7.6(m,2H),7.6–7.5(m,3H),7.5–7.4(m,3H),7.3–7.3(m,2H),7.2–7.2(m,3H),6.9(d,J=8.0Hz,1H),5.2(d,J=2.3Hz,1H),4.5(dd,J=11.6,2.3Hz,1H),4.0(d,J=11.6Hz,1H).13C NMR(101MHz,DMSO)δ160.21,159.01,153.08,143.43,140.58,134.16,132.92,130.56,129.47,128.93,128.20,127.54,127.15,127.00,126.70,125.80,124.78,124.43,123.80,120.98,116.45,116.21,115.45,115.40,100.80,87.54,68.62.HRMS:[M+Na]+calculated forC29H19NNaNO4 +:468.1206,found:468.1208.
实施例4
氮气条件下,噁嗪化合物1d(0.20mmol),4-羟基香豆素化合物2a(0.20mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.22mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物6-甲基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3da),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,84%的产率,熔程:214–215℃.核磁谱图如图7和8所示,1H NMR(400MHz,Chloroform-d)δ8.8(dd,J=8.0,1.2Hz,1H),7.8(dd,J=7.9,1.6Hz,1H),7.6–7.5(m,3H),7.4(td,J=7.5,1.3Hz,1H),7.3(dd,1H),7.2–7.1(m,1H),6.9(d,J=8.1Hz,1H),6.7(dd,J=8.2,2.0Hz,1H),6.6(d,J=2.0Hz,1H),5.0(d,J=2.1Hz,1H),4.5(dd,J=11.5,2.3Hz,1H),3.9(d,J=11.6Hz,1H),2.3(s,3H).13C NMR(101MHz,CDCl3)δ160.25,159.11,153.10,141.04,132.88,131.93,130.49,129.71,128.90,128.41,127.59,125.77,124.76,124.37,123.84,121.36,116.60,116.44,115.51,100.79,87.73,68.53,20.96.HRMS:[M+H]+calculated for C24H18NNO4 +:384.1230,found:384.1236.
实施例5
氮气条件下,噁嗪化合物1e(0.20mmol),4-羟基香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.004mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应3h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物6-硝基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ea),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:黄色固体,87%的产率,熔程:253–254℃.核磁谱图如图9和10所示,1H NMR(400MHz,DMSO-d6)δ8.6(d,J=7.8Hz,1H),8.6(s,1H),7.7(d,J=2.4Hz,1H),7.7–7.6(m,2H),7.6–7.5(m,4H),7.5(d,J=8.2Hz,1H),7.3(t,J=7.5Hz,1H),7.1(d,J=8.8Hz,1H),4.9(d,J=11.5Hz,1H),4.2(d,J=11.6Hz,1H).13C NMR(101MHz,DMSO-d6)δ159.1,157.9,152.4,148.2,141.9,133.2,131.6,130.1,128.8,127.6,127.0,125.3,124.7,124.6,122.7,116.4,116.3,115.5,114.9,110.1,100.8,86.3,68.2.HRMS:[M+Na]+calculated forC23H14N2NaO6 +:437.0744,found:437.0753.
实施例6
氮气条件下,噁嗪化合物1f(0.20mmol),4-羟基香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.008mmol),PhI(OAc)2(0.2mmol),NaOAc(0.04mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物6-氟-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3fa),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,90%的产率,熔程:219–220℃.核磁谱图如图11和12所示,1H NMR(400MHz,Chloroform-d)δ8.7(dd,J=8.0,1.2Hz,1H),7.7(dd,J=7.9,1.6Hz,1H),7.6–7.4(m,3H),7.4(td,J=7.5,1.3Hz,1H),7.3–7.3(m,1H),7.2–7.2(m,1H),6.9(q,J=9.7,5.1Hz,1H),6.6–6.5(m,2H),5.2(d,J=2.3Hz,1H),4.5(dd,J=11.6,2.3Hz,1H),3.9(d,J=11.6Hz,1H).13C NMR(101MHz,CDCl3)δ160.15,158.82 158.2(d,J=238.5Hz),153.09,139.19,139.16,132.99,130.9(d,J=10.9Hz),130.64,128.98,127.7(d,J=43.4Hz),125.85,124.64,124.46,123.69,117.4(d,J=9.5Hz),116.51,115.39,106.9(d,J=23.2Hz),102.9(d,J=27.3Hz),100.82,87.05,68.54.HRMS:[M+H]+calculated for C23H15FNO4 +:388.0980,found:388.0975.
实施例7
氮气条件下,噁嗪化合物1g(0.20mmol),4-羟基香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),Na2CO3(0.4mmol),溶剂HFIP(2.0mL)加入到10mL密封管中,在40℃的反应模块中反应5h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物6-甲氧基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ga),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,65%的产率,熔程:197–198℃.核磁谱图如图13和14所示,1H NMR(400MHz,DMSO-d6)δ8.6(d,J=7.8Hz,1H),8.0(s,1H),7.7–7.6(m,2H),7.6–7.5(m,2H),7.5(dd,J=18.0,7.7Hz,2H),7.4(t,J=7.6Hz,1H),6.8(d,J=8.7Hz,1H),6.4(d,J=2.7Hz,1H),6.3(dd,J=8.7,2.8Hz,1H),4.6(d,J=11.4Hz,1H),3.9(d,J=11.5Hz,1H),3.7(s,3H).13C NMR(101MHz,DMSO-d6)δ159.2,158.4,154.4,152.4,136.5,133.1,131.5,129.8,128.6,128.5,127.1,125.3,124.5,122.9,116.3,115.2,104.0,101.0,100.6,87.8,67.7,55.2.(两个单峰丢失由于覆盖).HRMS:[M+Na]+calculated for C24H17NNaO5 +:422.0999,found:422.1003.
实施例8
氮气条件下,噁嗪化合物1h(0.20mmol),4-羟基香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂PC(碳酸丙烯酯)(2.0mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物9'-氯-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ha),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,87%的产率,熔程:223–224℃.核磁谱图如图15和16所示,1H NMR(400MHz,DMSO-d6)δ8.7(s,1H),8.0(s,1H),7.7–7.6(m,1H),7.6–7.5(m,3H),7.5–7.4(m,1H),7.4–7.3(m,1H),6.9–6.8(m,3H),6.8–6.7(m,1H),4.7(dd,J=11.5,2.0Hz,1H),4.0(d,J=11.6Hz,1H).13C NMR(101MHz,DMSO)δ159.37,159.14,152.54,142.43,134.71,133.54,130.66,129.18,128.13,127.58,127.09,124.66,123.89,123.00,121.94,119.35,116.36,116.02,115.44,114.92,99.51,87.91,67.60.HRMS:[M+Na]+calculated for C23H14ClNNaO4 +:426.0504,found:426.0506.
实施例9
氮气条件下,噁嗪化合物1i(0.20mmol),4-羟基香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.2mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物9'-溴-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ia),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,88%的产率,熔程:230–231℃.核磁谱图如图17和18所示,1H NMR(400MHz,Chloroform-d)δ8.9(d,J=2.0Hz,1H),7.7(dd,J=7.9,1.6Hz,1H),7.6–7.5(m,2H),7.4(d,J=8.3Hz,1H),7.3(dd,J=8.4,1.0Hz,1H),7.2–7.2(m,1H),7.0–6.9(m,2H),6.9–6.8(m,2H),5.1(d,J=2.4Hz,1H),4.5(dd,J=11.6,2.4Hz,1H),3.9(d,J=11.6Hz,1H).13C NMR(101MHz,CDCl3)δ159.87,159.85,153.17,143.16,133.36,131.79,129.81,129.46,128.52,126.91,126.58,125.32,124.54,123.94,122.47,121.09,116.93,116.52,116.10,115.15,99.60,87.62,68.36.HRMS:[M+Na]+calculated for C23H14BrNNaO4 +:469.9998,found:469.9993.
实施例10
氮气条件下,噁嗪化合物1j(0.20mmol),4-羟基香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物9'-甲基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ja),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,90%的产率,熔程:226–227℃.核磁谱图如图19和20所示,1H NMR(400MHz,Chloroform-d)δ8.6(d,J=1.7Hz,1H),7.7(dd,J=8.0,1.6Hz,1H),7.6–7.5(m,1H),7.3(dd,J=18.7,8.1Hz,2H),7.2–7.1(m,2H),7.0–6.8(m,3H),6.8(dd,J=7.6,1.6Hz,1H),5.1(d,J=2.4Hz,1H),4.5(dd,J=11.5,2.3Hz,1H),3.9(d,J=11.6Hz,1H),2.4(s,3H).13C NMR(101MHz,CDCl3)δ160.23,159.06,153.02,143.18,140.62,132.77,130.14,129.57,127.31,126.27,125.53,124.71,124.34,123.76,122.30,120.75,116.84,116.39,115.91,115.55,100.78,87.60,68.57,21.81.HRMS:[M+H]+calculated for C24H18NO4 +:384.1230,found:384.1228.
实施例11
氮气条件下,噁嗪化合物1k(0.20mmol),4-羟基香豆素化合物2a(0.44mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物8'-氯-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ka),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,88%的产率,熔程:202–203℃.核磁谱图如图21和22所示,1H NMR(400MHz,Chloroform-d)δ8.7(d,J=8.6Hz,1H),7.8(d,J=8.0Hz,1H),7.6–7.4(m,3H),7.3(d,J=8.3Hz,1H),7.2(d,J=7.9Hz,1H),7.0(t,J=7.8Hz,2H),6.9–6.8(m,2H),5.1(s,1H),4.5(dd,J=11.7,2.4Hz,1H),3.9(d,J=11.7Hz,1H).13C NMR(101MHz,CDCl3)δ160.16,159.01,153.00,143.09,134.57,133.09,130.49,129.83,129.62,127.20,126.10,125.08,124.44,123.73,122.38,121.08,116.85,116.44,116.01,115.12,100.13,87.14,68.13.HRMS:[M+H]+calculated for C23H15ClNO4 +:404.0684,found:404.0674.
实施例12
氮气条件下,噁嗪化合物1l(0.20mmol),香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在80℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物8'-甲氧基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3la),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,61%的产率,熔程:196–197℃.核磁谱图如图23和24所示,1H NMR(400MHz,DMSO-d6)δ8.6(d,J=8.8Hz,1H),7.9(s,1H),7.7–7.6(m,1H),7.6–7.5(m,1H),7.4(dd,J=8.3,1.0Hz,1H),7.4–7.3(m,1H),7.2(dd,J=8.9,2.8Hz,1H),7.1(d,J=2.7Hz,1H),6.9–6.8(m,3H),6.8–6.7(m,1H),4.6(dd,J=11.5,2.0Hz,1H),4.0(d,J=11.5Hz,1H),3.8(s,3H).13C NMR(101MHz,DMSO)δ160.02,159.76,157.21,152.54,142.93,133.02,131.40,130.89,126.82,124.92,123.02,122.30,120.00,119.62,116.63,116.39,115.94,115.76,115.42,111.57,101.28,87.92,67.92,55.95.HRMS:[M+H]+calculated for C24H18NO5 +:400.1179,found:400.1180.
实施例13
氮气条件下,噁嗪化合物1m(0.20mmol),香豆素化合物2a(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaHCO3(0.4mmol),溶剂HFIP(2.0mL)加入到10mL密封管中,在30℃的反应模块中反应12h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物8',9'-二氯-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ma),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,53%的产率,熔程:232–233℃.核磁谱图如图25和26所示,1H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.1(s,1H),7.8(s,1H),7.7(t,J=7.8Hz,1H),7.6(d,J=7.9Hz,1H),7.5(d,J=8.3Hz,1H),7.4(t,J=7.6Hz,1H),7.0–6.8(m,3H),6.8(t,J=6.5Hz,1H),4.7(d,J=11.6Hz,1H),4.1(d,J=11.6Hz,1H).13C NMR(101MHz,DMSO)δ159.49,159.07,152.54,142.44,133.73,132.69,130.50,130.41,128.73,127.88,127.81,125.83,124.75,123.03,121.99,119.48,116.42,116.07,115.47,114.79,99.03,87.56,67.37.HRMS:[M+Na]+calculated forC23H13Cl2NNaO4 +:460.0114,found:460.0115.
实施例14
氮气条件下,噁嗪化合物1a(0.20mmol),香豆素化合物2b(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物3'-甲基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ab),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,90%的产率,熔程:230–231℃.核磁谱图如图27和28所示,1H NMR(400MHz,DMSO-d6)δ8.7–8.6(m,1H),8.0(s,1H),7.6–7.5(m,2H),7.5–7.4(m,2H),7.4(d,J=2.1Hz,1H),7.3(d,J=8.4Hz,1H),6.9(d,J=7.9Hz,1H),6.9–6.8(m,2H),6.8–6.7(m,1H),4.7(dd,J=11.5,1.9Hz,1H),4.0(d,J=11.5Hz,1H),2.3(s,3H).13C NMR(101MHz,DMSO)δ159.28,158.44,150.65,142.45,134.05,133.67,130.98,129.72,128.54,127.14,125.29,124.50,122.12,121.94,119.10,116.13,115.98,115.33,114.87,100.49,87.96,67.68,20.45.HRMS:[M+Na]+calculated for C24H17NNaO4 +:406.1050,found:406.1056.
实施例15
氮气条件下,噁嗪化合物1a(0.20mmol),香豆素化合物2c(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),NaOAc(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物3'-溴-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ac),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,89%的产率,熔程:220–221℃.核磁谱图如图29和30所示,1H NMR(400MHz,DMSO-d6)δ8.7–8.5(m,1H),8.0(d,J=1.9Hz,1H),7.8(dd,J=8.8,2.4Hz,1H),7.6–7.5(m,3H),7.5–7.5(m,1H),7.4(d,J=8.8Hz,1H),6.9(d,J=7.9Hz,1H),6.9–6.8(m,2H),6.8–6.7(m,1H),4.7(dd,J=11.5,1.9Hz,1H),4.0(d,J=11.5Hz,1H).13CNMR(101MHz,DMSO)δ158.74,157.06,151.45,142.44,135.43,130.77,129.84,128.98,128.67,126.69,125.45,124.66,124.55,121.97,119.33,118.78,117.14,116.09,115.92,115.46,101.53,88.34,67.65.HRMS:[M+Na]+calculated forC23H14BrNNaO4 +:469.9998,found:470.0002.
实施例16
氮气条件下,噁嗪化合物1a(0.20mmol),香豆素化合物2d(0.22mmol),[Cp*RhCl2]2(0.002mmol),PhI(OAc)2(0.2mmol),特戊酸(PivOH)(0.4mmol),溶剂EC(0.8mL)和HFIP(0.2mL)加入到10mL密封管中,在40℃的反应模块中反应10h,反应结束后用EA和水进行萃取,收集有机相,用无水硫酸钠对有机相进行干燥,减压旋蒸除去溶剂,用硅胶柱分离得到目标产物1',3'-二甲基-2H,4H,11'H-螺[苯并[b][1,4]噁嗪-3,6'-异色[4,3-c]噻嗪]-11'-酮(3ad),所用洗脱剂为石油醚和乙酸乙酯和二氯甲烷按20:1:1的比例配制而成。产物数据表征:白色固体,52%的产率,熔程:218–219℃.核磁谱图如图31和32所示,1H NMR(400MHz,DMSO-d6)δ8.6(d,J=7.9Hz,1H),8.0(s,1H),7.6–7.5(m,2H),7.5(t,J=7.2Hz,1H),7.4(s,1H),7.2(s,1H),6.9(d,J=7.8Hz,1H),6.9–6.8(m,2H),6.8–6.7(m,1H),4.6(dd,J=11.3,1.3Hz,1H),4.0(d,J=11.5Hz,1H),2.4(s,3H),2.2(s,3H).13C NMR(151MHz,DMSO)δ159.2,158.7,149.0,142.4,135.1,133.0,131.0,129.7,128.5,128.5,127.2,125.2,125.0,124.5,121.9,119.8,119.1,115.9,115.3,114.7,100.2,87.8,67.7,20.4,14.9.HRMS:[M+Na]+calculated for C25H19NNaO4 +:420.1206,found:420.1208.
抑菌性能测试
采用菌丝生长速率法,测定合成的含螺吡喃结构的香豆素类化合物的抑菌效果,通过十字交叉法测量菌落生长直径(减去菌饼直径),根据下列公式计算出含螺吡喃结构的香豆素类化合物对不同菌种的生长抑制率。
以对数表示浓度系数,抑制率转化为机率值,创建直线图表得到回归曲线与相关系数,通过SPSS软件模拟,求出有效中浓度EC50值:半最大效应浓度,抑制50%菌生长的药物浓度,数值越小,药效越好。
在200、100和50μg·mL-1的浓度梯度下,重复三组平行试验,CK为不添加药物的空白培养基对照组,采用菌丝生长速率法测定含螺吡喃结构的香豆素类化合物的抑菌活性,计算出其毒力回归方程、相关系数R2值以及EC50值,结果如表1所示。
表1含螺吡喃结构的香豆素类化合物的抑菌率、毒力回归方程、R2值与EC50值
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图33-图38,从图中可以看出,化合物3aa对油菜菌核和喙角担菌有良好的抑菌效果,其中对油菜菌核的效果更为明显,部分化合物3ea、3fa、3ha、3ia对油菜菌核也有不错的抑菌效果。
本发明开创性地选取简单易得的噁嗪类化合物和香豆素类化合物作为反应物,在金属铑催化剂的作用下,通过[3+3]一步实现了含螺吡喃结构的香豆素类化合物骨架的构建,为复杂的含螺吡喃结构的香豆素类化合物的构建提供了一种简单有效的合成方法,并且该方法具有反应条件温和、操作简单、反应溶剂绿色、经济效益高以及官能团耐受性强等特点,并对所得部分化合物进行了生物活性测试,展现出良好的抑菌效果。
本发明中提到的反应模块是平行反应管加热铝反应模块,但也可以使用其他能够实现这一反应条件的其他仪器。
以上内容是结合具体的优选实施方式对本发明所作出的进一步详细说明,不能认定本发明的具体实施仅限于这些说明。对于本发明所属领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以作出若干简单推演或替换,都应该视为属于本发明的保护范围。
Claims (10)
1.一种含螺吡喃结构的香豆素类化合物,其特征在于,化学结构式如下所示:
其中,R1为氢基、碳原子数为1-8的烷基或卤素基;R2为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基或卤素基;R3为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基、卤素基、硝基或苯基。
2.权利要求1所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:在惰性氛围下将噁嗪类化合物、香豆素类化合物和铑催化剂、添加剂一起加入到溶剂中进行加热反应,反应结束后经萃取和提纯分离得到含螺吡喃结构的香豆素类化合物;反应方程式如下所示:
3.根据权利要求2所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于,所述噁嗪类化合物的化学结构式如下所示:
其中,R2为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基或卤素基;R3为氢基、碳原子数为1-8的烷基、碳原子数为1-8的烷氧基、卤素基、硝基或苯基;
所述香豆素类化合物的化学结构式如下所示:
其中,R1为氢基、碳原子数为1-8的烷基或卤素基。
4.根据权利要求2所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:所述铑催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体。
5.根据权利要求2所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:添加剂包括碘苯二乙酸和第二添加剂,所述第二添加剂为醋酸钠、碳酸钠、碳酸氢钠或特戊酸中的任意一种。
6.根据权利要求2所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:所述溶剂为六氟异丙醇、碳酸乙烯酯或碳酸丙烯酯中任意一种或两种。
7.根据权利要求2所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:所述噁嗪类化合物、香豆素类化合物和铑催化剂、添加剂的摩尔比为1:(1.0~2.2):(0.001~0.04):(1.2~3.1)。
8.根据权利要求5所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:碘苯二乙酸和第二添加剂的摩尔比为(1~1.1):(0.2~2)。
9.根据权利要求2所述含螺吡喃结构的香豆素类化合物的合成方法,其特征在于:所述加热反应的反应温度为30℃~80℃,反应时间为1~12h,所述惰性氛围为氮气氛围;噁嗪类化合物在溶剂中的浓度为0.1~0.2mol·L-1。
10.权利要求1所述含螺吡喃结构的香豆素类化合物在农药中作为抑菌剂的应用。
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