CN108640918B - 一种氮杂环取代对醌骨架螺环化合物的合成方法 - Google Patents
一种氮杂环取代对醌骨架螺环化合物的合成方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种氮杂环取代对醌骨架螺环化合物的合成方法,这是一种以对亚甲基苯醌作为氢受体的氢迁移反应实现对醌化合物的构建策略,2,6‑二叔丁基苯酚与氨基甲醛类化合物以芳香化为驱动力,通过“一锅法”最终得到螺环对醌产物。本发明提供的合成方法,不需要预先合成对位取代基团,实现了分子间的酚类脱芳构化的化学选择性和位点特异性。本发明原料简单易得;在室温下即可反应,反应条件温和,无需金属或质子催化剂,操作方便,经济高效;本发明方法的反应活性高,产率高达99%,原料转化完全;产物分离方便,且反应具有绿色经济性,对环境友好。
Description
技术领域
本发明属于化学合成技术领域,具体涉及一种氮杂环取代对醌骨架螺环化合物的合成方法。
背景技术
在各种具有生物活性的天然和非天然产物中存在大量对醌类化合物,对其进行人工合成以及功能化改造,获得了有机合成、制药等行业研究人员的广泛关注。
取代对醌类化合物的有机合成策略中,通过酚类和苯胺类化合物的催化脱芳构化反应,可以实现对醌类化合物的高效功能化改造,合成众多含有季碳中心、螺环或桥环的三维立体结构化合物。例如,以上两种天然分子已经通过酚类衍生物的催化脱芳构化合成。
经典的酚类脱芳构化方法包括分子间氧化脱芳构化反应和非氧化脱芳构化反应。2013年Harned等人利用新型的手性芳基碘催化剂,将对位取代苯酚的酚羟基首先氧化,产生的中间体与亲核试剂合成呋喃取代对醌化合物(Chem.Commun.,2013,49,3001-3003)。2010年,Hamada及其同事公开了借助Pd催化剂,将烯丙基烷基对位取代的苯酚利用分子内脱芳构化合成五元环取代对醌化合物(Org.Lett.,2010,12,5020-5023);2011年,You等人利用相同反应机理,利用Ir催化剂实现了氮杂五元环取代对醌化合物的合成(Angew.Chem,Int.Ed.,2011,50,4455-4458)。Hamada和You的工作利用了酚对位取代基的亲核部分来避免反应过程中,来自酚氧和/或邻位的烷基化压力。但是当面对分子间的酚类脱芳构化时,如何实现化学选择性和位点特异性仍然面临巨大的挑战。
由于,目前的催化脱芳构化合成取代对醌类化合物反应,仍然依赖过渡金属催化剂等众多特殊的手性催化剂,严重限制了新的具有复杂结构的对醌化合物的串联反应合成策略的发展。目前,利用串联[1,n]-氢迁移/环化反应(叔胺基效应)在路易斯酸、布朗斯特酸或者手性胺催化剂甚至在简单的加热条件下,就能直接形成碳-碳、碳-氮、碳-氧键等,在构成五元、六元杂环和全碳环的反应中表现出巨大的潜力。中国专利CN201711248907.X和CN201711254567.1公开了在酸性条件下,利用氢迁移策略,生成亚胺正离子,分别借助樟脑磺酸、联萘酚磷酸两种非过渡金属催化剂,生成苯并氮杂环化合物二苯并[b,e]吖庚因类化合物、八氢二吡咯并喹啉骨架化合物。但是对于合成属于非芳香、α,β-不饱和酮的对醌化合物,由于以上两种策略无法实现稠环芳烃的去芳香化,因此并不适合对醌化合物的高效合成。
而且,利用串联[1,n]-氢迁移/环化反应(叔胺基效应)在反应过程中,存在其他竞争反应,如,羟基间位进攻氢迁移生成的亚胺正离子可以构建七元环,羟基进攻该正离子可以生成八元环,并且由于苯醌具有恢复成苯环结构的强烈趋势,阻碍了氢迁移/环化反应的有效去芳香化,难以形成稳定的对醌化合物。
因此,需要一种新的酚类和苯胺类化合物的催化脱芳构化方法,以改善对醌化合物合成反应的反应条件和反应效率。
发明内容
本发明的目的在于提供一种氮杂环取代对醌骨架螺环化合物的合成方法。本发明操作简单实用,产率好,且反应具有绿色经济性,对环境友好。
本发明所提供的合成方法,包括下述步骤:
由酚类化合物A与氨基甲醛类化合物B进行反应,以哌啶为添加剂,在甲苯中、120℃条件下反应12h,冷却至室温25℃,制得反应中间体,再向反应体系中加入六氟异丙醇,即得所述氮杂环取代对醌骨架螺环化合物。
将所述反应中间体分离,加入六氟异丙醇中,即得所述氮杂环取代对醌骨架螺环化合物。
所述氮杂环取代对醌骨架螺环化合物为式Ⅰ、式Ⅱ所示化合物中任意一种:
其中
式Ⅰ、式Ⅱ中,虚线表示任选的单键;
n为0或1;
X选自碳或氮;
R1选自氢、氯、溴、甲基、三氟甲基、甲氧基、氰基、对苯乙酰基、丙烯酸甲酯中任意一种。
所述酚类化合物A为式Ⅲ所示化合物;
所述氨基甲醛类化合物B为式Ⅳ、式Ⅴ所示化合物中任意一种:
其中
式Ⅲ、式Ⅳ、式Ⅴ中,虚线表示任选的单键;
n为0或1;
X选自碳或氮;
R1选自氢、氯、溴、甲基、三氟甲基、甲氧基、氰基、对苯乙酰基、丙烯酸甲酯中任意一种。
所述化合物A与所述化合物B的摩尔比为1.3:1。
所述哌啶与化合物B的摩尔比为1:2。
本发明提供了式Ⅰ、式Ⅱ所示化合物的合成方法,包括以下步骤:
按比例将化合物A、化合物B和哌啶加入到甲苯中,在120℃条件下反应12h,冷却至25℃,得到中间体对醌化合物;
向反应体系中加入六氟异丙醇,在25℃条件下搅拌反应10min,反应完毕进行浓缩、纯化,制得氮杂环取代对醌骨架螺环化合物;
其中可将中间体对醌化合物分离纯化,在25℃-100℃条件下,于六氟异丙醇中进行反应,反应完毕进行浓缩、纯化,制得氮杂环取代对醌骨架螺环化合物。
本发明的技术方案取得了如下有益效果:
本发明公开的取代对醌骨架螺环化合物的合成方法。本发明中2,6-二叔丁基苯酚与氨基甲醛类化合物以芳香化为驱动力,通过氮原子α位氢迁移策略,亚胺正离子受到富电子芳环的进攻最终实现苯酚的去芳香化,以对亚甲基苯醌作为氢受体的氢迁移反应,通过“一锅法”生成氮杂环取代对醌骨架螺环化合物,不需要中间产物的分离,氢供体和受体可以在一个反应中原位完成,构成螺环化合物。本发明的合成策略不需要预先合成对位取代基团,实现了分子间的酚类脱芳构化的化学选择性和位点特异性。无需金属或质子催化剂,操作方便,经济高效;反应活性高,产率高达99%,原料转化完全;产物分离方便,且反应具有绿色经济性,对环境友好。
具体实施方式
通过以下实施例提供的具体实施方案,对本发明的上述内容进行进一步详细说明,对于本研究领域的技术人员而言,不应将此理解为本发明上述主题的范围仅限于以下实例;凡基于本发明上述内容所实现的技术均属于本发明的范围。
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
取化合物A1(2,6-二叔丁基苯酚)0.13mmol、化合物B1(2-吡咯烷基苯甲醛)0.1mmol和哌啶0.2mmol于反应瓶中,加入1mL甲苯,在120℃搅拌反应12h,之后冷却至室温;
随后向反应体系中加入1mL的六氟异丙醇HFIP,在25℃下搅拌10min,待反应结束后,将反应产物进行旋蒸浓缩,在硅胶柱上纯化分离。
对分离产物进行检测分析,分析数据结果如下,所得产物为目标产物,产率为60%。
化学式:C25H33NO
精确分子量:363.2562
分子量:363.5450
产率:60%
1H核磁共振(500MHz,CDCl3)δ7.14(t,J=7.7Hz,1H),6.99(d,J=7.4Hz,1H),6.62(t,J=7.3Hz,1H),6.51(d,J=8.1Hz,1H),6.35(d,J=2.9Hz,1H),6.33(d,J=2.8Hz,1H),3.63(dd,J=9.2,6.2Hz,1H),3.45(td,J=8.6,3.6Hz,1H),3.24(dd,J=16.5,8.2Hz,1H),3.18(d,J=15.8Hz,1H),2.55(d,J=15.8Hz,1H),1.91(ddd,J=15.2,9.0,5.7Hz,2H),1.79(ddd,J=12.5,6.3,3.0Hz,1H),1.27(s,9H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.8,149.1,148.2,144.3,143.5,139.5,129.0,127.7,118.6,115.9,110.6,64.3,47.5,39.9,38.4,34.9,34.9,30.4,29.5,27.7,23.3.高分辨质谱分析(ESI)calcd.for C25H33NO[M+H]+:364.2562,实际值:364.2560.
实施例2
取化合物A1(2,6-二叔丁基苯酚)0.13mmol、化合物B1(2-吡咯烷基苯甲醛)0.1mmol和哌啶0.2mmol于反应瓶中,加入1mL甲苯,在120℃搅拌反应12h,之后冷却至室温,将反应中间体分离纯化;
将反应中间体加入2mL的六氟异丙醇HFIP中,在25℃下搅拌10min,待反应结束后,将反应产物进行旋蒸浓缩,在硅胶柱上纯化分离。
对分离产物进行检测分析,分析数据结果如下,所得产物为目标产物,产率为90%。
化学式:C25H33NO
精确分子量:363.2562
分子量:363.5450
产率:90%
1H核磁共振(500MHz,CDCl3)δ7.14(t,J=7.7Hz,1H),6.99(d,J=7.4Hz,1H),6.62(t,J=7.3Hz,1H),6.51(d,J=8.1Hz,1H),6.35(d,J=2.9Hz,1H),6.33(d,J=2.8Hz,1H),3.63(dd,J=9.2,6.2Hz,1H),3.45(td,J=8.6,3.6Hz,1H),3.24(dd,J=16.5,8.2Hz,1H),3.18(d,J=15.8Hz,1H),2.55(d,J=15.8Hz,1H),1.91(ddd,J=15.2,9.0,5.7Hz,2H),1.79(ddd,J=12.5,6.3,3.0Hz,1H),1.27(s,9H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.8,149.1,148.2,144.3,143.5,139.5,129.0,127.7,118.6,115.9,110.6,64.3,47.5,39.9,38.4,34.9,34.9,30.4,29.5,27.7,23.3.高分辨质谱分析(ESI)calcd.for C25H33NO[M+H]+:364.2562,实际值:364.2560.
下列实施例3-9中,按照实施例1的操作步骤,原料化合物A与化合物B按摩尔比1.3:1进行反应。
实施例3
原料:4-溴-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
产物:化学式:C25H32BrNO
精确分子量:441.1667
分子量:442.4410
产率:50%
1H核磁共振(500MHz,CDCl3)δ6.83(d,J=7.8Hz,1H),6.72(dd,J=7.9,1.9Hz,1H),6.61(d,J=1.9Hz,1H),6.33(d,J=2.9Hz,1H),6.24(d,J=2.9Hz,1H),3.61(dd,J=9.5,6.0Hz,1H),3.43(td,J=8.8,3.2Hz,1H),3.20(dd,J=16.4,8.7Hz,1H),3.08(dd,J=15.8,0.8Hz,1H),2.51(d,J=15.8Hz,1H),1.98–1.84(m,2H),1.79(dtd,J=10.0,6.4,3.2Hz,1H),1.29–1.23(m,11H),1.13(s,10H);13C核磁共振(126MHz,CDCl3)δ186.7,149.4,148.5,144.5,143.7,138.7,130.2,121.3,118.5,117.5,113.1,77.3,77.0,76.8,64.1,47.5,39.5,38.0,35.0,34.9,29.5,29.5,27.7,23.3.高分辨质谱分析(ESI):calcd.forC25H32BrNO[M+H]+:442.1667,实际值:442.1677.
实施例4
原料:4-甲基-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
产物:化学式:C26H35NO
精确分子量:377.2719
分子量:377.5720
产率:85%
1H核磁共振(500MHz,CDCl3)δ6.88(d,J=7.5Hz,1H),6.45(d,J=7.4Hz,1H),6.34(d,J=11.1Hz,3H),3.59(dd,J=9.0,6.3Hz,1H),3.43(td,J=8.7,3.5Hz,1H),3.24(q,J=8.1Hz,1H),3.13(d,J=15.7Hz,1H),2.52(d,J=15.7Hz,1H),2.31(s,3H),1.95–1.83(m,2H),1.77(dtd,J=9.6,6.5,3.0Hz,1H),1.31–1.21(m,10H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.9,148.9,148.1,144.4,143.3,139.7,137.3,128.8,116.7,115.7,111.4,77.3,77.0,76.8,64.3,47.4,39.6,38.7,34.9,34.8,29.6,29.5,27.7,23.3,21.6.高分辨质谱分析(ESI):calcd.for C26H35NO[M+H]+:378.2719,实际值:378.2723.
实施例5
原料:4-丙烯酸甲脂-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
产物:化学式:C29H37NO3
精确分子量:447.2773
分子量:447.6190
产率:80%
1H核磁共振(500MHz,CDCl3)δ7.66(d,J=16.0Hz,1H),7.00(d,J=7.5Hz,1H),6.81(d,J=7.5Hz,1H),6.62(s,1H),6.41(d,J=15.9Hz,1H),6.34(s,1H),6.27(s,1H),3.81(s,3H),3.68–3.59(m,1H),3.48(t,J=8.5Hz,1H),3.26(d,J=8.2Hz,1H),3.16(d,J=16.1Hz,1H),2.58(d,J=16.1Hz,1H),1.93(dd,J=16.7,7.8Hz,2H),1.80(dd,J=7.7,4.4Hz,1H),1.31(s,1H),1.26(s,9H),1.12(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,167.7,149.4,148.5,145.8,143.7,143.7,138.9,133.8,129.4,121.6,116.6,116.3,109.5,64.3,51.6,47.5,40.0,38.2,35.0,34.9,29.5,27.8,23.3.高分辨质谱分析(ESI):calcd.for C29H37NO3[M+H]+:448.2773,实际值:448.2770.
实施例6
原料:5-氯-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
产物:化学式:C25H32ClNO
精确分子量:397.2172
分子量:397.9870
产率:62%
1H核磁共振(500MHz,CDCl3)δ7.08(d,J=8.6Hz,1H),6.95(s,1H),6.41(d,J=8.6Hz,1H),6.32(d,J=1.7Hz,1H),6.25(s,1H),3.60(dd,J=9.0,6.3Hz,1H),3.50–3.39(m,1H),3.20(d,J=8.2Hz,1H),3.12(d,J=15.9Hz,1H),2.51(d,J=15.9Hz,1H),1.90(dd,J=17.2,9.0Hz,2H),1.79(dd,J=7.4,4.5Hz,1H),1.34–1.23(m,10H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,149.4,148.5,143.7,142.1,138.8,128.6,127.5,120.3,120.1,111.6,64.3,47.6,39.7,38.1,35.0,34.9,29.5,27.7,23.3.高分辨质谱分析(ESI):calcd.for C25H32ClNO[M+H]+:398.2172,实际值:398.2174.
实施例7
原料:6-溴-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
产物:化学式:C25H32BrNO
精确分子量:441.1667
分子量:442.4410
产率:52%
1H核磁共振(500MHz,CDCl3)δ6.99(t,J=7.9Hz,1H),6.89(d,J=7.9Hz,1H),6.46(d,J=8.1Hz,1H),6.35(s,1H),6.27(s,1H),3.61–3.50(m,1H),3.43(d,J=3.0Hz,1H),3.27(d,J=8.2Hz,1H),2.92(d,J=16.7Hz,1H),2.84(d,J=16.7Hz,1H),1.98–1.84(m,2H),1.81(dd,J=9.8,6.3Hz,1H),1.31(d,J=11.7Hz,1H),1.28(s,9H),1.15(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,149.3,148.6,144.9,143.6,138.8,128.4,125.5,119.9,118.2,109.9,63.7,47.7,40.2,38.9,35.0,34.9,29.5,29.5,27.5,23.4.高分辨质谱分析(ESI):calcd.for C25H32BrNO[M+H]+:442.1667,实际值:442.1670.
实施例8
原料:2-全氢异吲哚基苯甲醛,2,6-二叔丁基苯酚
产物:化学式:C29H39NO
精确分子量:417.3032
分子量:417.6370
产率:75%
1H核磁共振(500MHz,CDCl3)δ7.13(t,J=7.3Hz,1H),6.93(d,J=7.0Hz,1H),6.57(t,J=6.9Hz,1H),6.46(d,J=7.8Hz,1H),6.40(s,1H),6.31(s,1H),3.58(t,J=7.5Hz,1H),3.39(d,J=7.2Hz,1H),3.14(d,J=15.3Hz,1H),2.72(t,J=9.4Hz,1H),2.40(d,J=15.4Hz,1H),1.97(d,J=12.0Hz,1H),1.81-1.61(m,4H),1.26(s,10H),1.11(s,10H),1.08-0.94(m,3H);13C核磁共振(126MHz,CDCl3)δ186.7,148.4,147.0,144.8,143.2,140.2,128.7,127.8,117.8,115.2,109.4,68.8,51.7,48.3,43.4,40.8,37.9,34.9,34.9,29.8,29.5,29.3,29.2,25.7.高分辨质谱分析(ESI):calcd.for C29H39NO[M+H]+:418.3032,实际值:418.3034.
实施例9
原料:8-吡咯烷基-1-萘基甲醛,2,6-二叔丁基苯酚
产物:化学式:C29H37NO
精确分子量:413.2719
分子量:413.6050
产率:91%
1H核磁共振(500MHz,CDCl3)δ7.65(d,J=8.2Hz,1H),7.31(s,3H),7.05(d,J=6.6Hz,1H),6.86(s,1H),6.71(s,2H),3.78(d,J=13.0Hz,1H),3.66(d,J=9.3Hz,1H),3.56(d,J=6.4Hz,1H),3.07(d,J=8.7Hz,1H),2.48(d,J=13.0Hz,1H),1.92(d,J=6.8Hz,2H),1.67-1.59(m,1H),1.33(s,9H),1.24(s,10H);13C核磁共振(126MHz,CDCl3)6186.7,150.5,148.5,147.5,142.9,142.9,135.5,134.7,127.3,126.8,125.9,125.8,125.5,119.1,107.6,70.8,51.7,49.4,44.3,35.1,34.9,29.6,26.9,25.3.高分辨质谱分析(ESI):calcd.for C29H37NO[M+H]+:416.2875,实际值:416.2877.
下列实施例10-24中,按照实施例2的操作步骤制得反应中间体,各实施例中间体在HFIP中进行反应的温度和时间随原料不同而变化。原料化合物A与化合物B按摩尔比1.3:1进行反应。
实施例10
原料:4-氯-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,3min
产物:化学式:C25H32ClNO
精确分子量:397.2172
分子量:397.9870
产率:94%
1H核磁共振(500MHz,CDCl3)δ6.89(d,J=7.9Hz,1H),6.57(d,J=7.9Hz,1H),6.46(s,1H),6.33(s,1H),6.25(s,1H),3.67–3.57(m,1H),3.43(t,J=8.4Hz,1H),3.20(d,J=8.3Hz,1H),3.09(d,J=15.7Hz,1H),2.52(d,J=15.8Hz,1H),1.91(dd,J=17.1,8.1Hz,2H),1.83–1.74(m,1H),1.26(s,11H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,149.4,148.5,144.3,143.7,138.8,133.1,129.8,117.0,115.6,110.2,64.2,47.5,39.5,38.0,35.0,34.9,29.5,29.5,27.8,23.3.高分辨质谱分析(ESI):calcd.for C25H32ClNO[M+H]+:398.2172,实际值:398.2170.
实施例11
原料:4-溴-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,10min
产物:化学式:C25H32BrNO
精确分子量:441.1667
分子量:442.4410
产率:93%
1H核磁共振(500MHz,CDCl3)δ6.83(d,J=7.8Hz,1H),6.72(dd,J=7.9,1.9Hz,1H),6.61(d,J=1.9Hz,1H),6.33(d,J=2.9Hz,1H),6.24(d,J=2.9Hz,1H),3.61(dd,J=9.5,6.0Hz,1H),3.43(td,J=8.8,3.2Hz,1H),3.20(dd,J=16.4,8.7Hz,1H),3.08(dd,J=15.8,0.8Hz,1H),2.51(d,J=15.8Hz,1H),1.98–1.84(m,2H),1.79(dtd,J=10.0,6.4,3.2Hz,1H),1.29–1.23(m,11H),1.13(s,10H);13C核磁共振(126MHz,CDCl3)δ186.7,149.4,148.5,144.5,143.7,138.7,130.2,121.3,118.5,117.5,113.1,77.3,77.0,76.8,64.1,47.5,39.5,38.0,35.0,34.9,29.5,29.5,27.7,23.3.高分辨质谱分析(ESI):calcd.forC25H32BrNO[M+H]+:442.1667,实际值:442.1677.
实施例12
原料:4-氰基-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,50min
产物:化学式:C26H32N2O
精确分子量:388.2515
分子量:388.5550
产率:98%
1H核磁共振(500MHz,CDCl3)δ7.04(d,J=7.6Hz,1H),6.89(d,J=7.5Hz,1H),6.68(s,1H),6.33(s,1H),6.16(s,1H),3.66(dd,J=9.2,6.2Hz,1H),3.47(t,J=8.5Hz,1H),3.27–3.12(m,2H),2.59(d,J=16.2Hz,1H),1.95(dt,J=17.3,8.0Hz,2H),1.83(dt,J=11.9,5.8Hz,1H),1.34–1.22(m,11H),1.12(s,9H);13C核磁共振(126MHz,CDCl3)δ186.5,149.8,148.9,143.6,143.0,137.9,129.5,123.8,119.8,119.4,112.8,111.3,64.3,47.5,40.1,37.5,35.0,34.9,29.5,27.8,23.3.高分辨质谱分析(ESI):calcd.for C26H32N2O[M+H]+:389.2515,实际值389.2118.
实施例13
原料:4-三氟甲基-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,5min
产物:化学式:C26H32F3NO
精确分子量:431.2436
分子量:431.5432
产率:96%
1H核磁共振(500MHz,CDCl3)δ7.06(d,J=7.6Hz,1H),6.85(d,J=7.6Hz,1H),6.67(s,1H),6.34(s,1H),6.24(s,1H),3.71–3.61(m,1H),3.49(t,J=8.4Hz,1H),3.26(q,J=8.2Hz,1H),3.17(d,J=16.0Hz,1H),2.60(d,J=16.1Hz,1H),2.02–1.88(m,2H),1.82(dd,J=12.1,5.9Hz,1H),1.34–1.22(m,11H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.6(s),149.6(s),148.7(s),143.5(s),138.5(s),130.1(s),129.9(s),129.6(s),129.1(s),127.8(s),125.6(s),123.5(s),122.2(s),121.3(s),112.7–112.1(m),107.0–106.5(m),64.3(s),47.5(s),39.8(s),37.8(s),34.9(d,J=12.5Hz),29.5(s),27.8(s),23.3(s).高分辨质谱分析(ESI):calcd.for C26H32F3NO[M+H]+:364.2562,实际值:364.2560.
实施例14
原料:4-甲基-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,10min
产物:化学式:C26H35NO
精确分子量:377.2719
分子量:377.5720
产率:91%
1H核磁共振(500MHz,CDCl3)δ6.88(d,J=7.5Hz,1H),6.45(d,J=7.4Hz,1H),6.34(d,J=11.1Hz,3H),3.59(dd,J=9.0,6.3Hz,1H),3.43(td,J=8.7,3.5Hz,1H),3.24(q,J=8.1Hz,1H),3.13(d,J=15.7Hz,1H),2.52(d,J=15.7Hz,1H),2.31(s,3H),1.95–1.83(m,2H),1.77(dtd,J=9.6,6.5,3.0Hz,1H),1.31–1.21(m,10H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.9,148.9,148.1,144.4,143.3,139.7,137.3,128.8,116.7,115.7,111.4,77.3,77.0,76.8,64.3,47.4,39.6,38.7,34.9,34.8,29.6,29.5,27.7,23.3,21.6.高分辨质谱分析(ESI):calcd.for C26H35NO[M+H]+:378.2719,实际值:378.2723.
实施例15
原料:4-丙烯酸甲脂-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,8min
产物:化学式:C29H37NO3
精确分子量:447.2773
分子量:447.6190
产率:88%
1H核磁共振(500MHz,CDCl3)δ7.66(d,J=16.0Hz,1H),7.00(d,J=7.5Hz,1H),6.81(d,J=7.5Hz,1H),6.62(s,1H),6.41(d,J=15.9Hz,1H),6.34(s,1H),6.27(s,1H),3.81(s,3H),3.68–3.59(m,1H),3.48(t,J=8.5Hz,1H),3.26(d,J=8.2Hz,1H),3.16(d,J=16.1Hz,1H),2.58(d,J=16.1Hz,1H),1.93(dd,J=16.7,7.8Hz,2H),1.80(dd,J=7.7,4.4Hz,1H),1.31(s,1H),1.26(s,9H),1.12(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,167.7,149.4,148.5,145.8,143.7,143.7,138.9,133.8,129.4,121.6,116.6,116.3,109.5,64.3,51.6,47.5,40.0,38.2,35.0,34.9,29.5,27.8,23.3.高分辨质谱分析(ESI):calcd.for C29H37NO3[M+H]+:448.2773,实际值:448.2770.
实施例16
原料:4-对乙酰苯基-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,8min
产物:化学式:C23H39NO2
精确分子量:481.2981
分子量:481.6800
产率:85%
1H核磁共振(500MHz,CDCl3)δ8.02(d,J=7.4Hz,2H),7.72(d,J=7.4Hz,2H),7.09(d,J=7.3Hz,1H),6.90(d,J=7.4Hz,1H),6.72(s,1H),6.48–6.31(m,2H),3.67(t,J=6.8Hz,1H),3.54(t,J=8.3Hz,1H),3.33(d,J=8.1Hz,1H),3.21(d,J=15.9Hz,1H),2.63(s,3H),2.60(s,1H),2.02–1.87(m,2H),1.82(d,J=2.9Hz,1H),1.33(s,1H),1.30(d,J=18.9Hz,9H),1.15(s,9H);13C核磁共振(126MHz,CDCl3)δ197.82,186.79,149.30,148.43,146.54,143.98,143.85,139.40,139.18,135.66,129.56,128.84,127.11,119.03,115.01,109.17,64.38,47.54,39.74,38.40,35.04,34.93,29.59,29.56,27.78,26.68,23.34.高分辨质谱分析(ESI):calcd.for C23H39NO2[M+H]+:482.2981,实际值:482.2986.
实施例17
原料:5-氯-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,10min
产物:化学式:C25H32ClNO
精确分子量:397.2172
分子量:397.9870
产率:81%
1H核磁共振(500MHz,CDCl3)δ7.08(d,J=8.6Hz,1H),6.95(s,1H),6.41(d,J=8.6Hz,1H),6.32(d,J=1.7Hz,1H),6.25(s,1H),3.60(dd,J=9.0,6.3Hz,1H),3.50—3.39(m,1H),3.20(d,J=8.2Hz,1H),3.12(d,J=15.9Hz,1H),2.51(d,J=15.9Hz,1H),1.90(dd,J=17.2,9.0Hz,2H),1.79(dd,J=7.4,4.5Hz,1H),1.34-1.23(m,10H),1.13(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,149.4,148.5,143.7,142.1,138.8,128.6,127.5,120.3,120.1,111.6,64.3,47.6,39.7,38.1,35.0,34.9,29.5,27.7,23.3.高分辨质谱分析(ESI):calcd.for C25H32ClNO[M+H]+:398.2172,实际值:398.2174.
实施例18
原料:5-氰基-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,20min
产物:化学式:C26H32N2O
精确分子量:388.2515
分子量:388.5550
产率:91%
1H核磁共振(500MHz,CDCl3)δ7.41(d,J=8.4Hz,1H),7.23(s,1H),6.47(d,J=8.5Hz,1H),6.33(d,J=2.3Hz,1H),6.14(d,J=2.3Hz,1H),3.70(dd,J=9.8,6.0Hz,1H),3.54(t,J=8.9Hz,1H),3.25(dd,J=17.0,9.0Hz,1H),3.13(d,J=15.8Hz,1H),2.56(d,J=15.8Hz,1H),2.04-1.89(m,2H),1.84(dt,J=12.2,6.1Hz,1H),1.33-1.23(m,11H),1.12(s,9H);13C核磁共振(126MHz,CDCl3)δ186.4,149.9,149.0,146.3,142.8,137.5,132.5,132.5,120.7,118.9,110.2,97.4,64.5,47.5,39.5,37.4,35.1,34.9,29.5,29.5,27.8,23.2.高分辨质谱分析(ESI):calcd.for C26H32N2O[M+H]+:389.2515,实际值:389.2516.
实施例19
原料:6-氯-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,3min
产物:化学式:C25H32ClNO
精确分子量:397.2172
分子量:397.9870
产率:97%
1H核磁共振(500MHz,CDCl3)δ7.06(t,J=8.0Hz,1H),6.71(d,J=7.9Hz,1H),6.42(d,J=8.2Hz,1H),6.35(d,J=2.2Hz,1H),6.28(s,1H),3.55(t,J=7.2Hz,1H),3.43(td,J=8.5,3.9Hz,1H),3.27(q,J=8.1Hz,1H),2.95–2.83(m,2H),1.97–1.85(m,2H),1.84–1.76(m,1H),1.33–1.24(m,11H),1.14(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,149.3,148.6,144.8,143.7,138.9,134.6,128.0,116.7,116.6,109.2,63.6,47.7,38.5,37.2,35.0,34.9,29.5,27.6,23.4.高分辨质谱分析(ESI):calcd.for C25H32ClNO[M+H]+:398.2172,实际值:398.2175.
实施例30
原料:6-溴-2-吡咯烷基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,3min
产物:化学式:C25H32BrNO
精确分子量:441.1667
分子量:442.4410
产率:99%
1H核磁共振(500MHz,CDCl3)δ6.99(t,J=7.9Hz,1H),6.89(d,J=7.9Hz,1H),6.46(d,J=8.1Hz,1H),6.35(s,1H),6.27(s,1H),3.61–3.50(m,1H),3.43(d,J=3.0Hz,1H),3.27(d,J=8.2Hz,1H),2.92(d,J=16.7Hz,1H),2.84(d,J=16.7Hz,1H),1.98–1.84(m,2H),1.81(dd,J=9.8,6.3Hz,1H),1.31(d,J=11.7Hz,1H),1.28(s,9H),1.15(s,9H);13C核磁共振(126MHz,CDCl3)δ186.7,149.3,148.6,144.9,143.6,138.8,128.4,125.5,119.9,118.2,109.9,63.7,47.7,40.2,38.9,35.0,34.9,29.5,29.5,27.5,23.4.高分辨质谱分析(ESI):calcd.for C25H32BrNO[M+H]+:442.1667,实际值:442.1670.
实施例21
原料:2-吡咯烷基萘甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,20min
产物:化学式:C29H35NO
精确分子量:413.2719
分子量:413.6050
产率:98%
1H核磁共振(500MHz,CDCl3)δ7.72(d,J=8.0Hz,1H),7.67(dd,J=8.3,3.7Hz,2H),7.41(t,J=7.6Hz,1H),7.21(t,J=7.4Hz,1H),7.00(d,J=8.9Hz,1H),6.48–6.38(m,2H),3.60(d,J=6.5Hz,2H),3.42(q,J=7.7Hz,1H),3.19(d,J=16.3Hz,1H),3.04(d,J=16.3Hz,1H),1.87(ddd,J=18.0,13.6,6.3Hz,3H),1.40–1.28(m,10H),1.10(s,9H);13C核磁共振(126MHz,CDCl3)δ186.8,148.9,148.4,144.6,141.1,139.8,133.2,128.6,128.0,126.8,126.5,121.4,121.4,115.0,108.9,63.6,47.9,38.8,35.6,34.9,34.9,29.6,29.5,27.5,26.9,23.6.高分辨质谱分析(ESI):calcd.for C29H35NO[M+H]+:414.2719,实际值:414.2716.
实施例22
原料:2-吡咯烷基喹啉甲醛,2,6-二叔丁基苯酚
反应条件:100℃/HFIP,10h
产物:化学式:C28H34N2O
精确分子量:414.2671
分子量:414.5930
产率:95%
1H核磁共振(500MHz,CDCl3)δ7.72(d,J=8.4Hz,1H),7.60–7.47(m,3H),7.19(t,J=7.4Hz,1H),6.39(d,J=2.8Hz,1H),6.29(d,J=2.8Hz,1H),3.98–3.91(m,1H),3.86(dd,J=9.6,5.8Hz,1H),3.71(dt,J=11.3,8.1Hz,1H),3.25(d,J=15.7Hz,1H),2.72(d,J=15.7Hz,1H),2.01–1.81(m,3H),1.38–1.24(m,11H),1.11(s,9H);13C核磁共振(126MHz,CDCl3)δ186.6,152.9,150.1,149.1,147.9,142.8,137.7,134.7,128.9,126.9,125.9,123.2,121.7,117.5,64.5,46.9,40.2,38.5,35.1,34.9,29.5,28.3,23.1.高分辨质谱分析(ESI):calcd.for C28H34N2O[M+H]+:415.2671,实际值:415.2673.
实施例23
原料:2-甲胺基苯甲醛,2,6-二叔丁基苯酚
反应条件:25℃/HFIP,40min
产物:化学式:C23H31NO
精确分子量:337.2406
分子量:337.5070
产率:45%
1H核磁共振(500MHz,CDCl3)δ7.16(t,J=7.7Hz,1H),6.97(d,J=7.3Hz,1H),6.69(dd,J=14.1,7.6Hz,2H),6.55(s,2H),3.11(s,2H),2.95(s,3H),2.79(s,2H),1.21(s,18H);13C核磁共振(126MHz,CDCl3)δ186.6,147.3,145.0,143.1,129.4,127.6,119.5,116.9,111.1,59.6,39.2,38.6,36.7,34.8,29.5.高分辨质谱分析(ESI):calcd.forC23H31NO[M+H]+:338.2406,实际值:338.2409.
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (5)
1.一种氮杂环取代对醌骨架螺环化合物的合成方法,其特征在于:
由酚类化合物A与氨基甲醛类化合物B进行反应,以哌啶为添加剂,在甲苯中、120℃条件下反应12h,冷却至室温25℃,制得反应中间体,再向反应体系中加入六氟异丙醇,即得所述氮杂环取代对醌骨架螺环化合物;
所述氮杂环取代对醌骨架螺环化合物为式Ⅰ、式Ⅱ所示化合物中任意一种:
其中
式Ⅰ、式Ⅱ中,虚线表示任选的单键;
n为0或1;
X选自碳或氮;
R1选自氢、氯、溴、甲基、三氟甲基、甲氧基、氰基、对苯乙酰基、丙烯酸甲酯中任意一种;
所述酚类化合物A为式Ⅲ所示化合物;
所述氨基甲醛类化合物B为式Ⅳ、式Ⅴ所示化合物中任意一种:
其中
式Ⅲ、式Ⅳ、式Ⅴ中,虚线表示任选的单键;
n为0或1;
X选自碳或氮;
R1选自氢、氯、溴、甲基、三氟甲基、甲氧基、氰基、对苯乙酰基、丙烯酸甲酯中任意一种。
2.根据权利要求1所述的合成方法,其特征在于:将所述反应中间体分离,加入六氟异丙醇中,即得所述氮杂环取代对醌骨架螺环化合物。
3.根据权利要求1-2任一项所述的合成方法,其特征在于:所述化合物A与所述化合物B的摩尔比为1.3:1。
4.根据权利要求3所述的合成方法,其特征在于:所述哌啶与化合物B的摩尔比为1:2。
5.根据权利要求4所述的合成方法,其特征在于:包括以下步骤:
按比例将化合物A、化合物B和哌啶加入到甲苯中,在120℃条件下反应12h,冷却至25℃,得到中间体对醌化合物;
向反应体系中加入六氟异丙醇,在25℃条件下搅拌反应10min,反应完毕进行浓缩、纯化,制得氮杂环取代对醌骨架螺环化合物;
其中可将中间体对醌化合物分离纯化,在25℃-100℃条件下,于六氟异丙醇中进行反应,反应完毕进行浓缩、纯化,制得氮杂环取代对醌骨架螺环化合物。
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