CN116444534A - 一种氟代醇促进的[5+1]去芳香化反应 - Google Patents

一种氟代醇促进的[5+1]去芳香化反应 Download PDF

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CN116444534A
CN116444534A CN202210002348.9A CN202210002348A CN116444534A CN 116444534 A CN116444534 A CN 116444534A CN 202210002348 A CN202210002348 A CN 202210002348A CN 116444534 A CN116444534 A CN 116444534A
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胡方芝
李帅帅
张晓梅
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Abstract

本发明公开了一种氟代醇促进的[5+1]去芳香化反应在构建螺环色螨骨架中的应用，所述螺环色螨的结构式为

Description

一种氟代醇促进的[5+1]去芳香化反应
技术领域
本发明涉及化学合成技术领域，尤其涉及一种氟代醇促进的[5+1]去芳香化反应在构建螺环色螨骨架中的应用。
背景技术
色螨和假吲哚是许多天然产物、药物及药物中间体的核心结构，是具有重要药物活性的结构片段，发展绿色合成技术高效构建这两类活性骨架，并将这两类活性骨架进行有效拼接，制造出新型稠杂化合物，对开发新型药物分子、推动医药健康事业发展具有极其重要的意义。
2015年，中国药科大学的许庆龙教授等人报道了对甲苯磺酸催化的取代邻胺基苯甲醛和2-甲基吲哚参与的[5+1]去芳香化反应，通过缩合/负氢迁移/去芳香化-环化过程将廉价易得的吲哚类化合物转化为高附加值的螺环四氢喹啉衍生物，为含有假吲哚结构的螺环四氢喹啉骨架的高效构建提供了一种新策略(J.Org.Chem.2015,80,1155-1162)。
2020年，青岛农业大学的李帅帅教授等人报道了以取代邻胺基苯甲醛为五元合成子与 4-羟基吲哚以及4-羟基咔唑的反应，通过[5+1]去芳香化过程实现了4-羟基吲哚以及4-羟基咔唑中含碳环的去芳香化，合成了一系列螺环二烯酮稠杂的四氢喹啉衍生物(Org.Chem. Front.,2020,7,2511-2517)。
但上述已经报道的方法都是以取代邻胺基苯甲醛为五元合成子，所构建产物都局限于含氮的四氢喹啉杂环衍生物。因此，发展新型的五元合成子，突破上述产物结构的限制，高效构建含氧等杂环化合物对于开发新型药物分子具有重要意义。
发明内容
针对上述问题，本发明提供了一种以取代邻氧苯甲醛为新型五元合成子，通过氟代醇促进的[5+1]去芳香化反应构建螺环色螨骨架的方法。本发明提供的合成方法操作简单实用，产率较高，且不需要外加催化剂，具有绿色、经济的特点；此外，所述合成方法反应条件相对温和，降低了产物的制备成本，便于后期工业化应用。
本发明的技术方案如下：
本发明提供螺环色螨类生物活性骨架，其结构式如下：
式中，R1为氢、烷基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为烷基、烯基、芳基中任意一种；R4为氢原子、烷基、卤素中任意一种。
本发明还提供上述螺环色螨类生物活性骨架的合成方法，其包括以下步骤：
将取代的邻氧苯甲醛和取代的2-甲基吲哚溶于氟代醇并置于反应管中，在室温至加热条件下反应，制得螺环色螨类化合物；
其中，上述取代的邻氧苯甲醛类化合物的结构式如下：
其中，R1为氢、烷基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为烷基、烯基、芳基中任意一种；
其中，上述取代的2-甲基吲哚类化合物的结构式如下：
其中，R4为氢原子、烷基、卤素中任意一种。
可通过薄层色谱法检测上述反应情况，待反应完毕进行纯化，得到螺环色螨类化合物的纯化产物。
上述反应过程具体为：
取代的邻氧苯甲醛与2-甲基吲哚在氟代醇溶剂的促进下发生缩合生产缺电子的3-烯基亚胺中间体I，缺电子的3-烯基亚胺中间体I引发分子内负氢迁移形成氧鎓离子中间体 II，继而通过分子内的去芳香化环化过程，生成含有假吲哚结构的螺环色螨类化合物。合成路线具体如下：
优选地，上述反应中使用的溶剂为氟代醇。溶剂的用量为：每摩尔取代的邻氧苯甲醛和取代的2-甲基吲反应物添加5～10L氟代醇溶剂。
可选地，上述合成反应可无需外加催化剂，具有绿色、经济的特点；此外，所述合成方法反应条件相对温和，有效降低产物合成成本。
本发明涉及的化合物可以以一种或者多种立体异构体的形式存在。各种异构体包括几何异构体。这些异构体包括这些异构体的混合物均在本发明的保护范围内。
本发明还提供上述螺环色螨类生物活性骨架在制备抗菌、抗炎、抗肿瘤、抗HCV、抗HIV、抗老年痴呆、抗疟疾、抗真菌、抗结核和抗精神病的药物中的应用。
本发明实施例具有以下有益效果：
1、本发明在无催化剂，温和(25-100℃)条件下，在氟代醇溶剂中一步反应高效合成了螺环色螨类活性骨架，本发明的技术方案为螺环色螨类生物活性骨架提供了绿色、简洁、高效的合成方法，首次实现了氟代醇促进的[5+1]去芳香化反应高效构建螺环色螨类骨架。
2、该方法反应条件温和，一步反应合成螺环色螨类化合物，底物普适性好，底物取代基可以是吸电子基或供电子基，且取代基的位置对反应产率没有明显的影响。本发明为具有良好生物活性的螺环色螨类骨架的高效构建提供了实验依据，具有很好的实践意义和应用价值。
具体实施方式
下面将结合本发明实施例，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，本领域技术人员在没有作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。除非另有定义，本说明书所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本说明书所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
下面实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料、仪器等，如无特殊说明，均可从商业途径得到。
实施例1：
1、本实施例提供一种3,3’-位含有螺环假吲哚结构的色螨类化合物的合成方法，其包括以下步骤：
取0.26mmol O-苄基取代的邻氧苯甲醛类化合物于反应瓶中，依次加入2mL溶剂、0.2 mmol 2-甲基吲哚，最后再加入催化剂。控制体系的反应温度，持续搅拌，通过薄层色谱板点样跟踪反应至原料反应完全。待反应完成后，使用硅胶柱进行分离纯化，将纯化后的产品旋蒸得目标产物A。反应式如下：
2、按照上述方法，设立7组平行试验组，分别采用不同的催化剂、溶剂。催化剂分别为三氟甲烷磺酸钪Sc(OTf)3、三氟甲烷磺酸镍Ni(OTf)2、三氟甲烷磺酸、对甲苯磺酸一水合物TsOH·H2O、三氟乙酸TFA。溶剂分别为1,2-二氯乙烷DCE，1,1,1,3,3,3-六氟-2-丙醇HFIP，2,2,2-三氟乙醇TFE。试验组具体使用的催化剂、溶剂种类及对应产率如表1所示：
表1不同催化剂条件下取代的邻氧苯甲醛与2-甲基吲哚反应产率表
注：HFIP＝1,1,1,3,3,3-六氟-2-丙醇；TFE＝2,2,2-三氟乙醇；上述产率为分离产率。
根据以上平行试验结果分析可知：采用布朗斯特酸和路易斯酸作催化剂时不能催化本发明的合成反应进行；以氟代醇HFIP作为溶剂时，不加任何催化剂反应即可进行，且可取得较高收率；而另一种氟代醇TFE不能促进反应进行。
3、按照上述方法，设置以下8组平行试验组，分别采用不同的反应条件，如：不同的原料比例、不同的溶剂体积、不同的反应温度。溶剂为HFIP。不同试验组的具体设置见表2：
表2 以HFIP为溶剂，取代的邻氧苯甲醛与2-甲基吲哚在不同反应条件下反应产率表
根据以上平行试验结果分析可知：本发明的合成反应在以HFIP作为溶剂时，每摩尔取代的邻氧苯甲醛与2-甲基吲哚反应物添加5-10L溶剂，反应都可进行，当每摩尔取代的邻氧苯甲醛与2-甲基吲哚反应物添加5L溶剂时，收率最高；在25～60℃条件下反应都可进行，其中50℃的转化效果最好。
下列实施例2-20中，按照实施例1的操作步骤进行反应；反应体系中，原料取代的邻氧苯甲醛与2-甲基吲哚分别为0.26mmol、0.2mmol，以1mL HFIP作溶剂，在50℃温度下持续搅拌反应至原料反应完全，分别得到相应的目标产物。
实施例2
原料：2-甲基吲哚
产物：化学式：C26H25NO
分子量：367.2009
结构式：
产率：81％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane:petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2:1)as a yellow solid,m.p.: 85.4-86.1℃.1H NMR(300MHz,Chloroform-d)δ7.41–7.32(m,1H),7.27(dtt,J＝8.6,4.5, 2.1Hz,2H),7.19–7.14(m,1H),7.13–7.07(m,3H),7.06–6.97(m,3H),6.93–6.88(m,2H), 5.41(s,1H),3.70(d,J＝16.0Hz,1H),3.45–3.32(m,1H),2.59(d,J＝16.1Hz,1H),2.43(s, 3H),1.31(d,J＝7.5Hz,6H).13CNMR(75MHz,Chloroform-d)δ183.3,181.4,155.0,154.6, 152.1,151.7,141.0,139.0,136.9,136.6,136.0,135.9,128.7,128.5,128.4,128.1,127.7,127.6, 127.5,127.0,126.7,126.6,125.2,124.9,124.8,124.4,122.2,121.4,121.3,120.1,120.0,119.2,118.6,81.9,80.6,59.9,59.5,33.4,33.2,27.1,23.2,23.0,22.3,22.2,20.3,17.3.
实施例3
原料：2-甲基吲哚
产物：化学式：C27H27NO
分子量：381.2165
结构式：
产率：74％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane:petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2:1)as a yellow solid,m.p.: 84.0-85.1℃.1H NMR(300MHz,Chloroform-d)δ7.40–7.34(m,1H),7.33–7.27(m,1H), 7.26–7.19(m,1H),7.19–7.15(m,1H),7.11–7.04(m,4H),7.00(d,J＝5.1Hz,2H),6.91(d, J＝7.2Hz,2H),5.41(s,1H),3.71(d,J＝16.0Hz,1H),3.49–3.32(m,1H),2.60(d,J＝16.1 Hz,1H),2.44(s,3H),1.79–1.62(m,1H),1.31(s,3H),1.28(s,1H),1.04–0.88(m,3H).13C NMR(75MHz,Chloroform-d)δ183.3,181.4,155.1,154.7,152.2,151.8,141.1,139.1,136.9, 136.6,136.1,136.0,128.71,128.66,128.5,128.4,128.1,127.7,127.6,127.5,127.4,126.7, 126.6,125.2,124.9,124.8,124.5,122.2,121.4,121.3,120.1,120.0,119.3,118.6,81.9,80.6, 60.0,59.6,34.3,33.7,33.4,33.2,30.1,29.2,27.1,23.1,23.0,22.3,22.2,21.0,20.3,17.3,12.4, 12.3.
实施例4
原料：2-甲基吲哚
产物：化学式：C28H29NO
分子量：395.2249
结构式：
产率：76％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝4:1)as a yellow solid,m.p.:93.9-94.5℃.1H NMR(300MHz,Chloroform-d)δ7.38(d,J＝7.7Hz,1H),7.36– 7.26(m,1H),7.26–7.19(m,1H),7.19–7.14(m,1H),7.14–7.04(m,4H),6.89(d,J＝7.1Hz, 2H),6.84(s,1H),5.36(s,1H),3.68(d,J＝16.0Hz,1H),2.57(d,J＝16.2Hz,1H),2.39(s,3H), 2.33(s,4H),1.42(s,9H).13C NMR(75MHz,Chloroform-d)δ183.7,181.5,155.0,154.6, 151.5,151.3,141.0,139.3,138.2,137.9,136.0,135.8,130.3,130.1,128.7,128.4,128.3,128.0, 127.9,127.7,127.5,126.8,126.2,126.1,125.3,125.2,124.6,122.2,120.9,119.9,119.1,110.3, 100.4,82.3,80.7,60.0,59.8,34.8,33.6,33.3,29.9,29.8,21.0,20.2,17.3,13.8.
实施例5
原料：2-甲基吲哚
产物：化学式：C31H35FN2O
分子量：437.2719
结构式：
产率：71％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2:1)as a yellow solid,m.p.:99.8-101.5℃.1H NMR(300MHz,Chloroform-d)δ7.39(d,J＝7.6Hz,1H),7.36 –7.21(m,3H),7.18–7.01(m,5H),6.90(d,J＝7.7Hz,2H),5.39(s,1H),3.75(d,J＝16.6Hz, 1H),2.62(d,J＝16.2Hz,1H),2.42(s,3H),1.45(s,9H),1.36(s,9H).13C NMR(75MHz, Chloroform-d)δ183.7,181.5,155.0,154.6,151.3,151.1,143.6,143.3,141.1,139.4,137.6, 137.3,136.0,135.9,128.6,128.42,128.38,128.0,127.7,127.5,126.8,126.7,125.2,125.1, 124.6,124.1,122.5,122.4,122.1,120.0,119.9,119.3,118.4,82.2,80.7,60.1,59.9,35.1,34.4, 33.8,33.5,31.7,30.0,29.9,27.0,22.8,20.3,17.3.
实施例6
原料：2-甲基吲哚
产物：化学式：C27H26ClNO
分子量：415.1703
结构式：
产率：91％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝3:1)as a yellow solid,m.p.:142.6-143.1℃.1H NMR(300MHz,Chloroform-d)δ7.40(d,J＝7.6Hz,1H),7.37 –7.24(m,3H),7.18–6.92(m,5H),6.88(t,J＝2.0Hz,1H),6.74(d,J＝7.8Hz,1H),5.35(s, 1H),3.71(d,J＝16.2Hz,1H),2.63(d,J＝16.3Hz,1H),2.41(s,3H),1.41(s,9H).13C NMR (75MHz,Chloroform-d)δ183.0,180.9,155.0,154.6,153.4,153.1,140.5,138.7,138.5,138.2, 137.8,137.7,133.6,133.3,129.1,128.94,128.89,128.8,128.7,128.3,128.2,127.8,127.14, 127.09,125.5,125.4,125.3,124.9,124.7,124.4,122.0,121.6,121.4,120.2,120.1,119.2,81.5, 80.1,59.7,59.5,34.9,33.3,33.1,29.9,29.8,20.2,17.3.
实施例7
原料：2-甲基吲哚
产物：化学式：C28H29NO
分子量：395.2249
结构式：
产率：97％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2.5:1)as a yellow solid,m.p.:94.7-95.6℃.1H NMR(300MHz,Chloroform-d)δ7.54(d,J＝7.7Hz,1H), 7.40–7.28(m,2H),7.24–7.03(m,4H),7.03–6.89(m,2H),6.86–6.78(m,1H),6.46(d,J＝ 7.9Hz,1H),3.53(d,J＝16.2Hz,1H).2.72(d,J＝16.2Hz,1H),2.28(s,3H),2.22(s,3H),1.37 (s,9H).13C NMR(75MHz,Chloroform-d)δ184.0,182.7,154.9,154.3,154.1,153.9,141.0, 140.2,138.3,137.9,135.8,135.3,134.9,134.8,130.5,130.2,128.8,128.5,128.3,128.2,127.8, 126.3,126.2,126.1,125.9,125.5,125.4,125.2,124.9,124.2,121.8,121.1,120.9,120.2,120.0, 119.4,77.5,75.6,59.2,58.4,34.9,34.6,34.1,29.9,29.6,27.0,20.3,20.2,19.8,17.3.
实施例8
原料：2-甲基吲哚
产物：化学式：C28H29NO
分子量：395.2249
结构式：
产率：98％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝3:1)as a yellow solid,m.p.:98.7-100.1℃.1H NMR(300MHz,Chloroform-d)δ7.39(d,J＝7.6Hz,1H),7.37 –7.22(m,3H),7.21–7.17(m,1H),7.14–7.06(m,1H),7.06–6.80(m,4H),6.67(d,J＝8.9 Hz,1H),5.36(s,1H),3.72(d,J＝16.1Hz,1H),2.62(d,J＝16.2Hz,1H),2.40(s,3H),2.15(s, 3H),1.43(s,9H).13C NMR(75MHz,Chloroform-d)δ183.5,181.4,155.0,154.6,153.7,153.4, 141.0,139.2,138.4,138.1,137.2,136.9,135.7,135.6,129.5,128.8,128.4,128.2,127.7,127.6, 127.4,125.2,125.2,125.1,124.5,123.8,123.6,122.2,121.2,121.0,120.2,119.95,119.88,119.3,82.2,80.8,59.7,59.6,34.9,33.6,33.3,29.9,29.7,27.0,21.4,20.2,17.2.
实施例9
原料：2-甲基吲哚
产物：化学式：C28H29NO
分子量：395.2249
结构式：
产率：99％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2.5:1)as a yellow solid,m.p.:193.7-194.6℃.1H NMR(300MHz,Chloroform-d)δ7.40(d,J＝7.5Hz, 1H),7.36–7.22(m,3H),7.19(d,J＝7.5Hz,1H),7.14–7.06(m,1H),7.05–6.97(m,1H), 6.94(d,J＝7.7Hz,1H),6.88(d,J＝8.3Hz,2H),6.77(d,J＝8.1Hz,1H),5.38(s,1H),3.72(d, J＝16.5Hz,1H),2.61(d,J＝16.1Hz,1H),2.40(s,3H),2.22(s,3H),1.42(s,9H).13C NMR (75MHz,Chloroform-d)δ183.6,181.5,155.0,154.5,153.7,153.5,141.0,139.2,138.4,138.0, 137.6,132.8,132.7,128.5,128.4,128.3,128.2,127.7,126.6,126.5,125.2,125.1,124.4,122.1, 121.2,121.0,120.1,120.0,119.9,119.3,82.0,80.6,59.8,59.6,34.9,33.6,33.3,29.8,29.7,21.2, 21.1,20.2,17.2.
实施例10
原料：2-甲基吲哚
产物：化学式：C28H29NO2
分子量：411.2198
结构式：
产率：97％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,2:5:50)afforded the product as inseparablediastereomers(dr＝6:1)as a yellow solid,m.p.:152.0-152.9℃.1H NMR(300MHz,Chloroform-d)δ7.39(d,J＝7.7Hz,1H),7.33 –7.28(m,2H),7.18(d,J＝6.8Hz,1H),7.14–7.04(m,1H),7.04–6.92(m,3H),6.76–6.68 (m,1H),6.62(dd,J＝17.1,8.0Hz,1H),6.31–6.26(m,1H),5.37(s,1H),3.72(d,J＝16.1Hz, 1H),3.41(s,3H),2.62(d,J＝16.2Hz,1H),2.39(s,3H),1.41(s,9H).13C NMR(75MHz, Chloroform-d)δ181.4,158.9,155.2,153.7,139.4,138.1,137.2,128.7,128.5,128.2,125.3, 125.2,124.5,121.1,120.1,119.4,115.5,111.3,80.6,59.8,54.9,35.0,33.6,29.7,17.3.
实施例11
原料：2-甲基吲哚
产物：化学式：C28H29NO2
分子量：411.2198
结构式：
产率：83％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,2:5:50)afforded the product as inseparablediastereomers(dr＝2.5:1)as a yellow solid,m.p.:128.5-129.2℃.1H NMR(300MHz,Chloroform-d)δ7.40(d,J＝7.6Hz, 1H),7.36–7.27(m,2H),7.25–7.20(m,1H),7.17(d,J＝6.8Hz,1H),7.13–7.05(m,1H), 7.02–6.92(m,2H),6.83–6.75(m,1H),6.64–6.55(m,2H),5.35(s,1H),3.76–3.66(m,4H), 2.60(d,J＝16.2Hz,1H),2.38(s,3H),1.41(s,9H).13C NMR(75MHz,Chloroform-d)δ183.6, 181.6,159.7,159.1,155.1,154.6,153.8,153.6,141.1,139.3,138.4,138.1,128.4,128.2,128.1, 128.0,127.9,127.7,125.2,125.2,125.1,124.5,122.0,121.2,121.0,120.2,120.0,119.4,113.2, 113.0,81.9,80.4,59.8,59.7,55.1,34.9,33.7,33.4,29.9,29.7,20.2,17.2.
实施例12
原料：2-甲基吲哚
产物：化学式：C28H26F3NO
分子量：449.1966
结构式：
产率：87％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2:1)as a yellow solid,m.p.:105.3-106.3℃.1H NMR(300MHz,Chloroform-d)δ7.40–7.26(m,5H),7.21– 7.06(m,2H),7.00(q,J＝7.4,6.7Hz,4H),5.44(s,1H),3.73(d,J＝16.1Hz,1H),2.64(d,J＝ 16.3Hz,1H),2.42(s,3H),1.39(s,9H).13CNMR(75MHz,Chloroform-d)δ182.9,180.7, 155.0,154.6,153.4,153.1,140.4,139.7,138.7,138.3,129.0,128.8,128.3,127.8,127.2,127.1, 125.54,125.48,125.4,124.9(q,J＝3.7Hz),124.6(q,J＝3.7Hz),124.5,124.0(q,J＝272.9Hz), 122.0,121.7,121.5,120.4,120.3,120.2,119.3,81.7,80.2,59.8,59.6,35.0,33.4,33.1,30.0,29.8, 20.2,17.3.
实施例13
原料：2-甲基吲哚
产物：化学式：C27H25F2NO
分子量：417.1904
结构式：
产率：67％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝1.5:1)as a yellow solid,m.p.:136.1-137.0℃.1H NMR(300MHz,Chloroform-d)δ7.42(d,J＝7.5Hz, 1H),7.37–7.26(m,2H),7.23–7.07(m,2H),7.07–6.78(m,4H),6.21–6.15(m,1H),5.81(s, 1H),3.75(d,J＝16.4Hz,1H),2.66(d,J＝16.1Hz,1H),2.39(s,3H),1.38(s,9H).13C NMR (75MHz,Chloroform-d)δ182.7,181.5,159.9,159.7,156.6,156.5,155.5(dd,J＝241.6,2.2 Hz),155.2(dd,J＝242.9,2.2),155.1,154.2,153.41,153.37,139.4,138.6,138.5,138.3129.0, 128.7,128.3127.9,125.6,125.5125.4125.3,124.4,122.6(d,J＝3.7Hz),121.7,121.6120.3 120.2119.8,119.3,117.1,116.84(dd,J＝24.2,4.7),116.81,116.5,116.0(dd,J＝25.9,8.6Hz), 115.0(dd,J＝26.1,3.5Hz),114.0(dd,J＝25.2,3.1Hz),74.572.0(d,J＝4.1Hz),59.5,59.2, 34.9,33.9,33.41,29.9,29.8,20.4,16.6,16.5.
实施例14
原料：2-甲基吲哚
产物：化学式：C28H26N2O
分子量：406.2045
结构式：
产率：55％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,3:5:50)afforded the product separablediastereomers(dr＝3:1)as a yellow solid, m.p.:141.9-142.8℃.1H NMR(300MHz,Chloroform-d)δ7.68–7.52(m,1H),7.48–7.25(m, 4H),7.13(d,J＝7.4Hz,3H),7.08–6.92(m,2H),6.52(d,J＝8.1Hz,1H),5.92(s,1H),3.81(d, J＝16.1Hz,1H),2.65(d,J＝16.1Hz,1H),2.46(s,3H),1.35(s,9H).13C NMR(75MHz, Chloroform-d)δ181.5,155.1,153.4,139.2,138.7,138.0,132.8,132.7,129.6,129.0,128.4, 127.5,125.7,125.5,124.6,121.7,120.3,119.2,118.0,111.7,77.5,59.5,34.9,33.9,29.7,17.3.
实施例15
原料：2-甲基吲哚
产物：化学式：C27H26N2O3
分子量：426.1943
结构式：
产率：53％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,3:5:50)afforded the product as separablediastereomers(dr＝3:1)as a yellow solid,m.p.:148.4-149.1℃.1H NMR(300MHz,Chloroform-d)δ8.08–7.99(m,1H),7.84(t,J ＝2.0Hz,1H),7.37–7.28(m,3H),7.26–7.10(m,4H),7.07–6.95(m,2H),5.49(s,1H),3.75 (d,J＝16.3Hz,1H),2.68(d,J＝16.3Hz,1H),2.45(s,3H),1.40(s,9H).13C NMR(75MHz, Chloroform-d)δ180.5,154.9,153.1,147.6,138.3,138.2,137.8,132.5,129.1,128.8,128.3, 125.8,125.6,124.5,123.8,122.0,121.7,120.3,119.2,79.6,59.9,35.0,32.9,29.9,17.4.
实施例16
原料：2-甲基吲哚
产物：化学式：C29H29NO3
分子量：439.2147
结构式：
产率：44％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,2:5:50)afforded the product as separablediastereomers(dr＝2:1)as a yellow solid,m.p.:128.2-129.0℃.1H NMR(300MHz,Chloroform-d)δ7.76(d,J＝8.4Hz,2H),7.37 (dd,J＝5.9,3.3Hz,1H),7.29(d,J＝6.4Hz,2H),7.26(d,J＝2.5Hz,2H),7.16–7.07(m,3H), 6.99(t,J＝7.6Hz,1H),5.45(s,1H),3.85(s,3H),3.75(d,J＝17.6Hz,1H),2.86(d,J＝17.5Hz, 1H),2.36(s,3H),1.42(s,9H).13CNMR(75MHz,Chloroform-d)δ183.0,166.8,154.6,153.2, 140.7,140.5,138.6,129.9,128.9,128.8,127.8,126.8,125.42,125.37,122.1,121.6,120.3, 120.2,81.9,59.6,52.2,35.0,33.2,29.9,20.2.
实施例17
原料：2-甲基吲哚
产物：化学式：C31H29NO
分子量：431.2249
结构式：
产率：99％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝3:1)as a yellow solid,m.p.:191.6-192.2℃.1H NMR(300MHz,Chloroform-d)δ7.70(ddd,J＝14.2,8.2,4.0 Hz,2H),7.62–7.27(m,8H),7.22–6.98(m,3H),6.92(dd,J＝8.7,1.7Hz,1H),5.58(s,1H), 3.78(d,J＝15.9Hz,1H),2.68(d,J＝16.2Hz,1H),2.45(s,3H),1.46(s,9H).13C NMR(75 MHz,Chloroform-d)δ183.4,181.3,155.0,154.6,153.7,153.4,140.9,139.2,138.5,138.1, 133.5,133.4,133.0,132.64,132.57,128.5,128.25,128.16,127.8,127.6,127.5,127.2,126.5, 126.4,126.3,126.1,126.04,125.96,125.3,125.2,124.5,124.4,124.3,122.1,121.3,121.1, 120.1,119.4,82.3,81.0,59.8,59.7,34.9,33.7,33.5,29.9,29.8,27.0,20.3,17.2.
实施例18
原料：2-甲基吲哚
产物：化学式：C23H25NO
分子量：331.1936
结构式：
产率：86％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝2:1)as a yellow solid,m.p.:85.7-86.4℃.1H NMR(300MHz,Chloroform-d)δ7.56(d,J＝7.7Hz,H),7.41– 7.27(m,2H),7.26–7.21(m,1H),7.12–6.97(m,2H),6.95–6.87(m,1H),5.47–5.34(m,1H), 5.33–5.15(m,1H),5.06(ddd,J＝10.4,7.6,1.8Hz,1H),4.92–4.77(m,1H),3.59(d,J＝16.0 Hz,1H),2.52(d,J＝16.2Hz,1H),2.36(s,3H),1.46(s,9H).13C NMR(75MHz,Chloroform-d) δ184.2,181.9,154.9,154.8,152.9,152.7,145.7,141.9,139.4,138.0,132.3,131.9,131.4,128.7, 128.4,128.1,128.0,127.7,126.7,125.7,125.5,125.3,125.2,124.1,123.6,121.6,121.2,120.9, 120.2,120.0,119.7,119.2,118.5,78.9,78.7,58.6,58.3,34.9,32.8,32.8,30.6,29.8,29.7,19.6, 19.1,16.7.
实施例19
原料：2-甲基吲哚/>
产物：化学式：C28H26F3NO
分子量：333.2093
结构式：
产率：91％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as a yellowoil.1H NMR(300MHz,Chloroform-d) δ7.55(d,J＝7.6Hz,1H),7.41–7.28(m,2H),7.27–7.12(m,2H),6.96(dd,J＝7.5,1.7Hz, 1H),6.88(t,J＝7.6Hz,1H),3.33(d,J＝17.6Hz,1H),2.73(d,J＝17.6Hz,1H),2.23(s,3H), 1.48(s,5H),1.44(s,9H),1.12(s,3H).13C NMR(75MHz,Chloroform-d)δ185.6,155.2,151.8, 141.1,138.4,128.5,127.5,125.2,125.1,123.4,120.5,120.1,119.5,76.6,61.6,34.9,30.8,29.9, 23.8,23.6,19.5.
实施例20
原料：2-甲基-5-甲氧基吲哚
产物：化学式：C28H29NO2
分子量：411.2198
结构式：
产率：97％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,2:5:50)afforded the product as inseparablediastereomers(dr＝3:1)as a yellow solid,m.p.:89.2-90.3℃.1H NMR(300MHz,Chloroform-d)δ7.34–7.28(m,2H),7.23–7.17 (m,1H),7.16–7.02(m,3H),6.99(d,J＝7.3Hz,2H),6.95–6.93(m,1H),6.87(dd,J＝8.4,2.6 Hz,1H),6.80(d,J＝2.4Hz,1H),5.41(s,1H),3.78(d,J＝16.1Hz,1H),3.69(s,3H),2.64(d,J ＝16.2Hz,1H),2.39(s,3H),1.44(s,9H).13C NMR(75MHz,Chloroform-d)δ181.2,179.1, 157.9,157.7,153.6,153.4,148.8,148.3,142.5,140.7,138.4,138.1,135.9,135.8,129.5,128.8, 128.3,128.1,127.8,127.7,127.6,126.9,126.8,125.3,125.2,121.3,121.2,120.3,120.2,119.2, 113.6,112.6,110.6,109.2,82.3,80.7,59.8,59.7,55.9,55.6,34.9,33.7,33.6,29.9,29.8,27.0, 20.1,17.1.
实施例21
原料：2，5-二甲基吲哚
产物：化学式：C28H29NO
分子量：395.2249
结构式：
产率：92％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr＝3:1)as a yellow solid,m.p.:98.4-99.5℃.1H NMR(300MHz,Chloroform-d)δ7.30(d,J＝8.1Hz,2H),7.25–7.09(m,5H),7.06(d,J＝10.6Hz,2H),6.93(d,J＝7.3Hz,2H),5.41(s,1H),3.76(d,J＝16.2 Hz,1H),2.67(d,J＝16.2Hz,1H),2.43(s,3H),2.33(s,3H),1.47(s,9H).13C NMR(75MHz, Chloroform-d)δ182.4,180.2,153.8,153.5,152.9,152.5,141.1,139.3,138.5,138.1,136.0, 135.9,135.0,134.9,129.05,128.99,128.7,128.2,128.1,127.8,127.7,127.6,126.9,126.8, 125.4,125.2,125.2,122.9,121.3,121.1,120.4,119.6,119.5,82.3,80.9,59.6,59.5,34.9,33.7, 33.5,29.9,29.7,21.7,21.6,20.2,17.2.
实施例22
原料：2-甲基-5-氟吲哚
产物：化学式：C27H26FNO
分子量：399.1998
结构式：
产率：86％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as separablediastereomers(dr＝3:1)as a yellow solid,m.p.:159.8-160.6℃.1H NMR(300MHz,Chloroform-d)δ7.32–7.26(m,2H),7.22– 7.16(m,2H),7.15–7.09(m,3H),7.09–7.02(m,3H),6.97(t,J＝7.6Hz,1H),5.34(s,1H), 3.67(d,J＝17.4Hz,1H),2.84(d,J＝17.3Hz,1H),2.33(s,3H),1.40(s,9H).13C NMR(75 MHz,Chloroform-d)δ184.0,153.4(d,J＝12.0Hz),142.9,137.1(d,J＝241.3Hz),131.0, 128.5(d,J＝22.8Hz),127.84,127.80(d,J＝8Hz),126.8,125.4,122.7,121.5,121.0,119.8, 82.2,60.3,35.0,33.3,29.9,20.2.
实施例23
原料：2-甲基-5-氯吲哚
产物：化学式：C27H26ClNO
分子量：415.1703
结构式：
产率：83％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as separablediastereomers(dr＝2.5:1)as a yellow solid,m.p.:161.2-162.3℃.1H NMR(300MHz,Chloroform-d)δ7.30–7.26(m,1H),7.21– 7.15(m,1H),7.15–7.08(m,3H),7.07–7.03(m,3H),7.02–6.93(m,2H),6.92–6.86(m,1H), 5.33(s,1H),3.65(d,J＝17.4Hz,1H),2.85(d,J＝17.4Hz,1H),2.33(s,3H),1.40(s,9H).13C NMR(75MHz,Chloroform-d)δ183.4,153.4,150.7,143.0,138.6,135.5,128.4,127.8,127.7, 126.8,125.4,121.5,120.9,120.8,119.9,115.2,114.9,110.1,109.8,82.3,60.3,35.0,33.4,29.9, 20.3.
实施例24
原料：2-甲基-6-甲氧基吲哚
产物：化学式：C28H29NO2
分子量：411.2198
结构式：
产率：89％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,2:5:50)afforded the product as inseparablediastereomers(dr＝3:1)as a yellow solid,m.p.:129.6-131.1℃.1H NMR(300MHz,Chloroform-d)δ7.35–7.26(m,1H),7.22– 7.14(m,1H),7.14–7.00(m,4H),7.00–6.82(m,4H),6.64(dd,J＝8.3,2.4Hz,1H),5.36(s, 1H),3.78(s,2H),3.69(d,J＝16.1Hz,1H),2.58(d,J＝16.1Hz,1H),2.38(s,3H),1.40(s,9H). 13C NMR(75MHz,Chloroform-d)δ184.8,182.7,160.5,156.5,156.0,153.7,153.5,138.5, 138.2,136.05,135.97,133.0,131.2,128.8,128.2,128.1,127.8,127.7,127.6,126.9,126.8, 125.3,125.2,124.7,122.3,121.3,121.1,120.4,119.5,111.3,111.2,105.9,82.4,81.0,59.4,59.2, 55.6,34.9,34.1,33.6,29.9,29.8,20.3,17.3.
实施例25
原料：2,4-二甲基吲哚
产物：化学式：C28H29NO
分子量：3952249
结构式：
产率：50％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,1:5:50)afforded the product as inseparablediastereomers(dr>20:1)as a yellow solid,m.p.:117.6-119.8℃.1H NMR(300MHz,Chloroform-d)δ7.27(d,J＝6.7Hz,1H),7.17 –7.04(m,8H),7.00(d,J＝7.6Hz,1H),6.98–6.93(m,1H),5.72(s,1H),4.02(d,J＝17.9Hz, 1H),2.77(d,J＝17.9Hz,1H),2.63(s,3H),2.37(s,3H),1.43(s,9H).13C NMR(75MHz, Chloroform-d)δ183.4,155.0,153.8,138.8,138.1,136.0,132.6,128.6,128.2,128.0,127.8, 127.7,126.1,125.1,121.5,120.2,118.0,79.0,61.4,34.9,29.9,29.8,20.3,18.8.
实施例26
原料：2-甲基-5-甲氧基吲哚
产物：化学式：C24H29NO2
分子量：393.2198
结构式：
产率：90％
Flash column chromatography on a basic alumina(ethyl acetate:dichloromethane: petroleum ether,2:5:50)afforded the product as a yellowsolid,m.p.:152.7-153.3℃.1H NMR (300MHz,Chloroform-d)δ7.44(d,J＝9.1Hz,1H),7.21(dd,J＝7.5,1.8Hz,1H),6.99–6.91 (m,1H),6.92–6.81(m,3H),3.78(s,3H),3.23(d,J＝17.4Hz,1H),2.77(d,J＝17.6Hz,1H), 2.20(s,3H),1.44(s,12H),1.16(s,3H).13C NMR(75MHz,Chloroform-d)δ183.1,157.8, 151.8,148.9,142.8,138.4,127.6,125.1,120.5,120.3,119.5,112.6,110.8,76.6,61.7,55.8,35.0, 31.0,29.9,23.9,23.4,19.4.
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (7)

1.螺环色螨类生物活性骨架，其特征在于，其结构式如下：
式中，R1为氢、烷基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为烷基、烯基、芳基中任意一种；R4为氢原子、烷基、卤素中任意一种。
2.根据权利要求1所述的螺环色螨类生物活性骨架的合成方法，其特征在于，包括以下步骤：
将取代的邻氧苯甲醛和取代的2-甲基吲哚溶于氟代醇并置于反应管中，在室温至加热条件下反应，制得螺环色螨类化合物；
其中，上述取代的邻氧苯甲醛类化合物的结构式如下：
其中，R1为氢、烷基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为烷基、烯基、芳基中任意一种；
其中，上述取代的2-甲基吲哚类化合物的结构式如下：
其中，R4为氢原子、烷基、卤素中任意一种。
3.根据权利要求2所述的合成方法，其特征在于，上述反应溶剂为2,2,2-三氟乙醇或1,1,1,3,3,3-六氟-2-丙醇。
4.根据权利要求2所述的合成方法，其特征在于，溶剂的用量为：每摩尔取代的邻氧苯甲醛和取代的2-甲基吲反应物添加5～10L氟代醇溶剂。
5.根据权利要求2所述的合成方法，其特征在于，反应时无需加入催化剂。
6.根据权利要求2所述的合成方法，其特征在于，反应温度为25-100℃。
7.氟代醇促进的[5+1]去芳香化反应构建螺环色螨类生物活性骨架在制备药物及药物中间体中的应用。
CN202210002348.9A 2022-01-05 2022-01-05 一种氟代醇促进的[5+1]去芳香化反应 Pending CN116444534A (zh)

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