CN113461700B - 一种氧气促进的去芳香化反应在构建螺环二烯酮骨架中的应用 - Google Patents

一种氧气促进的去芳香化反应在构建螺环二烯酮骨架中的应用 Download PDF

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CN113461700B
CN113461700B CN202110792351.0A CN202110792351A CN113461700B CN 113461700 B CN113461700 B CN 113461700B CN 202110792351 A CN202110792351 A CN 202110792351A CN 113461700 B CN113461700 B CN 113461700B
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李帅帅
胡方芝
李鑫瑶
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Abstract

本发明公开了一种氧气促进的去芳香化反应在构建螺环二烯酮骨架中的应用，所述螺环二烯酮的结构式为
Figure DDA0003159841550000011
式中，R1为烷氧基、胺基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为氢原子、烷基、烯基、烯丙基、芳基中任意一种。上述生物活性骨架的合成方法为：将含苯酚的二芳基甲烷类化合物溶于绿色溶剂正丁醇并置于密闭反应瓶中，插上充满氧气的氧气球，在加热条件下反应，制得螺环二烯酮类化合物。本发明提供了一种无需催化剂，一步反应高效合成螺环二烯酮类化合物的方法，首次实现了单一氧气分子促进的去芳香化反应，将含苯酚的二芳基甲烷类化合物绿色、高效的转化为高附加值的螺环二烯酮类化合物。

Description

一种氧气促进的去芳香化反应在构建螺环二烯酮骨架中的 应用
技术领域
本发明涉及化学合成技术领域，尤其涉及一种氧气促进的去芳香化反应在构建螺环二烯酮骨架中的应用。
背景技术
能源和环境是当今人类面临的两大问题。面向国家发展绿色化工、绿色制造的重大战略，发展具有重要生物活性的优势结构的绿色、高效合成方法是目前化学家急需解决的科学问题。环已二烯酮是许多天然产物、药物及药物中间体的核心结构，发展绿色合成技术高效构建该类活性骨架对于药物开发具有重要意义。苯酚类化合物廉价易得，通过苯酚的去芳香化反应来构建环己二烯酮骨架是目前最为方便快捷的策略。
Figure BDA0003159841530000011
2018年，青岛农业大学的李帅帅教授等人报道了六氟异丙醇促进的融合[1,5]-氢迁移过程的去芳香化反应，将廉价易得的苯酚类化合物转化为高附加值的螺环二烯酮类化合物，为螺环二烯酮类骨架的高效构建提供了一种新策略(Chem.Sci.,2018,9,8253-8259)。
Figure BDA0003159841530000012
2020年，青岛农业大学的李帅帅教授等人再次报道了螺环二烯酮类化合物的合成方法，将4-羟基吲哚类化合物作为原料，首次实现了吲哚碳环的去芳香化反应，合成了一系列含有螺环二烯酮结构的稠杂环化合物(Org.Chem.Front.,2020,7,2511-2517)。
Figure BDA0003159841530000013
基于上述对苯酚去芳香化构建螺环二烯酮反应的研究，我们希望能够发展更加绿色、高效的策略将苯酚类化合物去芳香化来合成高附加值的螺环二烯酮化合物，为医药化工企业服务。
发明内容
针对上述问题，本发明提供了一种氧气促进的去芳香化反应高效合成螺环二烯酮类化合物的方法。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、环境友好的特点；此外，所述合成方法反应条件温和，降低了产物的制备成本，便于工业化应用。
本发明的技术方案如下：
本发明提供螺环二烯酮类生物活性骨架，其结构式如下：
Figure BDA0003159841530000021
式中，R1为烷氧基、胺基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为氢原子、烷基、烯基、烯丙基、芳基中任意一种。
本发明还提供上述螺环二烯酮类生物活性骨架的合成方法，其包括以下步骤：
将含苯酚的二芳基甲烷类化合物溶于有机溶剂并置于密闭反应瓶中，插上充满氧气的氧气球，在加热条件下反应，制得螺环二烯酮类化合物；
其中，上述含苯酚的二芳基甲烷类化合物的结构式如下：
Figure BDA0003159841530000022
其中，R1为烷氧基、胺基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为氢原子、烷基、烯基、烯丙基、芳基中任意一种。
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，得到螺环二烯酮类化合物的纯化产物。
可选地，上述合成反应可无需外加催化剂，具有绿色、经济、环境友好的特点；此外，所述合成方法反应条件温和，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二烯酮类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(40-80℃)条件下，在绿色的正丁醇溶剂中一步反应高效合成了螺环二烯酮类活性骨架，本发明的技术方案为螺环二烯酮类骨架提供了绿色、方便、简洁的合成方法，首次实现了无催化剂、单一氧气分子促进的螺环二烯酮类骨架的高效构建。
2、该方法反应条件温和，一步反应合成螺环二烯酮类化合物，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二烯酮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。
附图说明
图1为本发明的合成工艺路线图。
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：
本实施例提供一种螺环二烯酮生物活性骨架的合成方法，其包括以下步骤：
取0.1mmol含苯酚的二芳基甲烷类化合物于反应瓶中并将反应瓶密闭，加入2mL正丁醇溶剂，控制体系的反应温度在40℃，并插上充满氧气的氧气球，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，收率为50％。反应式如下：
Figure BDA0003159841530000041
实施例2：
方法与实施例1基本相同，所不同的是加入2mL2-甲基四氢呋喃，收率为20％。
实施例3：
方法与实施例1基本相同，所不同的是加入2mL乙醇，收率为20％。
实施例4：
方法与实施例1基本相同，所不同的是控制体系的反应温度在60℃，收率为62％。
实施例5：
方法与实施例1基本相同，所不同的是控制体系的反应温度在80℃，收率为82％。
实施例6：
方法与实施例1基本相同，所不同的是控制体系的反应温度在100℃，收率为80％。
根据以上平行试验结果分析可知：本发明的合成反应以含苯酚的二芳基甲烷类化合物为原料，以正丁醇为溶剂，在密闭的反应瓶中插上充满氧气的氧气球，在80℃条件下收率最高。
下列实施例7-17中，按照实施例5的操作步骤进行反应；反应体系中，原料为含苯酚的二芳基甲烷类化合物，无催化剂，正丁醇绿色溶剂中，在密闭的反应瓶中插上充满氧气的氧气球，在80℃条件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7
原料：
Figure BDA0003159841530000051
产物：化学式：C21H26N2O
分子量：322.2108
结构式：
Figure BDA0003159841530000052
产率：82％
1H NMR(500MHz,CDCl3)δ7.12(t,J＝7.6Hz,1H),7.03(d,J＝7.3Hz,1H),6.58(t,J＝7.3Hz,1H),6.50(d,J＝8.1Hz,1H),6.39(dd,J＝10.5,2.2Hz,1H),6.16(d,J＝10.5Hz,1H),5.33(d,J＝2.1Hz,1H),3.86(dd,J＝9.9,5.1Hz,1H),3.54–3.43(m,2H),3.37(q,J＝7.1Hz,4H),3.18(d,J＝7.5Hz,1H),2.62(d,J＝15.8Hz,1H),1.99–1.87(m,3H),1.34–1.28(m,1H),1.22(t,J＝7.1Hz,6H)；13C NMR(125MHz,CDCl3)δ197.4,156.5,143.9,143.2,129.1,127.3,119.9,118.5,114.9,110.1,96.6,64.4,47.2,45.7,44.9,39.7,27.8,23.5.
实施例8
原料：
Figure BDA0003159841530000053
产物：化学式：C22H28N2O
分子量：336.2274
结构式：
Figure BDA0003159841530000061
产率：80％
1H NMR(500MHz,CDCl3)δ6.92(d,J＝7.5Hz,1H),6.44–6.35(m,2H),6.32(s,1H),6.17(d,J＝10.5Hz,1H),5.33(d,J＝2.2Hz,1H),3.84(dd,J＝9.8,5.3Hz,1H),3.49–3.40(m,2H),3.37(q,J＝7.1Hz,4H),3.18(d,J＝7.5Hz,1H),2.59(d,J＝15.7Hz,1H),2.31(s,3H),1.99–1.88(m,3H),1.34–1.25(m,1H),1.21(t,J＝7.1Hz,6H)；13C NMR(125MHz,CDCl3)δ197.5,156.5,144.1,143.1,136.9,129.0,118.4,117.0,115.9,110.9,96.6,64.4,47.2,46.0,44.9,39.5,27.8,23.5,21.6.
实施例9
原料：
Figure BDA0003159841530000062
产物：化学式：C21H25ClN2O
分子量：356.1720
结构式：
Figure BDA0003159841530000063
产率：90％
1H NMR(500MHz,CDCl3)δ7.02(t,J＝8.0Hz,1H),6.65(d,J＝7.9Hz,1H),6.42(dd,J＝16.1,5.3Hz,2H),6.12(d,J＝10.4Hz,1H),5.36(s,1H),3.80(dd,J＝9.8,5.1Hz,1H),3.45(t,J＝8.2Hz,1H),3.38(q,J＝7.1Hz,4H),3.25(d,J＝16.8Hz,1H),3.20(d,J＝7.8Hz,1H),2.97(d,J＝16.7Hz,1H),2.01–1.88(m,3H),1.38-1.28(m,1H),1.23(t,J＝7.1Hz,6H)；13CNMR(125MHz,CDCl3)δ196.8,156.6,144.4,143.5,134.7,127.5,118.8,117.8,115.9,108.7,96.6,63.8,47.5,45.6,44.9,37.0,27.8,23.6,18.5.
实施例10
原料：
Figure BDA0003159841530000071
产物：化学式：C21H25FN2O
分子量：340.2016
结构式：
Figure BDA0003159841530000072
产率：76％
1H NMR(500MHz,CDCl3)δ7.04(dd,J＝15.0,7.8Hz,1H),6.44(ddd,J＝36.8,10.5,2.0Hz,1H),6.37–6.27(m,2H),6.19(dd,J＝47.4,10.4Hz,1H),5.79(tdd,J＝10.6,8.7,5.1Hz,1H),5.35(dd,J＝10.8,2.0Hz,1H),5.10(dd,J＝15.1,9.2Hz,2H),3.96–3.74(m,2H),3.48–3.32(m,4H),3.18(dd,J＝31.4,16.6Hz,1H),2.83(dd,J＝16.0,11.6Hz,1H),2.54(dt,J＝18.7,9.3Hz,1H),2.26–1.96(m,1H),1.96–1.72(m,3H),1.43–1.32(m,1H),1.23(q,J＝7.0Hz,6H)；13C NMR(125MHz,CDCl3)δ197.10(s),196.78(s),162.1(d,J＝240.0Hz),161.7(d,J＝240.0Hz),156.6,143.5,143.3,143.2,135.3,134.9,127.4,127.3,118.7,118.6,117.5,117.2,107.9(d,J＝20.0Hz),106.9(d,J＝20.0Hz),106.46(d,J＝2.2Hz),106.1(d,J＝2.2Hz),101.9,101.7,96.7,96.6,65.1,62.6,59.1,57.0,45.1,45.0,44.9,37.0,36.1,32.1,31.8,28.5,27.7,26.0,25.2.
实施例11
原料：
Figure BDA0003159841530000081
产物：化学式：C21H25ClN2O
分子量：356.1728
结构式：
Figure BDA0003159841530000082
产率：83％
1H NMR(500MHz,CDCl3)δ7.05(d,J＝8.6Hz,1H),6.99(s,1H),6.41(t,J＝10.7Hz,2H),6.08(d,J＝10.4Hz,1H),5.33(s,1H),3.83(dd,J＝9.4,4.4Hz,1H),3.41(dq,J＝27.4,6.9Hz,6H),3.14(d,J＝7.7Hz,1H),2.56(d,J＝16.0Hz,1H),1.94(dt,J＝22.1,11.2Hz,3H),1.28(dd,J＝16.6,8.8Hz,1H),1.22(t,J＝7.1Hz,6H)；13C NMR(125MHz,CDCl3)δ196.9,156.5,143.3,141.8,128.7,127.0,121.4,119.5,118.9,111.1,96.6,64.4,47.4,45.3,39.4,27.8,23.5.
实施例12
原料：
Figure BDA0003159841530000083
产物：化学式：C21H25BrN2O
分子量：400.1223
结构式：
Figure BDA0003159841530000091
产率：70％
1H NMR(500MHz,CDCl3)δ6.95(t,J＝8.0Hz,1H),6.83(d,J＝7.8Hz,1H),6.47–6.39(m,2H),6.12(d,J＝10.4Hz,1H),5.36(d,J＝2.2Hz,1H),3.80(dd,J＝9.8,5.3Hz,1H),3.49–3.41(m,1H),3.39(q,J＝7.1Hz,4H),3.27(d,J＝16.7Hz,1H),3.20(dd,J＝16.2,8.8Hz,1H),2.94(d,J＝16.7Hz,1H),2.03–1.86(m,3H),1.31(dd,J＝14.5,6.6Hz,1H),1.27–1.19(m,6H)；13C NMR(125MHz,CDCl3)δ196.7,156.6,144.5,143.4,128.0,125.6,119.4,119.1,118.8,109.3,96.6,63.9,58.4,47.4,45.9,45.0,39.9,27.7,23.6.
实施例13
原料：
Figure BDA0003159841530000092
产物：化学式：C18H17NO3
分子量：295.1281
结构式：
Figure BDA0003159841530000093
产率：92％
1H NMR(500MHz,CDCl3)δ7.14(t,J＝7.7Hz,1H),7.02(d,J＝7.3Hz,1H),6.60(t,J＝7.3Hz,1H),6.51(d,J＝8.1Hz,1H),5.81(d,J＝9.9Hz,2H),5.71(s,1H),5.20(s,1H),3.75(dd,J＝9.8,5.4Hz,1H),3.52–3.43(m,1H),3.38(d,J＝15.5Hz,1H),3.19(dd,J＝16.3,8.7Hz,1H),2.69(d,J＝15.6Hz,1H),2.04–1.84(m,3H),1.46–1.34(m,1H)；13C NMR(125MHz,CDCl3)δ201.2,163.8,145.2,142.9,129.3,127.6,119.2,115.4,110.4,104.6,101.5,99.3,65.4,48.4,47.1,41.1,27.5,23.5.
实施例14
原料：
Figure BDA0003159841530000101
产物：化学式：C24H30N2O
分子量：362.2431
结构式：
Figure BDA0003159841530000102
产率：75％
dr 2:1.1H NMR(500MHz,CDCl3)δ7.11(t,J＝7.7Hz,1H),7.04(dd,J＝29.2,7.5Hz,1H),6.56(ddd,J＝32.1,18.0,4.4Hz,2H),6.42(ddd,J＝40.3,10.5,2.3Hz,1H),6.23(dd,J＝60.0,10.4Hz,1H),5.80(ddt,J＝17.0,10.3,7.1Hz,1H),5.33(dd,J＝10.4,2.3Hz,1H),5.15–5.04(m,2H),4.02–3.78(m,2H),3.48(t,J＝16.4Hz,1H),3.43–3.32(m,4H),2.66–2.51(m,2H),2.23–1.67(m,4H),1.43–1.32(m,1H),1.29–1.15(m,6H)；13C NMR(125MHz,CDCl3)δ197.4,197.1,156.6,156.5,144.1,144.0,142.1,141.7,135.6,135.2,129.8,129.4,127.2,127.0,120.7,119.8,118.5,118.3,117.3,117.0,115.0,114.9,110.9,110.3,96.6,96.5,65.6,63.3,58.6,56.5,45.9,45.8,44.9,39.8,39.4,37.2,36.0,28.7,27.8,26.2,25.2.
实施例15
原料：
Figure BDA0003159841530000111
产物：化学式：C25H32N2O
分子量：376.2587
结构式：
Figure BDA0003159841530000112
产率：70％
dr 2:1.1H NMR(500MHz,CDCl3)δ6.93(dd,J＝30.3,7.4Hz,1H),6.45-6.36(m,2H),6.36–6.15(m,2H),5.89–5.75(m,1H),5.32(dd,J＝10.6,2.0Hz,1H),5.10(dd,J＝16.4,11.2Hz,2H),4.00–3.77(m,2H),3.52–3.25(m,5H),2.66–2.50(m,2H),2.31(s,3H),2.23–1.72(m,4H),1.39-1.30(m,1H),1.25-1.19(m,6H)；13C NMR(125MHz,CDCl3)δ197.6,197.3,156.6,156.5,144.2,144.1,142.0,141.6,136.8,136.6,135.7,135.3,129.7,129.2,118.3,118.2,117.8,117.2,116.9,115.9,115.9,111.5,110.9,96.7,96.6,65.7,63.3,58.5,56.5,46.2,46.0,44.9,39.6,39.2,37.2,36.1,29.7,29.3,28.7,27.8,26.2,25.2,21.7.
实施例16
原料：
Figure BDA0003159841530000113
产物：化学式：C24H29ClN2O
分子量：396.2041
结构式：
Figure BDA0003159841530000121
产率：72％
dr 2:1.1H NMR(500MHz,CDCl3)δ7.10–6.95(m,2H),6.52–6.45(m,1H),6.44–6.36(m,1H),6.21(d,J＝10.4Hz,1H),6.10(d,J＝10.5Hz,1H),5.85–5.72(m,1H),5.33(dd,J＝9.5,2.0Hz,1H),5.11-5.07(m,2H),3.94(t,J＝7.0Hz,1H),3.87–3.75(m,2H),3.51–3.33(m,5H),2.61–2.46(m,2H),2.23–2.13(m,1H),2.02–1.69(m,4H),1.41–1.32(m,1H),1.27–1.19(m,6H)；13C NMR(125MHz,CDCl3)δ196.9,196.6,156.7,156.5,143.5,143.4,140.6,140.2,135.3,134.7,129.3,128.9,126.9,126.7,122.3,121.4,119.6,119.4,118.7,118.6,117.5,117.2,111.8,111.1,96.6,96.6,65.6,63.3,58.6,56.7,45.5,45.4,45.0,39.4,39.1,37.0,35.7,28.7,27.7,26.1,25.1.
实施例17
原料：
Figure BDA0003159841530000122
产物：化学式：C24H29FN2O
分子量：380.2337
结构式：
Figure BDA0003159841530000123
产率：82％
dr 2:1.1H NMR(500MHz,CDCl3)δ7.04(dd,J＝15.0,7.8Hz,1H),6.44(ddd,J＝36.8,10.5,2.0Hz,1H),6.37–6.27(m,2H),6.19(dd,J＝47.4,10.4Hz,1H),5.83-5.74m,1H),5.35(dd,J＝10.8,2.0Hz,1H),5.10(dd,J＝15.1,9.2Hz,2H),3.96–3.74(m,2H),3.48–3.32(m,4H),3.18(dd,J＝31.4,16.6Hz,1H),2.83(dd,J＝16.0,11.6Hz,1H),2.56-2.50(m,1H),2.26–1.96(m,1H),1.96–1.72(m,3H),1.43–1.32(m,1H),1.23(q,J＝7.0Hz,6H)；13CNMR(125MHz,CDCl3)δ197.1,196.8,163.1,162.6,161.2,160.7,156.6,143.5,143.4,143.3,135.3,134.9,127.5,127.4,127.3,118.7,118.6,117.5,117.2,107.9,107.8,106.9,106.5,106.5,106.1,101.9,101.7,96.7,96.6,65.1,62.6,59.1,57.0,45.1,45.0,44.9,37.0,36.1,32.2,32.1,31.9,28.5,27.7,26.0,25.2.
可以理解的是，对本领域普通技术人员来说，可以根据本发明的技术方案及本发明构思加以等同替换或改变，而所有这些改变或替换都应属于本发明所附的权利要求的保护范围。

Claims (6)

1.一种螺环二烯酮类生物活性骨架的合成方法，其特征在于，包括以下步骤：
将含苯酚的二芳基甲烷类化合物溶于有机溶剂并置于密闭反应瓶中，插上充满氧气的氧气球，在加热条件下反应，制得螺环二烯酮类化合物，其结构式如下：
Figure FDA0003575782450000011
其中，上述含苯酚的二芳基甲烷类化合物的结构式如下：
Figure FDA0003575782450000012
其中，R1为烷氧基、胺基中任意一种；R2为氢原子、烷基、卤素中任意一种；R3为氢原子、烷基、烯基、烯丙基、芳基中任意一种。
2.根据权利要求1所述的合成方法，其特征在于，上述反应溶剂为2-甲基四氢呋喃或正丁醇。
3.根据权利要求1所述的合成方法，其特征在于，反应时无需加入催化剂。
4.根据权利要求1所述的合成方法，其特征在于，反应温度为40-80℃。
5.根据权利要求1所述的合成方法，其特征在于，反应时只需插上充满氧气的氧气球。
6.氧气促进的去芳香化反应构建螺环二烯酮类生物活性骨架在制备药物及药物中间体中的应用，其特征在于，所述螺环二烯酮类生物活性骨架根据权利要求1所述的合成方法合成。
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