CN113845509A - 吲哚基取代螺[环丁烷-1,1′-茚]类化合物的合成方法 - Google Patents

吲哚基取代螺[环丁烷-1,1′-茚]类化合物的合成方法 Download PDF

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CN113845509A
CN113845509A CN202111180296.6A CN202111180296A CN113845509A CN 113845509 A CN113845509 A CN 113845509A CN 202111180296 A CN202111180296 A CN 202111180296A CN 113845509 A CN113845509 A CN 113845509A
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cyclobutane
indene
indolyl
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徐园双
张新迎
于彩云
范学森
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Henan Normal University
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Abstract

本发明公开了一种吲哚基取代螺[环丁烷‑1,1'‑茚]类化合物的合成方法，属于有机合成技术领域。以N‑(2‑吡啶基)吲哚类化合物1和炔基环丁醇类化合物2为原料，在铑/铱催化剂、银盐和羧酸添加剂存在下，有机溶剂中升温反应，得到吲哚基取代螺[环丁烷‑1,1'‑茚]类化合物3。本发明通过N‑(2‑吡啶基)吲哚和炔基环丁醇类化合物之间的串联反应，一步即可得到吲哚基取代螺[环丁烷‑1,1'‑茚]类化合物；该方法具有原料易得、官能团耐受性好、反应条件温和、区域选择性高、原子经济性好等优点，具有潜在的应用前景。

Description

吲哚基取代螺[环丁烷-1，1′-茚]类化合物的合成方法
技术领域
本发明属于有机合成技术领域，具体涉及一种吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法。
背景技术
碳螺环骨架广泛存在于天然产物、手性配体和临床药物中，用途非常广泛。在众多的碳螺环衍生物中，含环丁基结构单元的碳螺环化合物具有显著的抗癌和镇痛效果，具有重要的药用价值。吲哚为含有苯并五元氮杂环结构骨架的化合物，显现出多样的药物活性和良好的光学性能，在农药、医药、化工、香料和染料等领域发挥着重要作用。
根据药效基团的叠加作用，同时含有两种优势结构骨架的吲哚基取代螺[环丁烷-1,1'-茚]类化合物推测具有更为优异的生物活性及其它性能，因而具有更大潜在的应用价值。然而，目前尚未有关于核心结构吲哚基取代螺[环丁烷-1,1'-茚]类化合物合成的报道。
因此，研究并开发从简单易得的原料出发、通过简便的途径和过程合成吲哚基取代螺[环丁烷-1,1'-茚]类化合物的新方法，具有十分重要的理论意义和应用前景。
发明内容
本发明解决的技术问题是提供了一种吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，该方法通过N-(2-吡啶基)吲哚和炔基环丁醇类化合物之间的串联反应，合成了吲哚基取代螺[环丁烷-1,1'-茚]类化合物，具有原料易得、官能团耐受性好、反应条件温和、区域选择性高、原子经济性好等优点，具有潜在的应用前景。
本发明为解决上述技术问题，采用如下技术方案，一种吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，包括如下操作：以N-(2-吡啶基)吲哚类化合物1和炔基环丁醇类化合物2为原料，在铑/铱催化剂和添加剂存在下，有机溶剂中升温反应，得到吲哚基取代螺[环丁烷-1,1'-茚]类化合物3。
反应方程式为：
Figure BDA0003296820250000021
其中，R1为氢、卤素、三氟甲基、氰基、C1-4烷基或C1-4烷氧基，R2为氢或C1-4烷基，R3为氢、卤素、三氟甲基、苯基、C1-4烷基或C1-4烷氧基。
进一步地，在上述技术方案中，所述铑催化剂为[RhCp*Cl2]2{二氯(五甲基环戊二烯基)合铑(III)二聚体}或RhCp*(CH3CN)3(SbF6)2{二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III)}；铱催化剂为[IrCp*Cl2]2{二氯(五甲基环戊二烯基)合铱(III)二聚体}。
进一步地，在上述技术方案中，所述添加剂为银盐添加剂；银盐添加剂为六氟锑酸银、双三氟甲烷磺酰亚胺银、四氟硼酸银、三氟甲烷磺酸银或三氟乙酸银。
进一步地，在上述技术方案中，所述添加剂还包括羧酸添加剂；羧酸添加剂为特戊酸、醋酸、1-金刚烷甲酸、苯甲酸或2,4,6-三甲基苯甲酸。
进一步地，在上述技术方案中，所述反应溶剂为起到溶解原料的作用，优选1,2-二氯乙烷、四氢呋喃、1,2-二甲氧基乙烷、甲苯或乙腈。
进一步地，在上述技术方案中，所述N-(2-吡啶基)吲哚类化合物1、炔基环丁醇类化合物2、铑/铱催化剂与银盐添加剂摩尔比为1-1.2:1-1.2:0.04-0.06:0.08-0.12。
进一步地，在上述技术方案中，所述银盐添加剂与羧酸添加剂摩尔比为0.08-0.12:1-2。
进一步地，在上述技术方案中，所述反应温度为80-120℃。
发明有益效果：
本发明具有以下优点：(1)合成过程简单，反应条件温和，通过N-(2-吡啶基)吲哚类化合物和炔基环丁醇类化合物的一锅串联反应，即可合成吲哚基取代螺[环丁烷-1,1'-茚]类化合物；(2)原料廉价易得、底物适用范围广和官能团耐受性好、区域选择性高、原子经济性好。
说明书附图
图1为实施例3中化合物3y的X-射线单晶衍射图；
图2为实施例3中化合物3aa的X-射线单晶衍射图。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0003296820250000031
向15mL耐压管中，依次加入化合物1a、化合物2a、催化剂、银盐添加剂、羧酸添加剂和溶剂，在空气条件下将耐压管密封，升温反应。待反应结束后，冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，用硅藻土过滤，滤液用乙酸乙酯(10mL×3)萃取，合并有机相，并依次用水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，旋干，过硅胶柱分离(石油醚:乙酸乙酯＝20:1)得到淡黄色固体产物3a。
通过改变反应的溶剂、催化剂、银盐添加剂、羧酸添加剂、反应温度及用量比例等反应条件，得到的结果如下：
表1 不同条件下3a的合成a
Figure BDA0003296820250000032
Figure BDA0003296820250000041
实施例2
Figure BDA0003296820250000042
向15mL耐压管中，依次加入1a(38.8mg,0.2mmol)、2a(41.3mg,0.24mmol)、二氯(五甲基环戊二烯基)合铱(III)二聚体(8.0mg,0.01mmol)、六氟锑酸银(6.9mg,0.02mmol)、特戊酸(20.4mg,0.2mmol)和乙腈(1.5mL)，在空气条件下将耐压管密封，并将其置于110℃油浴中搅拌反应18小时。待反应结束后，冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，用硅藻土过滤，滤液用乙酸乙酯(10mL×3)萃取，合并有机相，并依次用水和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，旋干，过硅胶柱分离(石油醚:乙酸乙酯＝20:1)得到淡黄色固体产物3a(54.4mg,78％)。1H NMR(400MHz,CDCl3):δ8.64-8.62(m,1H),7.71-7.69(m,2H),7.61(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.47-7.44(m,1H),7.24-7.18(m,4H),7.16-7.13(m,2H),7.07-7.04(m,2H),6.02(s,1H),2.86-2.78(m,2H),2.47-2.35(m,3H),2.34-2.26(m,1H).13C{1H}NMR(100MHz,CDCl3):δ153.7,152.8,149.5,143.2,141.2,139.0,138.3,135.2,129.8,128.7,126.7,125.9,123.4,122.7,122.4,121.4,121.01,120.99,120.7,111.3,105.1,56.2,30.3,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C25H21N2 349.1699；Found349.1696.
实施例3
依照实施例2方法，反应条件为:1(0.2mmol)、2(0.24mmol)、[IrCp*Cl2]2(0.01mmol)、AgSbF6(0.02mmol)、PivOH(0.2mmol)、CH3CN(1.5mL)、110℃、18h和空气氛围；通过改变反应物1和反应物2，合成出各种吲哚基取代螺[环丁烷-1,1'-茚]类化合物3，具体结果如下：
Figure BDA0003296820250000051
代表性产物表征数据如下：
6-Methyl-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3b)
Brownish solid(54.4mg,75％).1H NMR(400MHz,CDCl3):δ8.79(dd,J1＝4.8Hz,J2＝1.6Hz,1H),7.83(d,J＝7.2Hz,1H),7.77(td,J1＝7.6Hz,J2＝2.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.38-7.30(m,3H),7.27(td,J1＝7.2Hz,J2＝0.8Hz,1H),7.21(s,1H),7.19-7.14(m,3H),6.10(s,1H),2.98-2.90(m,2H),2.60-2.49(m,6H),2.47-2.40(m,1H).13C NMR(100MHz,CDCl3):δ153.8,153.0,149.5,143.4,141.3,139.4,138.3,134.6,133.5,129.3,126.7,126.6,125.8,123.1,122.7,122.3,121.0,120.9,120.4,111.1,105.1,56.1,30.4,22.1,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2363.1856；Found 363.1857.
6-Methoxy-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3c)
Brownish solid(47.7mg,63％).1H NMR(400MHz,CDCl3):δ8.69-8.67(m,1H),7.71(d,J＝7.2Hz,1H),7.67(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.58(d,J＝8.8Hz,1H),7.28-7.20(m,2H),7.16(td,J1＝7.2Hz,J2＝0.8Hz,1H),7.09(s,1H),7.07-7.04(m,2H),7.00(d,J＝2.0Hz,1H),6.87(dd,J1＝8.8Hz,J2＝2.4Hz,1H),5.93(s,1H),3.79(s,3H),2.87-2.79(m,2H),2.49-2.38(m,3H),2.37-2.30(m,1H).13C NMR(100MHz,CDCl3):δ157.6,153.7,153.0,149.5,143.3,141.3,139.9,138.3,134.1,128.7,126.7,125.7,122.9,122.7,122.3,121.4,120.9,120.8,111.2,105.2,94.9,56.0,55.7,30.5,16.5.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2O379.1805；Found 379.1798.
6-Fluoro-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3d)
Brownish syrup(44.0mg,60％).1H NMR(400MHz,CDCl3):δ8.68-8.66(m,1H),7.73-7.66(m,2H),7.62-7.59(m,1H),7.29-7.15(m,4H),7.09-7.05(m,3H),6.98-6.93(m,1H),6.03(s,1H),2.84-2.76(m,2H),2.49-2.38(m,3H),2.36-2.26(m,1H).13C NMR(100MHz,CDCl3):δ160.8(d,1JC-F＝238.1Hz),153.6,152.5,149.6,142.9,141.0,139.0(d,3JC-F＝12.5Hz),138.4,135.6(d,4JC-F＝4.9Hz),129.8,126.7,125.9,125.1,122.5,122.4,121.4(d,3JC-F＝9.5Hz),121.0,110.0(d,2JC-F＝24.5Hz),105.0,98.1(d,2JC-F＝27.2Hz),56.1,30.3,16.6.19FNMR(376MHz,DMSO-d6):δ-118.6(td,J1＝9.4Hz,J2＝5.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H20FN2367.1605；Found 367.1600.
6-Chloro-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3e)
Yellowish solid(41.4mg,54％).1H NMR(400MHz,CDCl3):δ8.66(dd,J1＝4.2Hz,J2＝1.2Hz,1H),7.72-7.65(m,2H),7.59(d,J＝8.4Hz,1H),7.47(d,J＝1.6Hz,1H),7.29-7.22(m,2H),7.19-7.14(m,2H),7.09-7.04(m,3H),6.03(s,1H),2.82-2.74(m,2H),2.48-2.37(m,3H),2.34-2.23(m,1H).13C NMR(100MHz,CDCl3):δ153.7,152.3,149.7,142.7,141.0,139.2,138.5,135.9,130.2,129.3,127.2,126.8,126.1,122.7,122.5,122.0,121.5,121.1,121.0,111.4,104.9,56.1,30.3,16.6.HRMS(ESI)m/z:[M+H]+Calcd forC25H20ClN2383.1310；Found 383.1311.
1-(Pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-6-(trifluoromethyl)-1H-indole(3f)
Brownish solid(49.1mg,59％).1H NMR(400MHz,CDCl3):δ8.71-8.69(m,1H),7.78(d,J＝8.4Hz,1H),7.75-7.71(m,3H),7.44(dd,J1＝8.0Hz,J2＝0.8Hz,1H),7.34-7.31(m,1H),7.27(td,J1＝7.2Hz,J2＝0.8Hz,1H),7.19(td,J1＝7.6Hz,J2＝0.8Hz,1H),7.15(s,1H),7.12-7.09(m,2H),6.11(s,1H),2.83-2.75(m,2H),2.49-2.38(m,3H),2.33-2.26(m,1H).13C NMR(100MHz,CDCl3):δ153.6,152.0,149.8,142.5,140.8,138.6,137.8,137.7,131.1,131.0,126.8,126.3,125.2(q,1JC-F＝270.0Hz),125.1(q,2JC-F＝31.6Hz),122.9,122.6,121.2,121.1,121.0,117.9(q,3JC-F＝3.9Hz),108.9(q,3JC-F＝4.5Hz),104.7,56.3,30.1,16.6.19FNMR(376MHz,CDCl3):δ-60.6(s).HRMS(ESI)m/z:[M+H]+Calcd forC26H20F3N2417.1573；Found 417.1566.
1-(Pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole-6-carbonitrile(3g)
Yellowish solid(35.9mg,48％).1H NMR(400MHz,CDCl3):δ8.72-8.70(m,1H),7.79-7.74(m,4H),7.43(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.39-7.35(m,1H),7.29(td,J1＝7.6Hz,J2＝1.2Hz,1H),7.20(td,J1＝7.2Hz,J2＝1.2Hz,1H),7.15(s,1H),7.13-7.10(m,2H),6.14(s,1H),2.82-2.74(m,2H),2.51-2.40(m,3H),2.33-2.25(m,1H).13C NMR(100MHz,CDCl3):δ153.6,151.6,149.8,141.9,140.6,138.8,138.7,137.5,131.8,131.7,126.8,126.5,124.2,123.2,122.4,121.4,121.3,121.1,120.6,116.2,105.5,104.9,56.2,30.1,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C26H20N3374.1652；Found 374.1643.
5-Methyl-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3h)
Brownish solid(49.3mg,68％).1H NMR(600MHz,CDCl3):δ8.64-8.63(m,1H),7.70(d,J＝7.2Hz,1H),7.63(td,J1＝7.8Hz,J2＝1.8Hz,1H),7.49(s,1H),7.37(d,J＝8.4Hz,1H),7.22-7.18(m,2H),7.15(t,J＝7.8Hz,1H),7.07-7.03(m,4H),6.03(s,1H),2.84-2.79(m,2H),2.46-2.38(m,6H),2.32-2.28(m,1H).13C NMR(150MHz,CDCl3):δ153.7,153.0,149.5,143.4,141.2,138.2,137.5,135.2,130.6,129.6,129.0,126.7,125.8,125.0,122.5,122.2,121.02,120.95,120.4,111.0,104.9,56.2,30.4,21.5,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2363.1856；Found 363.1854.
5-Methoxy-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3i)
Brownish solid(45.4mg,60％).1H NMR(400MHz,CDCl3):δ8.65-8.63(m,1H),7.71(d,J＝7.2Hz,1H),7.64(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.41(d,J＝8.8Hz,1H),7.25-7.21(m,2H),7.18-7.15(m,2H),7.09-7.03(m,3H),6.87(dd,J1＝8.8Hz,J2＝2.4Hz,1H),6.05(s,1H),3.87(s,3H),2.85-2.77(m,2H),2.48-2.37(m,3H),2.34-2.27(m,1H).13C NMR(100MHz,CDCl3):δ155.3,153.7,152.9,149.4,143.3,141.1,138.2,135.6,134.2,129.7,129.2,126.7,125.8,122.4,122.1,120.99,120.96,113.4,112.2,105.1,102.3,56.1,55.9,30.3,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2O379.1805；Found 379.1808.
5-Fluoro-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3j)
Brownish solid(44.7mg,61％).1H NMR(400MHz,CDCl3):δ8.74(dd,J1＝5.2Hz,J2＝1.6Hz,1H),7.81(d,J＝7.6Hz,1H),7.76(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.51-7.48(m,1H),7.43(dd,J1＝9.2Hz,J2＝2.4Hz,1H),7.36-7.32(m,2H),7.26(td,J1＝7.2Hz,J2＝0.4Hz,1H),7.19-7.13(m,3H),7.04(td,J1＝8.8Hz,J2＝2.4Hz,1H),6.16(s,1H),2.92-2.83(m,2H),2.57-2.46(m,3H),2.42-2.35(m,1H).13C NMR(100MHz,CDCl3):δ158.8(d,1JC-F＝234.7Hz),153.7,152.6,149.5,142.9,141.0,138.4,136.7,135.4,130.4,129.1(d,3JC-F＝10.3Hz),126.7,126.1,122.49,122.48,121.1,121.0,112.2(d,3JC-F＝9.5Hz),111.5(d,2JC-F＝25.1Hz),105.5(d,2JC-F＝24.0Hz),104.9(d,4JC-F＝4.6Hz),56.2,30.2,16.6.19F NMR(376MHz,CDCl3):δ-123.0(td,J1＝8.3Hz,J2＝4.5Hz).HRMS(ESI)m/z:[M+H]+Calcd forC25H20FN2367.1605；Found 367.1601.
5-Chloro-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3k)
Brownish solid(56.7mg,74％).1H NMR(400MHz,CDCl3):δ8.74(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.81(d,J＝7.2Hz,1H),7.78-7.74(m,2H),7.47(d,J＝8.8Hz,1H),7.37-7.32(m,2H),7.28-7.23(m,2H),7.19-7.13(m,3H),6.15(s,1H),2.91-2.83(m,2H),2.57-2.46(m,3H),2.41-2.35(m,1H).13C NMR(100MHz,CDCl3):δ153.6,152.4,149.6,142.7,140.9,138.4,137.2,136.5,130.5,129.7,126.83,126.75,126.1,123.5,122.6,122.5,121.13,121.06,120.0,112.4,104.4,56.2,30.2,16.6.HRMS(ESI)m/z:[M+H]+Calcd forC25H20ClN2383.1310；Found 383.1300.
5-Bromo-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3l)
Brownish solid(55.6mg,65％).1H NMR(400MHz,DMSO-d6):δ8.67(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.99-7.95(m,2H),7.79(d,J＝7.2Hz,1H),7.52-7.49(m,1H),7.34-7.30(m,2H),7.27-7.23(m,3H),7.17(t,J＝7.2Hz,1H),7.11(d,J＝7.2Hz,1H),6.02(s,1H),2.78-2.70(m,2H),2.45-2.35(m,3H),2.30-2.24(m,1H).13C NMR(100MHz,DMSO-d6):δ153.5,151.7,150.1,142.6,140.8,139.7,137.6,136.6,130.5,130.3,127.2,126.7,126.0,124.0,123.4,123.0,121.6,121.4,113.8,113.3,104.1,55.9,30.1,16.3.HRMS(ESI)m/z:[M+H]+Calcd for C25H20BrN2427.0804；Found 427.0800.
4-Methyl-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3m)
Brown syrup(48.6mg,67％).1H NMR(400MHz,CDCl3):δ8.65-8.64(m,1H),7.72(d,J＝7.2Hz,1H),7.66(td,J1＝7.6Hz,J2＝2.0Hz,1H),7.30(d,J＝8.4Hz,1H),7.25-7.20(m,2H),7.19-7.12(m,3H),7.11-7.06(m,2H),7.00(d,J＝7.2Hz,1H),6.05(s,1H),2.87-2.81(m,2H),2.65(s,3H),2.49-2.37(m,3H),2.35-2.27(m,1H).13C NMR(100MHz,CDCl3):δ153.7,152.9,149.5,143.5,141.2,138.7,138.2,134.6,130.2,129.7,128.5,126.7,125.8,123.5,122.6,122.3,121.5,121.0,120.9,108.9,103.6,56.2,30.3,18.9,16.7.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2363.1856；Found 363.1863.
4-Methoxy-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3n)
Brown syrup(42.4mg,56％).1H NMR(400MHz,CDCl3):δ8.67-8.65(m,1H),7.72(d,J＝7.2Hz,1H),7.67(td,J1＝7.6Hz,J2＝2.0Hz,1H),7.28-7.25(m,2H),7.23-7.21(m,1H),7.18-7.12(m,2H),7.08-7.04(m,3H),6.61(d,J＝8.0Hz,1H),5.97(s,1H),4.00(s,3H),2.91-2.84(m,2H),2.48-2.33(m,4H).13C NMR(100MHz,CDCl3):δ153.8,153.3,152.9,149.5,143.2,141.2,140.3,138.3,133.7,129.3,126.6,125.7,124.3,122.7,122.4,120.95,120.86,119.4,104.5,102.2,101.1,56.1,55.5,30.4,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2O379.1805；Found 379.1808.
4-Fluoro-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3o)
Brown syrup(42.5mg,58％).1H NMR(400MHz,CDCl3):δ8.67-8.65(m,1H),7.73-7.67(m,2H),7.30-7.23(m,2H),7.22-7.15(m,3H),7.14-7.07(m,3H),6.89-6.84(m,1H),6.04(s,1H),2.86-2.78(m,2H),2.49-2.37(m,3H),2.36-2.28(m,1H).13C NMR(100MHz,CDCl3):δ156.2(d,1JC-F＝245.4Hz),153.7,152.5,149.6,142.7,141.2(d,3JC-F＝10.2Hz),140.9,138.4,135.2,130.4,126.7,126.1,123.8(d,3JC-F＝8.1Hz),122.74,122.66,121.1,121.0,117.9(d,2JC-F＝21.8Hz),107.3(d,4JC-F＝3.6Hz),106.0(d,2JC-F＝18.6Hz),100.5,56.2,30.2,16.6.19FNMR(376MHz,CDCl3):δ-122.3(dd,J1＝10.2Hz,J2＝5.3Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H20FN2367.1605；Found 367.1603.
7-Methoxy-1-(pyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3p)
Yellowish syrup(53.7mg,71％).1H NMR(600MHz,CDCl3):δ8.54(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.69-7.65(m,2H),7.33(d,J＝7.8Hz,1H),7.28-7.25(m,2H),7.21-7.18(m,1H),7.13-7.06(m,3H),7.01(d,J＝7.8Hz,1H),6.62(d,J＝7.2Hz,1H),5.85(s,1H),3.52(s,3H),2.92-2.87(m,2H),2.44-2.37(m,3H),2.36-2.30(m,1H).13C NMR(150MHz,CDCl3):δ154.4,153.8,148.4,147.1,143.0,141.3,137.2,136.2,130.5,128.75,128.70,126.6,125.7,124.4,123.1,121.3,120.9,113.7,104.8,104.1,56.3,55.8,30.3,16.5.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2O379.1805；Found 379.1809.
1-(5-Methylpyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3q)
Yellowish solid(50.7mg,70％).1H NMR(400MHz,CDCl3):δ8.48(dd,J1＝1.6Hz,J2＝0.4Hz,1H),7.72-7.69(m,2H),7.50-7.47(m,1H),7.39-7.37(m,1H),7.25-7.14(m,4H),7.12-7.08(m,2H),6.98(d,J＝8.0Hz,1H),6.04(s,1H),2.88-2.81(m,2H),2.48-2.39(m,3H),2.37-2.32(m,4H).13C NMR(100MHz,CDCl3):δ153.8,150.4,149.7,143.3,141.2,139.1,138.9,135.2,132.2,129.5,128.6,126.6,125.8,123.3,122.2,121.1,120.98,120.96,120.7,111.1,104.7,56.1,30.4,18.2,16.6.HRMS(ESI)m/z:[M+H]+Calcd forC26H23N2363.1856；Found 363.1859.
1-(4-Methylpyridin-2-yl)-2-(spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3r)
Brown syrup(52.2mg,72％).1H NMR(400MHz,CDCl3):δ8.51(d,J＝4.8Hz,1H),7.73-7.69(m,2H),7.34-7.32(m,1H),7.25-7.14(m,5H),7.11-7.07(m,2H),6.96(s,1H),6.01(s,1H),2.92-2.84(m,2H),2.50-2.42(m,3H),2.40-2.32(m,1H),2.28(s,3H).13C NMR(100MHz,CDCl3):δ153.9,152.9,149.9,149.3,143.2,141.2,139.2,135.3,129.1,128.6,126.6,125.8,123.8,123.5,123.3,121.1,120.93,120.91,120.7,111.0,104.8,56.1,30.5,21.1,16.5.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2363.1856；Found 363.1858.
2-(6'-Methylspiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3s)
Brown solid(52.2mg,72％).1H NMR(600MHz,CDCl3):δ8.67-8.65(m,1H),7.71-7.69(m,1H),7.66(td,J1＝7.8Hz,J2＝1.8Hz,1H),7.54(s,1H),7.47-7.46(m,1H),7.26-7.24(m,1H),7.22-7.17(m,2H),7.11(s,1H),7.06(d,J＝7.8Hz,1H),7.00-6.96(m,2H),6.00(s,1H),2.85-2.80(m,2H),2.47-2.37(m,6H),2.33-2.29(m,1H).13C NMR(150MHz,CDCl3):δ154.1,152.8,149.5,142.3,138.9,138.6,138.2,135.7,135.3,129.8,128.8,127.4,123.3,122.7,122.3,122.0,121.3,120.7,120.6,111.2,104.9,56.0,30.4,21.8,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C26H23N2363.1856；Found 363.1850.
2-(6'-(tert-Butyl)spiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3t)
Brown solid(51.0mg,63％).1H NMR(600MHz,CDCl3):δ8.67(dd,J1＝5.4Hz,J2＝1.8Hz,1H),7.76(d,J＝1.2Hz,1H),7.71-7.66(m,2H),7.47-7.45(m,1H),7.27-7.18(m,4H),7.13(s,1H),7.08(d,J＝7.8Hz,1H),7.02(d,J＝7.8Hz,1H),6.02(s,1H),2.84-2.79(m,2H),2.51-2.47(m,2H),2.44-2.32(m,2H),1.39(s,9H).13C NMR(100MHz,CDCl3):δ153.6,152.9,149.5,149.3,142.8,138.9,138.6,138.2,135.4,129.6,128.7,123.7,123.3,122.7,122.3,121.3,120.6,120.3,118.0,111.2,104.9,56.2,35.0,31.8,30.4,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C29H29N2405.2325；Found 405.2311.
2-(6'-Methoxyspiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3u)
Yellowish solid(33.3mg,44％).1H NMR(400MHz,DMSO-d6):δ8.68(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.98(td,J1＝7.6Hz,J2＝1.6Hz,1H),7.76-7.74(m,1H),7.52-7.49(m,1H),7.40(d,J＝2.4Hz,1H),7.33-7.28(m,2H),7.20-7.18(m,3H),7.03(d,J＝8.4Hz,1H),6.76(dd,J1＝8.4Hz,J2＝2.4Hz,1H),5.92(s,1H),3.83(s,3H),2.79-2.74(m,2H),2.46-2.37(m,3H),2.31-2.28(m,1H).13CNMR(150MHz,CDCl3):δ158.9,155.7,152.8,149.4,141.3,138.8,138.2,135.3,134.3,129.4,128.7,123.2,122.6,122.2,121.3,121.2,120.5,111.4,111.1,108.2,104.6,56.2,55.7,30.5,16.5.HRMS(ESI)m/z:[M+H]+Calcdfor C26H23N2O379.1805；Found 379.1810.
2-(6'-Fluorospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3v)
Yellowish solid(45.4mg,62％).1H NMR(400MHz,CDCl3):δ8.66(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.73-7.68(m,2H),7.46-7.41(m,2H),7.29-7.26(m,1H),7.23-7.18(m,2H),7.11-7.08(m,2H),7.00-6.97(m,1H),6.89-6.84(m,1H),5.97(s,1H),2.88-2.80(m,2H),2.45-2.28(m,4H).13C NMR(100MHz,CDCl3):δ162.2(d,1JC-F＝242.6Hz),155.9(d,3JC-F＝8.4Hz),152.7,149.5,143.0(d,4JC-F＝4.3Hz),138.9,138.3,137.0(d,5JC-F＝2.1Hz),134.8,128.8,128.6,123.4,122.6,122.4,121.5(d,3JC-F＝8.4Hz),121.3,120.7,113.3(d,2JC-F＝22.5Hz),111.2,109.0(d,2JC-F＝23.5Hz),105.1,56.4(d,4JC-F＝2.9Hz),30.3,16.5.19FNMR(376MHz,CDCl3):δ-116.4(td,J1＝9.4Hz,J2＝6.0Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H20FN2367.1605；Found 367.1600.
2-(6'-Chlorospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3w)
Yellow solid(39.1mg,51％).1H NMR(400MHz,CDCl3):δ8.66(dd,J1＝4.4Hz,J2＝0.8Hz,1H),7.73-7.69(m,3H),7.45-7.43(m,1H),7.30-7.27(m,1H),7.24-7.18(m,2H),7.15-7.13(m,2H),7.09(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),5.95(s,1H),2.88-2.81(m,2H),2.47-2.40(m,3H),2.37-2.28(m,1H).13C NMR(100MHz,CDCl3):δ155.4,152.6,149.6,143.6,139.6,139.0,138.3,134.6,131.6,128.6,126.8,123.6,122.6,122.4,121.7,121.6,121.4,120.8,111.2,105.3,56.2,30.2,16.5.HRMS(ESI)m/z:[M+H]+Calcdfor C25H20ClN2383.1310；Found 383.1309.
2-(6'-Bromospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3x)
Yellowish solid(38.5mg,45％).1H NMR(400MHz,CDCl3):δ8.68-8.66(m,1H),7.84(d,J＝2.0Hz,1H),7.75-7.70(m,2H),7.45-7.43(m,1H),7.31-7.28(m,2H),7.25-7.18(m,2H),7.14(s,1H),7.09(d,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),5.94(s,1H),2.89-2.81(m,2H),2.48-2.40(m,3H),2.38-2.29(m,1H).13C NMR(100MHz,DMSO-d6):δ155.8,152.1,150.1,143.9,140.2,139.6,139.0,134.8,130.1,128.6,128.5,124.8,123.8,123.7,123.00,122.95,121.6,121.3,119.6,111.3,105.2,56.1,30.0,16.1.HRMS(ESI)m/z:[M+H]+Calcd for C25H20BrN2427.0804；Found 427.0809.
1-(Pyridin-2-yl)-2-(6'-(trifluoromethyl)spiro[cyclobutane-1,1'-inden]-2'-yl)-1H-indole(3y)
Yellowish solid(38.3mg,46％).1H NMR(400MHz,CDCl3):δ8.67(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.93(s,1H),7.76-7.71(m,2H),7.45-7.43(m,2H),7.32-7.29(m,1H),7.26-7.20(m,3H),7.15-7.10(m,2H),6.00(s,1H),2.92-2.84(m,2H),2.54-2.45(m,3H),2.43-2.34(m,1H).13C NMR(100MHz,CDCl3):δ153.9,152.6,149.7,146.1,144.5,139.1,138.4,134.4,128.5,128.2,127.5(q,2JC-F＝30.7Hz),124.9(q,1JC-F＝270.0Hz),124.1(q,3JC-F＝3.1Hz),123.8,122.6,121.5,120.9,120.7,117.7(q,3JC-F＝3.8Hz),111.2,105.8,56.2,30.1,16.5.19FNMR(376MHz,CDCl3):δ-61.3(s).HRMS(ESI)m/z:[M+H]+Calcd forC26H20F3N2417.1573；Found 417.1571.
2-(6'-Phenylspiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3z)
Yellow solid(46.7mg,55％).1H NMR(400MHz,CDCl3):δ8.70-8.68(m,1H),7.94-7.95(m,1H),7.73-7.69(m,2H),7.67-7.64(m,2H),7.47-7.41(m,4H),7.36-7.32(m,1H),7.31-7.27(m,1H),7.25-7.18(m,3H),7.15(d,J＝7.6Hz,1H),7.10(d,J＝8.0Hz,1H),6.04(s,1H),2.93-2.86(m,2H),2.58-2.43(m,3H),2.41-2.33(m,1H).13C NMR(150MHz,CDCl3):δ154.5,152.8,149.6,143.6,141.9,140.5,139.2,139.0,138.3,135.1,129.3,128.9,128.7,127.3,127.1,125.9,123.5,122.7,122.4,121.4,121.1,120.7,120.0,111.2,105.2,56.2,30.5,16.6.HRMS(ESI)m/z:[M+H]+Calcd for C31H25N2425.2012；Found425.2005.
2-(5'-Methoxyspiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3aa)
Yellowish solid(33.3mg,44％).1H NMR(600MHz,CDCl3):δ8.67(dd,J1＝4.8Hz,J2＝1.8Hz,1H),7.72-7.68(m,2H),7.60(d,J＝8.4Hz,1H),7.47(d,J＝7.8Hz,1H),7.29-7.27(m,1H),7.23-7.18(m,2H),7.13(s,1H),7.07(d,J＝7.8Hz,1H),6.79(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.65(d,J＝2.4Hz,1H),5.98(s,1H),3.77(s,3H),2.84-2.80(m,2H),2.45-2.38(m,3H),2.32-2.27(m,1H).13C NMR(150MHz,CDCl3):δ159.0,152.8,149.5,146.1,144.4,142.4,138.9,138.2,135.1,129.6,128.7,123.4,122.6,122.3,121.5,121.3,120.7,111.5,111.2,106.5,105.2,55.6,55.5,30.5,16.5.HRMS(ESI)m/z:[M+H]+Calcdfor C26H23N2O379.1805；Found 379.1811.
2-(7'-Methoxyspiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3aa')
Yellowish syrup(6.8mg,9％).1H NMR(400MHz,DMSO-d6):δ8.66(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.97(td,J1＝7.6Hz,J2＝2.0Hz,1H),7.76-7.74(m,1H),7.50-7.47(m,1H),7.32(d,J＝8.0Hz,1H),7.27-7.25(m,2H),7.20-7.11(m,3H),6.87(d,J＝8.0Hz,1H),6.70(d,J＝7.6Hz,1H),5.84(s,1H),3.94(s,3H),2.90-2.82(m,2H),2.60-2.53(m,2H),2.43-2.38(m,1H),2.30-2.26(m,1H).13C NMR(100MHz,DMSO-d6):δ155.8,152.2,150.0,144.5,142.7,139.6,139.0,137.5,135.1,128.9,128.8,128.6,123.7,123.6,123.2,121.5,121.2,114.4,111.2,109.7,104.3,56.1,55.1,26.8,15.6.HRMS(ESI)m/z:[M+H]+Calcdfor C26H23N2O379.1805；Found 379.1800.
2-(5'-Fluorospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3bb)
Brownish solid(27.1mg,37％).1H NMR(400MHz,CDCl3):δ8.66(dd,J1＝4.8Hz,J2＝0.8Hz,1H),7.74-7.69(m,2H),7.63-7.60(m,1H),7.45-7.43(m,1H),7.30-7.27(m,1H),7.23-7.18(m,2H),7.15(s,1H),7.09(d,J＝8.0Hz,1H),6.93-6.88(m,1H),6.75(dd,J1＝8.8Hz,J2＝2.4Hz,1H),5.94(s,1H),2.88-2.80(m,2H),2.47-2.38(m,3H),2.36-2.29(m,1H).13C NMR(100MHz,CDCl3):δ162.3(d,1JC-F＝240.5Hz),152.6,149.6,149.1(d,4JC-F＝2.1Hz),145.2,142.8(d,3JC-F＝8.0Hz),139.0,138.3,134.7,128.63,128.58,123.6,122.6,122.5,121.7(d,3JC-F＝9.0Hz),121.4,120.8,112.1(d,2JC-F＝21.8Hz),111.2,107.9(d,2JC-F＝23.3Hz),105.4,55.6,30.4,16.4.19FNMR(376MHz,CDCl3):δ-116.9(td,J1＝8.6Hz,J2＝4.5Hz).HRMS(ESI)m/z:[M+H]+Calcd for C25H20FN2367.1605；Found 367.1602.
2-(7'-Fluorospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3bb')
Brown syrup(7.3mg,10％).1H NMR(400MHz,CDCl3):δ8.68(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.75-7.71(m,2H),7.44-7.42(m,1H),7.32-7.28(m,1H),7.25-7.18(m,3H),7.14-7.09(m,2H),6.90-6.83(m,2H),5.91(d,J＝2.0Hz,1H),2.88-2.74(m,4H),2.61-2.50(m,1H),2.40-2.31(m,1H).13C NMR(150MHz,CDCl3):δ158.9(d,1JC-F＝246.5Hz),152.7,149.6,144.7,144.5(d,3JC-F＝7.7Hz),139.1,138.3,137.2(d,2JC-F＝14.0Hz),134.4,128.6,128.509,128.506(d,3JC-F＝8.0Hz),123.6,122.7,122.5,121.4,120.8,117.0(d,4JC-F＝4.1Hz),113.0(d,2JC-F＝20.6Hz),111.1,105.2,55.0(d,3JC-F＝2.9Hz),28.0,15.5(d,5JC-F＝4.4Hz).19F NMR(376MHz,CDCl3):δ-122.58–-122.60(m).HRMS(ESI)m/z:[M+H]+Calcd for C25H20FN2367.1605；Found 367.1598.
2-(5'-Chlorospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3cc)
Yellowish solid(27.6mg,36％).1H NMR(600MHz,CDCl3):δ8.66(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.73-7.70(m,2H),7.61(d,J＝8.4Hz,1H),7.43(d,J＝7.8Hz,1H),7.30-7.28(m,1H),7.24-7.17(m,3H),7.15(s,1H),7.09(d,J＝7.8Hz,1H),7.04(d,J＝1.8Hz,1H),5.91(s,1H),2.87-2.82(m,2H),2.45-2.38(m,3H),2.35-2.31(m,1H).13C NMR(150MHz,CDCl3):δ152.6,151.9,149.6,144.8,142.8,139.0,138.3,134.6,132.3,128.6,128.3,125.5,123.6,122.59,122.53,121.9,121.4,121.0,120.8,111.2,105.4,55.8,30.3,16.5.HRMS(ESI)m/z:[M+H]+Calcd for C25H20ClN2383.1310；Found 383.1311.
2-(7'-Chlorospiro[cyclobutane-1,1'-inden]-2'-yl)-1-(pyridin-2-yl)-1H-indole(3cc')
Yellowish syrup(16.1mg,21％).1H NMR(600MHz,CDCl3):δ8.66(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.73-7.69(m,2H),7.45-7.43(m,1H),7.29-7.26(m,2H),7.24-7.19(m,2H),7.13(dd,J1＝7.8Hz,J2＝0.6Hz,1H),7.08-7.05(m,2H),6.92(dd,J1＝7.2Hz,J2＝0.6Hz,1H),5.88(s,1H),3.26-3.21(m,2H),2.65-2.60(m,2H),2.55-2.48(m,1H),2.46-2.39(m,1H).13C NMR(150MHz,CDCl3):δ152.7,149.6,146.6,145.4,144.1,139.1,138.3,134.4,129.9,128.7,128.4,128.2,126.8,123.6,122.8,122.4,121.4,120.9,119.5,111.2,104.9,56.2,25.6,15.5.HRMS(ESI)m/z:[M+H]+Calcd for C25H20ClN2383.1310；Found 383.1309.
本发明所合成的产物吲哚基取代螺[环丁烷-1,1'-茚]类化合物3可进行一系列反应，从而合成进一步衍生物。例如：
实施例4
Figure BDA0003296820250000151
向25mL圆底烧瓶中，加入3a(69.7mg,0.2mmol)，用5mL二氯甲烷将其溶解，在0℃下缓慢滴加三氟甲磺酸甲酯(27.2μL,0.24mmol)，然后将所得混合物置于室温下搅拌反应12小时。反应结束后，旋干溶剂，将残留物溶于甲醇(2mL)中，加入氢氧化钠水溶液(2M，1.1mL)，随后置于60℃(油浴)下搅拌反应10小时。冷却至室温，用乙酸乙酯萃取三次，合并有机相，并依次用水和饱和氯化钠水溶液洗涤，无水Na2SO4干燥，抽滤，旋干。使用石油醚/乙酸乙酯(20/1)作为洗脱剂，过硅胶柱分离得到化合物4(21.7mg，40％)。1H NMR(400MHz,CDCl3):δ8.22(br s,1H),7.80-7.78(m,1H),7.68(d,J＝8.0Hz,1H),7.37(dd,J1＝8.0Hz,J2＝0.4Hz,1H),7.34-7.26(m,3H),7.24-7.20(m,1H),7.15-7.11(m,1H),7.01(d,J＝1.2Hz,1H),6.85(s,1H),3.03-2.95(m,2H),2.63-2.53(m,1H),2.50-2.40(m,3H).13C NMR(150MHz,CDCl3):δ154.9,144.3,141.0,136.5,133.4,129.3,126.9,125.8,123.3,123.1,121.0,120.82,120.77,120.2,110.5,101.3,54.4,30.8,16.1.HRMS(ESI)m/z:[M+H]+Calcd forC20H18N 272.1434；Found 272.1432.
实施例5
Figure BDA0003296820250000161
向15mL圆底烧瓶中，依次加入3a(69.7mg,0.2mmol)、CHCl3(3.0mL)和NBS(35.6mg,0.2mmol)，将所得混合物置于室温下搅拌反应5小时。待反应结束后，旋干溶剂，使用石油醚/乙酸乙酯(20/1)作为洗脱剂，过硅胶柱分离得到化合物5(81.2mg，95％)。1H NMR(400MHz,CDCl3):δ8.58-8.56(m,1H),7.85-7.82(m,1H),7.69-7.65(m,1H),7.64-7.62(m,1H),7.59-7.55(m,1H),7.41-7.38(m,1H),7.35-7.24(m,5H),7.15-7.11(m,1H),7.07(s,1H),2.07-1.98(m,5H),1.70-1.66(m,1H).13C NMR(100MHz,CDCl3):δ152.7,152.1,149.1,142.6,140.9,138.4,136.8,135.7,133.1,127.8,126.8,126.3,124.4,122.1,121.8,121.5,121.3,120.7,119.6,112.3,97.9,58.6,29.3,17.6.HRMS(ESI)m/z:[M+H]+Calcdfor C25H20BrN2427.0804；Found 427.0801.
实施例6
向15mL圆底烧瓶中，加入3a(69.7mg,0.2mmol)，用DMF(1.5mL)将其溶解，然后缓慢滴加POCl3(28.0μL,0.3mmol)，将所得混合物置于50℃(油浴)中搅拌过夜。
Figure BDA0003296820250000171
反应完成后，加入H2O淬灭反应，用乙酸乙酯(10mL×3)萃取，合并有机相，并依次用水、饱和氯化钠水溶液洗涤，无水Na2SO4干燥，抽滤，旋干溶剂。使用石油醚/乙酸乙酯(20:1)作为洗脱剂，过硅胶柱分离得到化合物6(68.5mg，91％)。1H NMR(400MHz,CDCl3):δ9.82(s,1H),8.63-8.62(m,1H),8.52-8.50(m,1H),7.72-7.64(m,3H),7.42-7.34(m,4H),7.32-7.25(m,3H),7.12(s,1H),2.14-2.03(m,5H),1.71-1.65(m,1H).13C NMR(100MHz,CDCl3):δ187.4,152.5,150.8,149.5,146.3,140.2,140.1,138.7,137.7,137.3,127.1,126.9,125.4,125.0,124.0,123.2,122.1,121.8,121.6,121.4,119.2,112.0,58.4,29.2,17.4.HRMS(ESI)m/z:[M+H]+Calcd for C26H21N2O 377.1648；Found 377.1647.
实施例7
Figure BDA0003296820250000172
向25mL两颈瓶中依次加入3a(52.3mg,0.15mmol)、EtOH(5mL)和Pd/C(16.0mg,10wt％,0.015mmol)，然后将所得混合物在氩气氛围中室温下搅拌24小时。待反应完成后，旋干溶剂，使用石油醚/乙酸乙酯(20:1)作为洗脱剂，过硅胶柱分离得到化合物7(50.5mg，96％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ8.69-8.67(m,1H),7.88(td,J1＝7.6Hz,J2＝2.0Hz,1H),7.52-7.46(m,2H),7.39(d,J＝7.6Hz,1H),7.33-7.15(m,5H),7.13-7.08(m,2H),6.24(s,1H),4.03(t,J＝6.8Hz,1H),3.31(dd,J1＝16.0Hz,J2＝7.6Hz,1H),3.15(dd,J1＝15.6Hz,J2＝6.4Hz,1H),2.26-2.18(m,1H),2.09-2.00(m,2H),1.87-1.77(m,2H),1.53-1.44(m,1H).13C{1H}NMR(100MHz,CDCl3):δ151.8,150.7,149.9,142.8,141.4,138.5,137.3,128.5,127.0,126.6,124.3,122.4,122.3,122.2,121.8,120.8,120.2,110.3,102.2,54.7,47.1,38.2,33.9,30.4,15.9.HRMS(ESI)m/z:[M+H]+Calcd forC25H23N2351.1856；Found 351.1860.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (8)

1.一种吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于，包括如下操作：以N-(2-吡啶基)吲哚类化合物1和炔基环丁醇类化合物2为原料，在铑/铱催化剂和添加剂存在下，有机溶剂中升温反应，得到吲哚基取代螺[环丁烷-1,1'-茚]类化合物3；反应方程式为：
Figure FDA0003296820240000011
其中，R1为氢、卤素、三氟甲基、氰基、C1-4烷基或C1-4烷氧基，R2为氢或C1-4烷基，R3为氢、卤素、三氟甲基、苯基、C1-4烷基或C1-4烷氧基。
2.根据权利要求1所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述铑催化剂为[RhCp*Cl2]2{二氯(五甲基环戊二烯基)合铑(III)二聚体}或RhCp*(CH3CN)3(SbF6)2{二(六氟锑酸)三乙腈(五甲基环戊二烯基)铑(III)}；铱催化剂为[IrCp*Cl2]2{二氯(五甲基环戊二烯基)合铱(III)二聚体}。
3.根据权利要求1所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述添加剂为银盐添加剂；银盐添加剂为六氟锑酸银、双三氟甲烷磺酰亚胺银、四氟硼酸银、三氟甲烷磺酸银或三氟乙酸银。
4.根据权利要求1所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述反应溶剂为1,2-二氯乙烷、四氢呋喃、1,2-二甲氧基乙烷、甲苯或乙腈。
5.根据权利要求1所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述N-(2-吡啶基)吲哚类化合物1、炔基环丁醇类化合物2、铑/铱催化剂与银盐添加剂摩尔比为1-1.2:1-1.2:0.04-0.06:0.08-0.12。
6.根据权利要求3所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述添加剂还包括羧酸添加剂；羧酸添加剂为特戊酸、醋酸、1-金刚烷甲酸、苯甲酸或2,4,6-三甲基苯甲酸。
7.根据权利要求6所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述银盐添加剂与羧酸添加剂摩尔比为0.08-0.12:1-2。
8.根据权利要求1-7任意一项所述吲哚基取代螺[环丁烷-1,1'-茚]类化合物的合成方法，其特征在于：所述反应温度为80-120℃。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114436943A (zh) * 2022-02-18 2022-05-06 河南师范大学 一种双重氧化脱氢芳构化合成螺环吲哚类化合物的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111471047A (zh) * 2020-05-21 2020-07-31 河南师范大学 选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的方法
CN112939988A (zh) * 2021-03-02 2021-06-11 河南师范大学 茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究
CN113045496A (zh) * 2021-03-18 2021-06-29 河南师范大学 选择性合成二氢菲啶或菲啶类化合物的方法
CN113185523A (zh) * 2021-05-17 2021-07-30 河南师范大学 一种3-吲哚酮[螺]-3h-吲哚类化合物的合成方法
CN113336689A (zh) * 2021-06-03 2021-09-03 河南师范大学 3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111471047A (zh) * 2020-05-21 2020-07-31 河南师范大学 选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的方法
CN112939988A (zh) * 2021-03-02 2021-06-11 河南师范大学 茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究
CN113045496A (zh) * 2021-03-18 2021-06-29 河南师范大学 选择性合成二氢菲啶或菲啶类化合物的方法
CN113185523A (zh) * 2021-05-17 2021-07-30 河南师范大学 一种3-吲哚酮[螺]-3h-吲哚类化合物的合成方法
CN113336689A (zh) * 2021-06-03 2021-09-03 河南师范大学 3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ZHENG HUAIJI: "PtI2-Catalyzed tandem 3,3-rearrangement/Nazarov reaction of arylpropargylic esters: synthesis of indanone derivatives", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *
ZHU HAI-TAO ET AL.: "Electrophilic Carbocyclization of Aryl Propargylic Alcohols: A Facile Synthesis of Diiodinated Carbocycles and Heterocycles", 《ORGANIC LETTERS》 *
张凌华 等: "吡唑啉酮并苯并二氮杂卓类化合物的高效合成", 《河南省化学会2020年学术年会》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114436943A (zh) * 2022-02-18 2022-05-06 河南师范大学 一种双重氧化脱氢芳构化合成螺环吲哚类化合物的方法

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