CN103848773B - 一种制备双吲哚基芴衍生物的方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- C07D471/02—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
- C07D471/04—Ortho-condensed systems
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Abstract
本发明为一种制备双吲哚基芴衍生物的方法。它是将芴酮和吲哚作为反应物,溶于溶剂,在25℃~100℃下,用酸作催化剂,芴酮、吲哚和催化剂的摩尔比为1:1~4:0.05~0.2;反应获得双吲哚基芴衍生物。本发明采用的原料、催化剂价廉易得,反应条件温和;且通过串联反应一步构建双吲哚基芴衍生物,操作步骤少,分离、纯化方便,合成效率高;还可拓展到芳香杂环、苯环与芴酮反应制备具有重要应用研究意义的其它大共轭体系分子。
Description
技术领域
本发明属于有机合成领域,具体涉及一种制备双吲哚基芴衍生物的方法。
背景技术
双吲哚化合物为诸多陆地和海洋生物代谢产物,具有广泛的药学活性,可以促进人体内雌性激素的代谢,对癌细胞的增长具有很好的抑制活性,如双吲哚甲烷可以诱导人体内癌细胞凋亡,且不影响正常细胞生长。特别是对乳腺癌细胞的增长具有很好的抑制作用;它所具有的抗菌活性,可以缓解纤维肌疼痛。在生物学上,双吲哚还可被用作荧光探针等。
对于双吲哚的合成,双吲哚甲烷研究得最为广泛和深入。它常用醛与吲哚在如Lewis酸、质子酸、离子液体、固体催化剂等物质存在条件下催化合成。如果使用酮与吲哚反应,则得到季碳为中心的双吲哚烷烃;使用炔与吲哚发生两次Friedel-Crarfts反应,也会得到季碳为中心的双吲哚烷烃。但使用双芳基甲酮、或以稠环酮与吲哚缩合的反应还鲜有报道。由于双吲哚大共轭体系分子多数具有荧光性能,故在制备荧光增白剂、荧光染料、荧光探针、荧光颜料、紫外吸收剂等方面都具有潜在的应用价值,所以,研发制备一种双吲哚基芴的大共轭体系分子就有非常重要的意义。
发明内容
本发明提供一种制备双吲哚基芴衍生物的方法。该方法通过一步串联反应达到一步构建大共轭体系分子的双吲哚基芴衍生物的目的。
本发明的技术方案方案
一种制备双吲哚基芴衍生物的方法,它是将芴酮和吲哚作为反应物,溶于溶剂,在25℃~100℃下,用酸作为催化剂,芴酮﹑吲哚和选定催化剂的摩尔比为1:1 ~ 4 : 0.05 ~ 0.2;反应制备得双吲哚基芴衍生物:
该制备方法的反应式为
所述反应物芴酮选自:芴酮或其衍生物4,5-二氮杂芴-9-酮、9-芴酮中的一种;所述反应物吲哚选自:吲哚或其衍生物2-甲基吲哚﹑2-苯基吲哚﹑5-甲基吲哚﹑7-甲基吲哚、5-溴吲哚中的一种;
所述溶剂选自:甲醇﹑乙醇﹑丙醇﹑异丙醇或乙腈中的一种;
所述催化剂选自:乙酸﹑三氯乙酸﹑氨基磺酸﹑甲苯磺酸或甲烷磺酸中的一种;
所述反应时间可以通过薄层色谱 (TLC) 监控,直到反应进行完毕。
所述制备方法的反应式中,反应物芴酮结构式如下:
;
其中X选自C、N中的一种;
反应物吲哚的结构如下:
;
所述反应物吲哚的结构式取代基不同的选择方案为:
其中,R1﹑R2﹑R3﹑R4﹑R5中的任一取代基选自:氢﹑C1~C3烷基﹑C1~C3烷氧基、氰基、硝基、氟﹑氯﹑溴﹑碘或苯基、N,N-二甲氨基中的一种;R6选自氢﹑甲基﹑乙基﹑丙基、苯基、苄基、甲磺酰基、对甲苯磺酰基、乙酰基中的一种。
具体的选择采用下列方案之一:
(1) 当R1、R2、R3选自氢﹑C1~C3烷基﹑C1~C3烷氧基、氟﹑氯﹑溴﹑碘、氰基、硝基、苯基、N,N-二甲氨基中的一种时,R4 = R5 = H;
(2) 当R1、R2、R4选自氢﹑C1~C3烷基﹑C1~C3烷氧基、氟﹑氯﹑溴﹑碘、氰基、硝基、苯基、N,N-二甲氨基中的一种,R3 = R5 = H;
(3) 当R3、R4选氢﹑C1~C3烷基﹑C1~C3烷氧基、氟﹑氯﹑溴﹑碘、氰基、硝基、苯基、N,N-二甲氨基中的一种时;R5选氢﹑C1~C3烷基﹑氰基、硝基、苯基、N,N-二甲氨基中的一种时,R1 = R2 = H。
所述制备方法的优选技术条件为:
反应温度为50℃~ 80℃;
芴酮﹑吲哚和选定催化剂的摩尔比为1:2.5 : 0.1;
催化剂为甲烷磺酸。
本发明的有益效果
(一)本发明路线所采用的原料、催化剂价廉易得,反应条件温和。
(二)本发明通过串联反应一步构建双吲哚基芴衍生物,操作步骤少,分离、纯化方便,合成效率高。
(三)本发明路线可以拓展到其它芳香杂环、苯环与芴酮反应制备其它大共轭体系分子,对大共轭体系分子的应用研究具有重要意义。
具体实施方式
下面给出具体的实施例,以进一步说明本发明的技术解决方案,但并非为对本发明保护范围的限制。
实施例一:本实施例为9,9'-二(7-甲基-3-吲哚基)芴的合成;以9-芴酮和7-甲基吲哚为原料,其反应式如下:
实施步骤:
将9-芴酮 0.180克 (1 mmol)、7-甲基吲哚0.328克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL甲醇,加热至回流(反应液温度约65℃)温度,TLC跟踪直至反应结束,冷至室温,抽滤得到固体。将固体用二甲亚砜重结晶得到纯品 (产率74%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 6.5 Hz, 2H), 6.70 – 6.58 (m, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.91, 139.48, 136.96, 127.67 (d, J = 6.1 Hz), 126.11, 125.66, 123.52, 121.66, 121.05, 120.65, 119.10, 118.55, 55.49, 17.21。
实施例二:本实施例为9,9'-二(5-溴-3-吲哚基)芴的合成;以9-芴酮和5-溴吲哚为原料,其反应式如下:
实施步骤:
将9-芴酮 0.180克 (1 mmol)、5-溴吲哚0.485克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL乙醇,加热至回流(反应液温度约78℃),TLC跟踪直至反应结束,冷至室温,抽滤得到固体。将固体用二甲亚砜重结晶得到纯品 (产率88%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.49 – 7.37 (m, 2H), 7.35 – 7.24 (m, 2H), 7.10 (dd, J = 8.6, 1.5 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.74 (s, 1H); 13C NMR (101 MHz, DMSO-d6) δ 152.02, 139.41, 136.14, 128.08, 127.84, 125.86, 125.57, 123.78, 122.78, 120.88, 117.61, 114.32, 111.32, 54.94。
实施例三:本实施例为9,9'-二(2-甲基-3-吲哚基)芴的合成;以9-芴酮和2-甲基吲哚为原料,其反应式如下:
实施步骤:
将9-芴酮 0.180克 (1 mmol)、2-甲基吲哚0.328克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL丙醇,加热至回流(反应液温度约97℃),TLC跟踪直至反应结束,冷至室温,抽滤得到固体。将固体用二甲亚砜重结晶得到纯品 (产率97%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.2 Hz, 2H), 6.84 (t, J = 7.5 Hz, 1H), 6.54 (t, J = 7.1 Hz, 2H), 1.73 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 153.50, 139.32, 135.72, 132.05, 128.25, 127.66, 126.14, 120.51, 120.11, 118.23, 113.28, 110.74, 55.80, 13.93。
实施例四:本实施例为9,9'-二(3-吲哚基)-4,5-二氮杂芴的合成;以4,5-二氮杂芴-9-酮和吲哚为原料,其反应式如下:
实施步骤:
将4,5-二氮杂芴-9-酮 0.182克 (1 mmol)、吲哚0.292克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL异丙醇,加热至回流
(反应液温度约82℃),TLC跟踪直至反应结束,冷至室温,抽滤得到固体;将固体用二甲亚砜重结晶得到纯品 (产率86%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 2H), 8.73 (d, J = 4.2 Hz, 2H), 8.12 (d, J = 7.5 Hz, 2H), 7.47 – 7.31 (m, 4H), 7.00 (t, J = 7.5 Hz, 2H), 6.86 (dd, J = 12.0, 5.1 Hz, 4H), 6.75 (t, J = 7.4 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 155.22, 149.13, 148.22, 137.62, 134.50, 126.10, 124.82, 124.18, 121.58, 120.45, 119.11, 115.24, 112.45, 51.80, 40.92; MS (ESI): m/z [M + H]+ calcd for C27H19N4: 399.2; found: 399.3。
实施例五:本实施例为9,9'-二(2-甲基-3-吲哚基)-4,5-二氮杂芴的合成; 以4,5-二氮芴-9-酮和2-甲基吲哚为原料,其反应式如下:
实施步骤:
将4,5-二氮杂芴-9-酮 0.182克 (1 mmol)、2-甲基吲哚0.328克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL乙腈,加热至回流(反应液温度约81℃),TLC跟踪直至反应结束,冷至室温,抽滤得到固体。将固体用二甲亚砜重结晶得到纯品 (产率75%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 2H), 8.67 (s, 2H), 7.94 (d, J = 7.0 Hz, 2H), 7.31 (s, 2H), 7.21 (d, J = 7.5 Hz, 2H), 6.89 (s, 2H), 6.60 (s, 2H), 6.38 (s, 2H), 1.74 (s, 6H); 13C NMR (101 MHz, DMSO-d6) δ 150.15, 148.91, 146.59, 138.88, 135.59, 133.14, 127.25, 120.76, 119.32, 119.11, 111.53, 107.59, 53.43, 14.32; MS (ESI): m/z [M + H]+ calcd for C29H23N4: 427.2; found: 427.2。
实施例六:本实施例为9,9'-二(5-甲基-3-吲哚基)-4,5-二氮杂芴的合成;以4,5-二氮杂芴-9-酮和5-甲基吲哚为原料,其反应式如下:
实施步骤:
将4,5-二氮杂芴-9-酮 0.182克 (1 mmol)、5-甲基吲哚0.328克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL甲醇,加热至回流(反应液温度约65℃),TLC跟踪直至反应结束,冷至室温,抽滤得到固体。将固体用二甲亚砜重结晶得到纯品 (产率70%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 2H), 8.68 (d, J = 4.5 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H), 7.39 – 7.18 (m, 4H), 6.83 (d, J = 7.9 Hz, 4H), 6.58 (s, 2H), 2.13 (s, 6H); 13C NMR (101 MHz, DMSO-d6) δ 157.00, 149.89, 147.66, 136.00, 133.36, 127.15, 126.24, 124.37, 123.92, 123.13, 120.17, 115.37, 112.13, 51.45, 21.91; MS (ESI): m/z [M + H]+ calcd for C29H23N4: 427.2; found:427.3。
实施例七:本实施例为9,9'-二(2-苯基-3-吲哚基)-4,5-二氮杂芴的合成;以4,5-二氮杂芴-9-酮和2-苯基吲哚为原料,其反应式如下:
实施步骤:
将4,5-二氮杂芴-9-酮 0.182克 (1 mmol)、2-苯基吲哚0.482克 (2.5 mmol) 和甲烷磺酸0.096 克 (0.1 mmol) 置于反应瓶中,加入25mL甲醇,加热至回流(反应液温度约65℃),TLC跟踪直至反应结束,冷至室温,抽滤得到固体。将固体用二甲亚砜重结晶得到纯品 (产率72%)。
产物数据: 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 2H), 8.33 (d, J = 4.2 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.16 – 7.05 (m, 4H), 6.97 (dt, J = 26.7, 7.5 Hz, 6H), 6.65 (ddd, J = 12.4, 11.3, 6.2 Hz, 8H); 13C NMR (101 MHz, DMSO-d6) δ 156.43, 149.18, 146.23, 136.25, 134.19, 133.21, 129.21, 128.59, 127.57, 122.79, 121.54, 121.18, 119.15, 113.44, 111.51, 51.71, 40.90; MS (ESI): m/z [M + H]+ calcd for C39H24N4: 551.2; found: 551.4。
Claims (4)
1.一种制备双吲哚基芴衍生物的方法,其特征在于:该制备方法是将芴酮和吲哚作为反应物,溶于溶剂,在25℃~100℃下,用酸作为催化剂,芴酮﹑吲哚和催化剂的摩尔比为1:1 ~ 4 : 0.05 ~ 0.2;反应制备得双吲哚基芴衍生物:该制备方法的反应式为:
其中,
所述酸为甲磺酸、乙酸、三氯乙酸﹑氨基磺酸﹑甲苯磺酸中的一种;
所述反应物吲哚的结构式取代基不同的选择方案为:
R1﹑R2﹑R3﹑R4﹑R5中的任一取代基选自:氢﹑C1~C3烷基﹑C1~C3烷氧基、氰基、硝基、氟﹑氯﹑溴﹑碘或苯基、N,N-二甲氨基中的一种;R6选自氢﹑甲基﹑乙基﹑丙基、苯基、苄基、甲磺酰基、对甲苯磺酰基、乙酰基中的一种。
2.根据权利要求1所述的一种制备双吲哚基芴衍生物的方法,其特征在于:
所述反应物吲哚选自:吲哚或其衍生物2-甲基吲哚﹑2-苯基吲哚﹑5-甲基吲哚﹑7-甲基吲哚、5-溴吲哚中的一种;
所述溶剂选自:甲醇﹑乙醇﹑丙醇﹑异丙醇或乙腈中的一种;
所述反应时间是通过薄层色谱 (TLC) 监控,直到反应进行完毕。
3.根据权利要求1所述的一种制备双吲哚基芴衍生物的方法,其特征在于:所述反应物吲哚的结构式取代基不同的具体的选择方案为下列之一:
(1) 当R1、R2、R3选自氢﹑C1~C3烷基﹑C1~C3烷氧基、氟﹑氯﹑溴﹑碘、氰基、硝基、苯基、N,N-二甲氨基中的一种时,R4 = R5 = H;
(2) 当R1、R2、R4选自氢﹑C1~C3烷基﹑C1~C3烷氧基、氟﹑氯﹑溴﹑碘、氰基、硝基、苯基、N,N-二甲氨基中的一种时,R3 = R5 = H;
(3) 当R3、R4选氢﹑C1~C3烷基﹑C1~C3烷氧基、氟﹑氯﹑溴﹑碘、氰基、硝基、苯基、N,N-二甲氨基中的一种时;R5选氢﹑C1~C3烷基﹑氰基、硝基、苯基、N,N-二甲氨基中的一种时,R1 = R2 = H。
4.根据权利要求1所述的一种制备双吲哚基芴衍生物的方法,其特征在于:
所述反应温度优选为50℃~ 80℃;
所述芴酮﹑吲哚和选定催化剂的摩尔比优选为1:2.5 : 0.1;
所述催化剂优选为甲磺酸。
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