CN103833764A - 一种绿色催化合成螺羟吲哚衍生物的方法 - Google Patents
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Abstract
本发明提供一种绿色催化合成螺羟吲哚衍生物的方法,属于有机合成技术领域。该合成反应中靛红、丙二腈和β-二酮的摩尔比为1:1:1,碱性离子液体催化剂的摩尔量是所用靛红的2~5%,反应溶剂水的用量(ml)是靛红摩尔量(mmol)的2~5倍,反应温度为80~100℃,反应时间为8~35min。反应结束后冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯螺羟吲哚衍生物。本发明与其它碱性离子液体作催化剂合成螺羟吲哚衍生物的方法相比,具有催化活性好、催化剂使用量少且循环使用中损失量也较少、整个反应过程绿色经济,便于工业化大规模生产等特点。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种绿色催化合成螺羟吲哚衍生物的方法。
背景技术
螺羟吲哚衍生物作为一类结构特殊的杂环,具有许多重要的药理活性和生物活性,如抗感染、杀菌、抗焦虑、抗肿瘤和抗艾滋病等活性,因此,对此类化合物的合成和应用研究引起人们广泛的关注。最近,有相关文献报道以靛红、丙二腈以及各种类型的酮为原料一锅三组分合成了大量的螺羟吲哚衍生物,用于该类型反应的催化剂主要有脯氨酸、PEG-400、氯化铵、乙二胺二乙酸、苄基三乙基氯化铵、硝酸铈铵、硬脂酸钠等。但上述方法普遍存在反应时间长、催化剂有毒有害、使用量大且不能循环使用等缺点。因此,开发制备螺羟吲哚衍生物的高效、绿色催化剂成为许多有机合成工作者普遍关注的问题。
碱性功能化离子液体,特别是路易斯碱性离子液体,由于其具有种类多、碱性位密度高、碱强度分布均匀、碱性不易流失以及对水、空气稳定等特点而被应用到螺羟吲哚衍生物的合成反应中。比如郭红云等在碱性离子液体[H3N+CH2CH2OH][CH3COO-]催化作用下,由靛红、β-二酮与丙二腈或氰基乙酸乙酯三组分“一锅法”合成了一系列螺羟吲哚衍生物。该方法具有反应条件温和、操作简单、后处理方便、反应时间短、对环境友好且催化剂廉价易得等优点(碱性离子液体催化下一锅三组分合成螺环吲哚衍生物,有机化学,2011,31(5):752-756)。但该方法所用催化剂的物质的量为反应物的10%,且反应中需要大量的乙醇作为反应溶剂。为了克服上述缺点,国外的H.R.Shaterian等使用催化量的乙醇胺甲酸盐碱性离子液体[H3N+CH2CH2OH][HCOO-]作为催化剂,无溶剂、室温条件下可以催化靛红、丙二腈与5,5-二甲基-1,3-环己二酮或4-羟基香豆素合成螺环吲哚衍生物。但由于[H3N+CH2CH2OH][HCOO-]碱性较弱,导致其产率较低,最高产率只有66%(Domino Knoevenagel condensation,Michaeladdition,and cyclization using ionic liquid,2-hydroxyethylammonium formate,as arecoverable catalyst,Journal of Molecular Liquids,2011,158:145-150)。
上述采用的碱性离子液体都属于弱碱性离子液体,在催化合成螺环吲哚衍生物的反应过程中催化效率较差,且离子液体的使用量也较大。另外,虽然离子液体的制备费用相对较小,但离子液体在循环使用中大的流失量使得其在整个生产过程中效益较低,导致在工业化生产中难以被大规模的使用。
发明内容
本发明的目的在于克服现有技术中利用碱性离子液体催化合成螺环吲哚衍生物过程中存在碱性离子液体用量和循环使用中流失量都很大,需要使用大量可挥发性有机溶剂等缺点,而提供一种以碱度较高的含有OH-的碱性离子液体作催化剂,以水为溶剂条件下催化合成螺环吲哚衍生物的方法。
本发明所使用的碱性离子液体催化剂的结构式为:
本发明所提供的一种绿色催化合成螺羟吲哚衍生物的方法,其化学反应式为:
其中:上述反应中靛红(I)、丙二腈(II)和β-二酮(III)的摩尔比为1:1:1,碱性离子液体催化剂的摩尔量是所用靛红的2~5%,反应溶剂水的用量(ml)是靛红摩尔量(mmol)的2~5倍,反应压力为一个大气压,反应温度为80~100℃,反应时间为8~35min。反应结束后冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯螺羟吲哚衍生物(IV)。滤液(主要包含碱性离子液体的水相)无需任何处理直接用于下一次反应,可以重复使用5次,其产物收率未有明显降低。
本发明所用的β-二酮选自
中的任一种。
本发明所使用的碱性离子液体催化剂的制备方法,见相关文献(Biodieselproduction by transesterification catalyzed by an efficient choline ionic liquidcatalyst,Applied Energy,2013,108:333-339)。
本发明与其它碱性离子液体作催化剂的合成方法相比,具有以下优点:
1、含有OH-的碱性离子液体的碱密度高,催化活性好;
2、催化剂使用量少且循环使用中损失量也较少;
3、催化剂的制备过程比较简单,原料较为廉价;
4、催化剂可以生物降解,环境友好;
5、整个反应过程绿色经济,便于工业化大规模生产。
附图说明
图1为本发明碱性离子液体催化合成螺羟吲哚衍生物的工艺流程图。
图2为本发明碱性离子液体催化剂在合成2-氨基-5-氧代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈中循环使用时的产物收率图。
图3为本发明碱性离子液体催化剂在合成2-氨基-5-氧代-7,7-二甲基-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈中循环使用时的产物收率图。
具体实施方式
本发明的实质特点和显著效果可以从下述的实施例中得以体现,但它们并不对本发明作任何限制,本领域的技术人员根据本发明的内容做出一些非本质的改进和调整,均属于本发明的保护范围。下面通过具体实施方式对本发明作进一步的说明,其中实施例中反应产物的测试表征使用的是德国Bruker公司,型号为AVANCE-II500MHz和300MHz的核磁共振仪;反应产物的熔点采用毛细管法测定。
实施例1
将2mmol靛红、2mmol丙二腈、2mmol1,3-环己二酮和0.04mmol碱性离子液体加入到盛有4ml水的带有搅拌子和冷凝管的25ml单口瓶中。80℃剧烈搅拌下反应13min,TLC(薄板层析)检测,原料点消失,冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯2-氨基-5-氧代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈,收率为91%。滤液中直接加入靛红、丙二腈和1,3-环己二酮进行重复使用。
2-氨基-5-氧代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈:m.p.295~297℃;1H NMR(500MHz,DMSO-d6):δ=1.91~1.93(m,2H,CH2),2.28~2.35(m,2H,CH2),2.61~2.65(m,2H,CH2),6.77~7.11(m,4H,ArH),7.20(br s,2H,NH2),10.41(s,1H,NH)
实施例2
将2mmol靛红、2mmol丙二腈、2mmol5,5-二甲基-1,3-环己二酮和0.04mmol碱性离子液体加入到盛有6ml水的带有搅拌子和冷凝管的25ml单口瓶中。80℃剧烈搅拌下反应8min,TLC(薄板层析)检测,原料点消失,冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯2-氨基-5-氧代-7,7-二甲基-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈,收率为97%。滤液中直接加入靛红、丙二腈和5,5-二甲基-1,3-环己二酮进行重复使用。
2-氨基-5-氧代-7,7-二甲基-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈:m.p.287~289℃;1H NMR(500MHz,DMSO-d6):δ=1.01(s,3H,CH3),1.05(s,3H,CH3),2.16(d,J=16Hz,2H,CH2),2.57(d,J=3.2Hz,2H,CH2),6.77~7.13(m,4H,ArH),7.19(br s,2H,NH2),10.36(s,1H,NH)
实施例3
将2mmol靛红、2mmol丙二腈、2mmol5-羟基香豆素和0.04mmol碱性离子液体加入到盛有8ml水的带有搅拌子和冷凝管的50ml单口瓶中。85℃剧烈搅拌下反应18min,TLC(薄板层析)检测,原料点消失,冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯2-氨基-5-氧代-螺[(3’H)-吲哚-3’,4-4(H)-吡喃酮并(3,2-c)色满]-(1’)-(1’H)-2’酮-3-腈,收率为92%。滤液中直接加入靛红、丙二腈和5-羟基香豆素进行重复使用。
2-氨基-5-氧代-螺[(3’H)-吲哚-3’,4-4(H)-吡喃酮并(3,2-c)色满]-(1’)-(1’H)-2’酮-3-腈:m.p.289~290℃;1H NMR(500MHz,DMSO-d6):δ=6.84~8.04(m,8H,ArH),7.56(br s,2H,NH2),10.66(s,1H,NH)
实施例4
将2mmol靛红、2mmol丙二腈、2mmol巴比妥酸和0.10mmol碱性离子液体加入到盛有10ml水的带有搅拌子和冷凝管的50ml单口瓶中。100℃剧烈搅拌下反应32min,TLC(薄板层析)检测,原料点消失,冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯2-氨基-5,7-二氧代-螺[(3’H)-吲哚-3’,4,4(H)-5,6,7,8-四氢吡啶并(2,3-d)嘧啶]-(1’H)-2’酮-3-腈,收率为93%。滤液中直接加入靛红、丙二腈和巴比妥酸进行重复使用。
2-氨基-5,7-二氧代-螺[(3’H)-吲哚-3’,4,4(H)-5,6,7,8-四氢吡啶并(2,3-d)嘧啶]-(1’H)-2’酮-3-腈:m.p.268~269℃;1H NMR(500MHz,DMSO-d6):δ=6.74~7.12(m,4H,ArH),7.42(br s,2H,NH2),10.51(br s,1H,NH),12.06(brs,1H,NH),12.48(br s,1H,NH)
实施例5
将2mmol靛红、2mmol丙二腈、2mmol2-硫代巴比妥酸和0.10mmol碱性离子液体加入到盛有10ml水的带有搅拌子和冷凝管的50ml单口瓶中。100℃剧烈搅拌下反应34min,TLC(薄板层析)检测,原料点消失,冷却至室温,抽滤,所得滤渣用90%乙醇水溶液(质量比)进行重结晶、干燥后得到纯2-氨基-5-氧代-7-硫代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)--2’酮-3-腈,收率为90%。滤液中直接加入靛红、丙二腈和2-硫代巴比妥酸进行重复使用。
2-氨基-5-氧代-7-硫代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)--2’酮-3-腈:m.p.240~242℃;1H NMR(300MHz,DMSO-d6):δ=6.77(t,J=7.1Hz,1H,ArH),6.88(t,J=7.1Hz,1H,ArH),7.14(t,J=8.1Hz,2H,ArH),7.39(s,2H,NH2),10.51(s,1H,NH),12.48(s,1H,NH)
实施例6
以实施例1为探针反应,作反应催化剂碱性离子液体的活性重复性试验,离子液体使用6次。产物2-氨基-5-氧代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈的收率变化见图2。
实施例7
以实施例3为探针反应,作反应催化剂碱性离子液体的活性重复性试验,离子液体使用6次。产物2-氨基-5-氧代-螺[(3’H)-吲哚-3’,4-4(H)-吡喃酮并(3,2-c)色满]-(1’)-(1’H)-2’酮-3-腈的收率见图3。
由图2、3可以看出:碱性离子液体在循环使用合成2-氨基-5-氧代-螺[(4H)-5,6,7,8-四氢苯并吡喃-4,3’-(3’)-吲哚]-(1’H)-2’酮-3-腈和2-氨基-5-氧代-螺[(3’H)-吲哚-3’,4-4(H)-吡喃酮并(3,2-c)色满]-(1’)-(1’H)-2’酮-3-腈的过程中的收率稍有降低,但降低幅度均比较小。由以上可以表明,碱性离子液体可以在催化合成螺羟吲哚衍生物中被循环使用。
Claims (3)
3.如权利要求1所述的一种绿色催化合成螺羟吲哚衍生物的方法,其特征在于,所述抽滤后的滤液为包含碱性离子液体的水相,其无需任何处理可以重复使用至少5次。
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