WO2023142231A1 - 一种 c3- 烷基化吲哚的制备方法 - Google Patents

一种 c3- 烷基化吲哚的制备方法 Download PDF

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WO2023142231A1
WO2023142231A1 PCT/CN2022/079805 CN2022079805W WO2023142231A1 WO 2023142231 A1 WO2023142231 A1 WO 2023142231A1 CN 2022079805 W CN2022079805 W CN 2022079805W WO 2023142231 A1 WO2023142231 A1 WO 2023142231A1
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indole
alkylated
reaction
preparation
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万小兵
成雄略
王丽丽
刘忆德
江港钟
陶苏艳
万潇
李如一
项紫欣
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苏州大学
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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
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the invention relates to a simple preparation method of C3-alkylated indole, which belongs to the technical field of organic synthesis.
  • C3-Alkylated indoles are widely used in medicine for their multiple biological activities, including antagonist, anti-inflammatory, antiarrhythmic, antibiotic, antifungal, and antiviral, and they have also been clinically evaluated for therapeutic Cancer, the development of reliable and general methods for the construction of 3-alkyl substituted indoles is of great interest.
  • the Friedel-Crafts reaction is a classic method to obtain C3-alkylated indoles and has been widely used in drug synthesis. However, it suffers from narrow substrate scope (usually limited to activated organohalides), use of toxic organohalides and Lewis acids, generation of large amounts of inorganic salts, excessive alkylation, and poor regioselectivity.
  • This method requires the use of expensive catalysts, and the scope of substrates is relatively limited ( See: Adv. Synth. Catal. , 2021 , 363 , 2386–2391); Tsuchimoto used aldehyde or ketone as an alkylating agent to achieve the alkylation of indole under the catalysis of In(NTf) 3.
  • the method has mild conditions, But the catalysts used are expensive and not suitable for complex molecules.
  • the purpose of the present invention is to provide a method for preparing C3-alkylated indoles, which has the advantages of rich sources of raw materials, wide applicability of reaction substrates, simple and convenient operation, and mild reaction conditions. It is especially worth mentioning that this method does not require the use of metal catalysts and is suitable for the late modification of complex drug molecules, which has high practical value.
  • the technical scheme adopted in the present invention is: a simple preparation method of C3-alkylated indole, using carbonyl compounds and indole compounds as reaction substrates, and reacting to obtain C3 in the presence of silane and iodine - Alkylated indoles, preferably reacted in organic solvents to give C3-alkylated indoles.
  • the product that the present invention obtains is C3-alkylated indole, and its chemical structural formula is: .
  • the general chemical structure formula of carbonyl compound is: .
  • the general chemical structure formula of indole compound is: .
  • the general structural formula of silane is: .
  • R1 and R2 are independently selected from hydrogen, alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, ester or carbonyl;
  • R3 is selected from phenyl or methyl;
  • R 4 is selected from hydrogen, alkyl, ester group;
  • R 5 is selected from hydrogen, amino, boryl, alkyl, alkoxy, cyano, ester or halogen;
  • R 6 , R 7 , R 8 are independently selected from Hydrogen, alkyl, aryl or alkoxy; wherein the substituent in the substituted aryl is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone.
  • silane is added to react to obtain C3-alkylated indole.
  • the iodine is simple iodine, preferably, the amount of iodine is 5-20% of the carbonyl compound, preferably 8-12% in molar amount.
  • the dosage of the indole compound is 1 to 1.5 times the molar weight of the carbonyl compound; preferably, the dosage of the indole compound is 1.5 times the molar weight of the carbonyl compound; the dosage of the silane is 1.5 to 2.5 times the molar weight of the carbonyl compound, preferably 2 times.
  • the reaction temperature is 15-80° C.; the reaction time is 12-48 hours; the preferred reaction temperature is room temperature; the reaction time is 15-20 hours.
  • the reaction is carried out in an organic solvent;
  • the organic solvent is one or more of hexafluoroisopropanol, 1,2-dichloroethane, acetonitrile, nitromethane, toluene, and trifluoroethanol;
  • the organic solvent is hexafluoroisopropanol (HFIP) and acetonitrile (MeCN).
  • the reaction of the present invention is carried out in the air. After the reaction is finished, dry with anhydrous sodium sulfate, use a rotary evaporator to remove the solvent and then adsorb on silica gel, and finally carry out column chromatography with a mixed solvent of ethyl acetate and sherwood oil to obtain C3- Alkylated indoles.
  • the present invention has the following advantages compared with the prior art: the present invention uses elemental iodine as a catalyst and carbonyl compound as an alkylating agent to prepare C3-alkylated indole under the condition of silane existence, which is different from existing Compared with the large amount of raw materials and harsh conditions in the prior art, the reaction is more economical and the substrate has wider applicability.
  • the method disclosed by the invention has mild conditions, low catalyst cost and less consumption, convenient post-treatment, and is beneficial to the application in the synthesis of drug molecules.
  • the reactants, additives, catalysts and other raw materials used in the invention are cheap and easy to obtain, the reaction steps are few, no ligand is needed, and the target product can be obtained in only one step reaction, which meets the requirements and direction of green chemistry. Most importantly, this method does not need to use toxic and harmful metal catalysts, is green and friendly, and is especially suitable for the synthesis of drug molecules.
  • carbonyl compound of the present invention indole, iodine catalyst, silane and solvent are all commercial goods, can directly buy and obtain.
  • the specific operation method and test method of the experiment are conventional methods in the art, and the reaction is carried out in a conventional environment.
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • ketone 1aj (0.5 mmol), iodine (0.05 mmol), N-methylindole 2 (0.75 mmol), triethylsilane (1.0 mmol), MeCN ( 2.0 mL). Seal the test tube with a parafilm, and stir at 25°C for 16 h, then dry the reaction solution with anhydrous sodium sulfate, remove the solvent by a rotary evaporator, and then adsorb on silica gel, and finally carry out the reaction with a mixed solvent of ethyl acetate and petroleum ether.
  • the C3-alkylated indole can be obtained by column chromatography. puce oil, 92 % yield.
  • Embodiment twenty-two are identical to Embodiment twenty-two.
  • aldehyde 1a 0.5 mmol
  • iodine 0.05 mmol
  • indole 2a 0.5 mmol
  • triethylsilane 1.0 mmol
  • HFIP 2.0 mL
  • the C3-alkylated indole can be obtained by column chromatography.
  • Embodiment twenty-three Embodiment twenty-three.
  • aldehyde 1a 0.5 mmol
  • iodine 0.05 mmol
  • indole 2c 0.5 mmol
  • triethylsilane 1.0 mmol
  • HFIP 2.0 mL
  • the C3-alkylated indole can be obtained by column chromatography.
  • Embodiment twenty-five Embodiment twenty-five.
  • aldehyde 1a 0.5 mmol
  • iodine 0.05 mmol
  • indole 2c 0.5 mmol
  • triethylsilane 1.0 mmol
  • HFIP 2.0 mL
  • the C3-alkylated indole can be obtained by column chromatography.
  • Embodiment twenty-six Embodiment twenty-six.
  • Embodiment twenty-seven are identical to Embodiment twenty-seven.

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Abstract

一种C3-烷基化吲哚的制备方法，使用单质碘为催化剂，以硅烷为还原剂，以羰基化合物为烷基化试剂，温和条件下制备了C3-烷基化吲哚。本方法无需使用有毒有害的金属试剂，反应条件温和，催化剂廉价而且用量少，后处理方便，有利于在药物分子合成的应用。反应步骤少，无需配体，仅需一步反应就能得到目标产物，符合绿色化学的要求和方向。

Description

一种C3-烷基化吲哚的制备方法 技术领域
本发明涉及一种C3-烷基化吲哚的简单制备方法，属于有机合成技术领域。
 背景技术
C3-烷基化吲哚因其多种生物活性在药物中获得广泛的应用，包括拮抗剂、抗炎、抗心律失常、抗生素、抗真菌和抗病毒，并且它们也已被临床评估用于治疗癌症，开发构建 3-烷基取代吲哚的可靠且通用的方法具有很大的意义。Friedel-Crafts 反应是获得 C3-烷基化吲哚的经典方法，并在药物合成中得到了广泛应用。然而，它存在底物范围狭窄（通常仅限于活化的有机卤化物）、使用有毒有机卤化物和路易斯酸、产生大量无机盐、过度烷基化和区域选择性差等问题。Tang以三(五氟苯基)硼烷作为催化剂，以β-羟基酮作为烷基化试剂成功构建了C3-烷基化吲哚，该方法需要使用昂贵的催化剂，且底物范围比较局限（参见： Adv. Synth. Catal., 2021, 363, 2386–2391）；Tsuchimoto以醛或者酮作为烷基化试剂在In(NTf) 3催化下实现了吲哚的烷基化，该方法条件温和，但是使用的催化剂较为昂贵，且不适用于复杂分子。目前报道的这些构建C3-烷基化吲哚的方法仍然存在一些缺点，例如使用昂贵或有毒的催化剂，反应条件苛刻，底物范围窄。因此，发展一种原料来源丰富、底物范围广、绿色、温和的构建C3-烷基化吲哚的方法显得尤为重要。考虑到该骨架在药物中的广泛用途，新发展的方法必须排除金属的使用，另外，要适合用于复杂分子的后期修饰。
技术问题
本发明的目的是提供一种制备C3-烷基化吲哚的方法，该方法具有原料来源丰富、反应底物普适性广，操作简便，反应条件温和等优点。尤其值得一提的是，该方法无需使用金属催化剂，适用于复杂药物分子的后期修饰，具有很高的实用价值。
 技术解决方案
为达到上述发明目的，本发明采用的技术方案是：一种C3-烷基化吲哚的简单制备方法，以羰基化合物、吲哚化合物为反应底物，在硅烷、碘存在下，反应得到C3-烷基化吲哚，优选在有机溶剂中反应得到C3-烷基化吲哚。
本发明得到的产物为C3-烷基化吲哚，其化学结构式为： 。
本发明中：羰基化合物的化学结构通式为： 。吲哚化合物的化学结构通式为： 。硅烷的结构通式为： 。
上述化学结构式中，R 1和R 2独立的选自氢、烷基、芳基、取代芳基、杂芳香基、取代杂芳香基、酯基或者羰基；R 3选自苯基或者甲基；R 4选自氢、烷基、酯基；R 5选自氢、氨基、硼基、烷基、烷氧基、氰基、酯基或者卤素；R 6、R 7、R 8独立的选自氢、烷基、芳基或者烷氧基；其中取代芳基中的取代基选自氢、烷基、氟、氯、溴、羧酸、酰胺、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基。
上述技术方案中，将羰基化合物、碘、吲哚化合物在有机溶剂中混合后，再加入硅烷，反应得到C3-烷基化吲哚。
本发明中，所述碘为碘单质，优选的，按摩尔量，碘的用量为羰基化合物的5～20%，优选为8～12%。所述吲哚化合物用量为羰基化合物摩尔量的1～1.5倍；优选的，所述吲哚化合物用量为羰基化合物摩尔量的1.5倍；硅烷用量为羰基化合物摩尔量的1.5～2.5倍，优选2倍。
本发明中，所述反应的温度为15～80℃；反应时间为12～48小时；优选的反应温度为室温；反应时间为15～20小时。
本发明中，反应在有机溶剂中进行；所述有机溶剂为六氟异丙醇、1,2-二氯乙烷、乙腈、硝基甲烷、甲苯、三氟乙醇中的一种或几种；优选的，有机溶剂为六氟异丙醇（HFIP）和乙腈（MeCN）。
本发明的反应在空气中进行，反应结束后，用无水硫酸钠干燥，用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。
 有益效果
由于上述技术方案的运用，本发明与现有技术相比具有下列优点：本发明使用单质碘为催化剂以羰基化合物为烷基化试剂在硅烷存在条件制备了C3-烷基化吲哚，与现有技术中的原料用量大和条件苛刻相比，反应更经济、底物普适性更广。本发明公开的方法条件温和，催化剂廉价而且用量少，后处理方便，有利于在药物分子合成的应用。本发明使用的反应物、添加剂、催化剂等原料廉价易得，反应步骤少，无需配体，仅需一步反应就能得到目标产物，符合绿色化学的要求和方向。最重要的是，本方法无需采用有毒有害的金属催化剂，绿色友好，尤其适用于药物分子的合成。
 本发明的实施方式
下面结合实例对本发明作进一步描述：本发明的羰基化合物、吲哚、碘催化剂、硅烷和溶剂皆为市场化商品，可以直接购买获得。实验具体操作方法以及测试方法为本领域常规方法，反应在常规环境中进行。
实施例一。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1a（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）；将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。产率：96%； 1H NMR (400 MHz, Chloroform- d)δ7.43 (d, J = 7.9 Hz, 1H), 7.37-7.29 (m, 2H), 7.26-7.14 (m, 2H), 7.11-6.99 (m, 3H), 6.67 (s, 1H), 3.98 (s, 2H), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl 3)δ140.4, 137.1, 131.2, 130.3, 127.6, 127.1, 121.6, 119.5, 119.0, 118.8, 113.4, 109.2, 32.5, 30.9。
将上述制备方法中的六氟异丙醇更换为2.0mL的其它溶剂，其余不变，收率如下： 。
将上述制备方法中的三乙基硅烷更换为1.0 mmol的其它硅烷，其余不变，收率如下： 。
往上述反应体系中添加20 μL水，其余不变，产率：95 %。
省略上述制备方法中的碘，其余不变，产率：<1%。
省略上述制备方法中的硅烷，其余不变，产率：<1%。
实施例二。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1b（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL），将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。lavender solid, 92% yield. mp: 60 – 62℃. 1HNMR (400 MHz, Chloroform- d) δ 7.51 – 7.44 (m, 1H), 7.29 – 7.10 (m, 7H), 7.07 – 7.00 (m, 1H), 6.66 (s, 1H), 4.06 (s, 2H), 3.59 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 141.4, 137.1, 128.6, 128.3, 127.8, 127.0, 125.8, 121.5, 119.1, 118.7, 114.2, 109.1, 32.4, 31.5.HRMS(EI-TOF): Anal Calcd. For. C 16H 15N: 221.1199, Found: 221.1206.IR (neat, cm -1): υ 3027, 2889, 1614, 1475, 1325, 1253, 1151, 1006, 827, 728。
实施例三。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1c（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。puce oil, 98% yield. 1H NMR (400 MHz, Chloroform- d) δ 7.49 – 7.41 (m, 1H), 7.28 – 7.23 (m, 1H), 7.22 – 7.15 (m, 3H), 7.09 – 7.01 (m, 1H), 6.95 – 6.87 (m, 2H), 6.69 (s, 1H), 4.03 (s, 2H), 3.65 (s, 3H). 13C NMR (100 MHz, Chloroform- d) δ 161.2 (d, J = 243.4 Hz), 137.2, 137.0 (d, J = 3.2 Hz), 129.9 (d, J = 7.7 Hz), 127.6, 127.0, 121.6, 119.1, 118.8, 115.0 (d, J = 21.2 Hz), 114.0, 109.2, 32.5, 30.7. 19F NMR (376 MHz, CDCl 3) δ -117.67.HRMS(EI-TOF): Anal Calcd. For. C 16H 14FN: 239.1105, Found: 239.1108.IR (neat, cm -1): υ 3049, 2909, 1505, 1327, 1216, 1130, 1092, 1012, 853, 735。
实施例四。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1d（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 90 % yield. mp: 71 – 73℃. 1H NMR (400 MHz, Chloroform- d) δ 7.44 (d, J = 7.9 Hz, 1H), 7.27 – 7.21 (m, 1H), 7.22 – 7.12 (m, 5H), 7.04 (ddd, J = 7.9, 6.8, 1.2 Hz, 1H), 6.68 (s, 1H), 4.01 (s, 2H), 3.64 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 139.9, 137.1, 131.5, 129.9, 128.3, 127.6, 127.1, 121.6, 119.0, 118.8, 113.6, 109.2, 32.5, 30.8. HRMS (EI-TOF): Anal Calcd. For. C 16H 14 35ClN: 255.0810, Found: 255.0811. Anal Calcd. For. C 16H 14 37ClN: 257.0780, Found: 257.0792.IR (neat, cm -1): υ 3057, 2893, 1552, 1485, 1328, 1253, 1013, 779, 738。
实施例五。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1e（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。pink solid, 96% yield (166.5 mg). mp: 94 – 97℃. 1H NMR (400 MHz, Chloroform- d) δ 7.60 – 7.49 (m, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.22 – 7.16 (m, 1H), 7.05 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H), 7.00 – 6.96 (m, 2H), 6.69 (s, 1H), 3.99 (s, 2H), 3.65 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 141.0, 137.2, 137.1, 130.7, 127.6, 127.1, 121.6, 119.0, 118.8, 113.34, 109.2, 91.0, 32.5, 31.0.HRMS (EI-TOF): Anal Calcd. For. C 16H 14IN: 347.0166, Found: 347.0173.IR (neat, cm -1): υ 3052, 2972, 1614, 1473, 1326, 1231, 1001, 919, 775, 728。
实施例六。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1g（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 87 % yield. mp: 141 – 142 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.78 (d, J = 8.4 Hz, 2H), 7.46 – 7.35 (m, 3H), 7.32 – 7.24 (m, 1H), 7.20 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.04 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.78 (s, 1H), 4.13 (s, 2H), 3.68 (s, 3H), 2.95 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 148.0, 137.9, 137.0, 129.3, 127.3, 127.2, 121.6, 118.9, 118.7, 112.2, 109.2, 44.3, 32.4, 31.3.HRMS(ESI-TOF): Anal Calcd. For. C 17H 17NO 2S[M+Na] +: 322.0873, Found: 322.0846.IR (neat, cm -1): υ 2994, 2915, 1595, 1418, 1300, 1141, 1088, 955, 764, 732。
实施例七。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1h（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 95 % yield. mp: 111 – 113 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.52 – 7.44 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.29 – 7.25 (m, 1H), 7.21 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.05 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.77 (s, 1H), 4.10 (s, 2H), 3.70 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 147.1, 137.1, 132.0, 129.2, 127.4, 127.2, 121.7, 119.0, 118.9, 118.8, 112.2, 109.5, 109.3, 32.5, 31.5. HRMS(ESI-TOF): Anal Calcd. For. C 17H 14N 2[M+Na] +: 269.1050, Found: 269.1036.IR (neat, cm -1): υ 3048, 2898, 2222, 1606, 1478, 1431, 1322, 1153, 1066, 817, 737。
实施例八。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1j（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。yellow solid, 92 % yield. mp: 76 – 78 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.54 (d, J = 7.9 Hz, 1H), 7.25 – 6.90 (m, 7H), 6.72 (s, 1H), 4.08 (s, 2H), 3.59 (s, 3H). 13C NMR (100 MHz, Chloroform- d) δ 160.9 (d, J = 244.9 Hz), 137.0, 130.8 (d, J = 4.6 Hz), 128.3 (d, J = 15.5 Hz), 127.7, 127.5 (d, J = 8.1 Hz), 127.1, 123.9 (d, J = 3.6 Hz), 121.5, 119.0, 118.8, 115.1 (d, J = 22.1 Hz), 112.6, 109.1, 32.4, 24.1 (d, J = 3.8 Hz). 19F NMR (376 MHz, Chloroform- d) δ -118.30.HRMS (EI-TOF): Anal Calcd. For. C 16H 14FN: 239.1105, Found: 239.1112.IR (neat, cm -1): υ 3049, 2900, 2222, 1583, 1490, 1330, 1228, 1154, 1054, 919, 737。
实施例九。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1l（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。yellow solid, 98 % yield (127.5 mg). mp: 87 – 88 ℃. 1H NMR (400 MHz, Chloroform- d) δ 8.10 (s, 1H), 7.96 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 7.57 – 7.51 (m, 1H), 7.43 – 7.38 (m, 1H), 7.36 – 7.24 (m, 2H), 7.23 – 7.15 (m, 1H), 7.09 – 7.01 (m, 1H), 6.78 (s, 1H), 4.13 (s, 30H), 3.68 (s, 2H). 13C NMR (100 MHz, CDCl 3) δ 148.2, 143.5, 137.1, 134.7, 129.0, 127.3, 127.2, 123.3, 121.7, 120.9, 119.0, 118.7, 112.3, 109.3, 32.5, 31.1. HRMS(ESI-TOF): Anal Calcd. For. C 16H 14N 2O 2[M+Na] +: 289.0948, Found: 289.0960.IR (neat, cm -1): υ 2915, 2848, 1615, 1550, 1503, 1426, 1376,1325, 1247, 1155, 1030, 866, 731。
实施例十。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1p（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。brown solid, 88 % yield. mp: 191 – 193 ℃. 1H NMR (400 MHz, DMSO- d 6) δ 7.82 (dd, J = 7.7, 1.5 Hz, 1H), 7.52 – 7.43 (m, 1H), 7.43 – 7.37 (m, 1H), 7.37 – 7.31 (m, 2H), 7.30 – 7.24 (m, 1H), 7.16 – 7.07 (m, 1H), 7.02 – 6.91 (m, 2H), 4.44 (s, 2H), 3.69 (s, 3H). 13C NMR (100 MHz, DMSO) δ 169.2, 142.2, 136.7, 131.5, 130.8, 130.7, 130.1, 127.7, 127.5, 125.9, 121.2, 118.8, 118.5, 113.3, 109.6, 32.3, 28.6.HRMS(ESI-TOF): Anal Calcd. For. C 17H 15NO 2[M+Na] +: 288.0995, Found: 288.1005.IR (neat, cm -1): υ 3049, 2894, 2825, 1674, 1611, 1467, 1327, 1251, 1127, 1059, 827, 741。
实施例十一。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1q（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。purple solid, 92 % yield. mp: 87 – 90 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.66 (dd, J = 8.0, 1.2 Hz, 1H), 7.59 – 7.46 (m, 2H), 7.29 – 7.11 (m, 4H), 7.09 – 6.97 (m, 2H), 6.82 (s, 1H), 4.30 (s, 2H), 3.59 (s, 3H). 13CNMR (100 MHz, CDCl 3) δ 146.0, 140.1, 139.6, 137.0, 127.4, 127.2, 123.9, 123.3, 122.8, 122.1, 121.7, 121.0, 119.0, 118.9, 112.55, 109.2, 32.5, 26.7.HRMS(EI-TOF): Anal Calcd. For. C 18H 15NS: 277.0920, Found: 277.0921.IR (neat, cm -1): υ 3050, 2894, 1609, 1467, 1327, 1010, 827, 741。
实施例十二。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1s（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。pink solid, 91 % yield. mp: 95 – 96 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.62 – 7.48 (m, 1H), 7.26 – 7.12 (m, 2H), 7.12 – 7.01 (m, 1H), 7.00 (d, J = 5.3 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 6.82 (s, 1H), 4.19 (s, 2H), 3.62 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 139.7, 136.9, 129.6, 127.2, 127.1, 123.5, 121.7, 119.0, 118.9, 112.2, 109.2, 108.2, 77.3, 77.0, 76.7, 32.5, 25.1.HRMS (EI-TOF): Anal Calcd. For. C 14H 12 79BrNS: 304.9869, Found: 304.9877. Anal Calcd. For. C 14H 12 81BrNS: 306.9848, Found: 306.9856.IR (neat, cm -1): υ 3049, 2894, 1672, 1610, 1467, 1327, 1251, 1127, 1059, 827, 741。
实施例十三。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1u（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 83 % yield (115.4 mg). mp: 154 – 155 ℃. 1H NMR (400 MHz, Chloroform- d) δ 8.32 – 8.13 (m, 1H), 7.59 – 7.44 (m, 3H), 7.36 – 7.25 (m, 3H), 7.23 – 7.17 (m, 1H), 7.11 – 7.02 (m, 1H), 6.96 (s, 1H), 3.95 (s, 2H), 3.70 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 177.7, 156.3, 153.1, 137.0, 133.2, 127.7, 127.4, 125.7, 124.7, 124.0, 123.6, 121.5, 118.9, 117.9, 110.3, 109.2, 32.5, 21.0; HRMS(ESI-TOF): Anal Calcd. For. C 19H 15NO 2[M+Na] +: 312.0995, Found: 312.0981.IR (neat, cm -1): υ 3063, 3050, 2909, 1714, 1629, 1572, 1464, 1150, 1058, 841, 730。
实施例十四。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1u（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。green solid, 93 % yield. mp: 108 – 110 ℃. 1HNMR (400 MHz, DMSO- d 6) δ 7.81 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.47 (dd, J = 9.1, 6.6 Hz, 1H), 7.37 (dt, J = 8.2, 0.9 Hz, 1H), 7.28 (dd, J = 6.6, 1.0 Hz, 1H), 7.22 (s, 1H), 7.12 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.99 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 4.41 (s, 2H), 3.72 (s, 3H). 13C NMR (100 MHz, DMSO) δ 149.3, 149.2, 136.7, 133.0, 130.5, 129.4, 128.3, 127.2, 121.2, 118.7, 118.6, 113.5, 109.9, 109.7, 32.3, 26.9; HRMS(ESI-TOF): Anal Calcd. For. C 16H 13N 3O[M+Na] +:286.0951, Found:286.0962.IR (neat, cm -1): υ 3080, 2886, 1476, 1348, 1289, 997, 931, 782, 744。
实施例十五。
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空气中，向具有磁力搅拌子的试管中，依次添加醛1u（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。puce oil, 72 % yield. 1H NMR (400 MHz, Chloroform- d) δ 8.04 – 7.98 (m, 2H), 7.57 (dt, J = 7.9, 1.0 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.33 – 7.29 (m, 1H), 7.28 – 7.21 (m, 2H), 7.21 – 7.10 (m, 2H), 7.08 – 7.01 (m, 1H), 6.68 (s, 1H), 4.36 – 4.15 (m, 4H), 3.61 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl 3) δ 140.1, 138.5, 137.2, 131.7, 127.8, 127.1, 126.7, 125.4, 122.9, 122.8, 121.4, 120.4, 120.2, 119.2, 118.7, 118.4, 115.5, 109.1, 108.3, 108.2, 37.4, 32.4, 31.5, 13.8.HRMS(ESI-TOF): Anal Calcd. For. C 24H 22N 2[M+Na] +: 361.1676, Found: 361.1661.IR (neat, cm -1): υ 3051, 2975, 1732, 1682, 1485, 1326, 1231, 1121, 1012, 802, 738。
实施例十六。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1u（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。colorless oil, 92 % yield. 1H NMR (400 MHz, Chloroform- d) δ 7.78 – 7.71 (m, 1H), 7.43 – 7.32 (m, 2H), 7.24 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H), 6.94 (s, 1H), 5.81 (s, 2H), 3.84 (s, 3H), 2.96 – 2.72 (m, 2H), 2.37 – 2.02 (m, 4H), 2.03 – 1.81 (m, 2H), 1.54 – 1.35 (m, 1H). 13C NMR (100 MHz, CDCl 3) δ 136.9, 128.3, 126.9, 126.7, 126.6, 121.2, 119.2, 118.4, 113.5, 109.0, 34.7, 32.4, 32.0, 32.0, 28.8, 25.2.HRMS (EI-TOF): Anal Calcd. For. C 16H 19N: 225.1512, Found: 225.1518. IR (neat, cm -1): υ 3018, 2906, 2834, 1471, 1327, 1326, 1246, 1012, 734, 651。
实施例十七。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1y（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 86 % yield. mp: 41 – 43 ℃. 1HNMR (400 MHz, Chloroform- d) δ 7.62 – 7.51 (m, 1H), 7.24 – 7.11 (m, 2H), 7.06 (ddd, J = 7.9, 6.6, 1.4 Hz, 1H), 6.73 (s, 1H), 3.61 (s, 3H), 2.71 (t, J = 7.7 Hz, 2H), 1.80 – 1.53 (m, 2H), 1.45 – 1.11 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR(100 MHz, CDCl 3) δ 137.0, 128.0,125.8, 121.3, 119.0, 118.4, 115.6, 109.0, 32.3, 32.0, 30.5, 29.7, 29.7, 29.7, 29.6, 29.4, 25.1, 22.7, 14.1.HRMS (EI-TOF): Anal Calcd. For. C 21H 33N: 299.2608, Found: 299.2613.IR (neat, cm -1): υ 2916, 2848, 1615, 1472, 1426, 1325, 1246, 1155, 1030, 921, 866, 814, 731。
实施例十八。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1z（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。brown oil, 72 % yield. 1H NMR (400 MHz, Chloroform- d) δ 7.69 (dd, J = 7.9, 1.0 Hz, 1H), 7.44 – 7.36 (m, 3H), 7.36 – 7.26 (m, 4H), 7.25 – 7.15 (m, 1H), 6.92 (s, 1H), 3.82 (s, 3H), 3.02 – 2.87 (m, 2H), 2.87 – 2.75 (m, 2H), 2.22 – 2.09 (m, 2H). 13C NMR (100 MHz, CDCl 3) δ 142.5, 137.0, 128.4, 128.2, 127.9, 126.0, 125.6, 121.4, 119.0, 118.4, 114.9, 109.1, 35.7, 32.5, 31.9, 24.6.HRMS(ESI-TOF): Anal Calcd. For. C 18H 9NO[M+Na] +: 272.1410, Found: 272.1382.IR (neat, cm -1): υ 3024, 2931, 2854, 1602, 1472, 1324, 1246, 1012, 734, 697。
实施例十九。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1aa（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。brown oil, 90 % yield (76.1 mg). 1H NMR (400 MHz, Chloroform- d)δ7.73 (d, J = 7.9 Hz, 1H), 7.42-7.36 (m, 1H), 7.33 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.22 (ddd, J = 7.9, 6.7, 1.2 Hz, 1H), 7.02 (s, 1H), 3.82 (s, 3H), 2.80 (dd, J = 6.6, 1.0 Hz, 2H), 1.29-1.12 (m, 1H), 0.73-0.56 (m, 2H), 0.44 – 0.25 (m, 2H). 13C NMR (100 MHz, CDCl 3) δ 137.0, 128.0, 126.1, 121.3, 119.1, 118.5, 114.9, 109.0, 32.5, 29.9, 11.3, 4.9.HRMS(ESI-TOF): Anal Calcd. For. C 13H 15N[M+H] +: 186.1278, Found: 186.1297.IR (neat, cm -1): υ 3072, 2997, 2878, 1615, 1472, 1326, 1128, 1012, 827, 733。
实施例二十。
。
空气中，向具有磁力搅拌子的试管中，依次添加酮1ae（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），MeCN（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。91 % yield. 1H NMR (400 MHz, Chloroform- d) δ 7.77 (dt, J = 8.0, 1.0 Hz, 1H), 7.39 (dt, J = 8.2, 1.0 Hz, 1H), 7.33 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.21 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.90 (s, 1H), 3.81 (s, 3H), 3.19 – 3.11 (m, 1H), 1.95 – 1.87 (m, 1H), 1.79 – 1.67 (m, 1H), 1.53 – 1.28 (m, 13H), 1.01 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl 3) δ 137.1, 127.3, 124.7, 121.4, 121.2, 119.5, 118.3, 109.1, 37.9, 32.5, 31.9, 30.8, 29.8, 29.3, 27.8, 22.7, 21.6, 14.1. HRMS(EI-TOF): Anal Calcd. For. C 18H 27N: 257.2138, Found: 257.2151. IR (neat, cm -1): υ 3053, 2923, 2853, 1614, 1466, 1373, 1236, 1132, 1014, 978, 794, 734 。
实施例二十一。
。
空气中，向具有磁力搅拌子的试管中，依次添加酮1aj（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），MeCN（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。puce oil, 92 % yield. 1H NMR (400 MHz, Chloroform- d) δ 7.62 – 7.55 (m, 1H), 7.28 – 7.22 (m, 1H), 7.22 – 7.16 (m, 1H), 7.14 – 7.03 (m, 3H), 6.97 – 6.91 (m, 2H), 6.78 (s, 1H), 3.68 (s, 3H), 3.22 – 2.94 (m, 1H), 2.68 – 2.52 (m, 2H), 2.23 (s, 3H), 2.13 – 2.02 (m, 1H), 1.98 – 1.87 (m, 1H), 1.37 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl 3) δ 169.6, 148.5, 140.3, 137.1, 129.2, 127.1, 124.9, 121.3, 121.1, 120.4, 119.3, 118.4, 109.1, 39.3, 33.3, 32.4, 30.4, 21.8, 21.0.HRMS(EI-TOF): Anal Calcd. For. C 21H 23NO 2: 321.1724, Found: 321.1734.IR (neat, cm -1): υ 3050, 2919, 2852, 1757, 1505, 1368, 1189, 1015, 910, 737。
实施例二十二。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1a（0.5 mmol），碘（0.05 mmol），吲哚2a（0.5 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。brown oil, 85 % yield. 1H NMR (400 MHz, Chloroform- d) δ 7.40 – 7.26 (m, 2H), 7.23 (dd, J = 8.0, 1.0 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.94 (dd, J = 8.0, 7.0 Hz, 1H), 6.87 – 6.83 (m, 1H), 6.70 (s, 1H), 4.09 – 3.83 (m, 4H), 2.89 (t, J = 6.1 Hz, 2H), 2.21 – 2.02 (m, 2H). 13C NMR (100 MHz, CDCl 3) δ 140.6, 134.6, 131.2, 130.3, 125.0, 124.3, 121.6, 119.4, 119.2, 118.5, 116.5, 113.5, 43.7, 31.3, 24.6, 22.8.HRMS (ESI-TOF): Anal Calcd. For. C 18H 16 79BrN[M+Na] +: 348.0359 , Found: 348.0365. Anal Calcd. For. C 18H 16 81BrN[M+Na] +: 350.0338, Found: 350.0302.IR (neat, cm -1): υ 3050, 2931, 1681, 1484, 1344, 1247, 1068, 1010, 781, 744。
实施例二十三。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1a（0.5 mmol），碘（0.05 mmol），吲哚2b（0.5 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 86 % yield. mp: 124 – 126 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.44 – 7.33 (m, 4H), 7.30 (dd, J = 7.9, 1.7 Hz, 3H), 7.29 – 7.21 (m, 2H), 7.25 – 7.16 (m, 1H), 7.09 – 7.01 (m, 1H), 6.98 – 6.92 (m, 2H), 3.97 (s, 2H), 3.55 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 140.9, 138.7, 137.3, 131.6, 131.1, 130.4, 129.9, 128.4, 128.1, 127.6, 121.8, 119.4, 119.2, 119.2, 110.77, 109.4, 30.8, 30.1.HRMS (EI-TOF): Anal Calcd. For. C 22H 18 79BrN: 375.0618, Found: 375.0627. Anal Calcd. For. C 22H 18 81BrN: 377.0597, Found: 377.0605. IR (neat, cm -1): υ 3040, 2901, 1603, 1468, 1360, 1232, 1069, 1009, 815, 746, 696。
实施例二十四。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1a（0.5 mmol），碘（0.05 mmol），吲哚2c（0.5 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。brown solid, 46 % yield. mp: 64-66 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.62 (d, J = 1.9 Hz, 1H), 7.47-7.36 (m, 2H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H), 7.20-7.08 (m, 3H), 6.76 (s, 1H), 3.99 (s, 2H), 3.71 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 139.8, 135.8, 131.4, 130.2, 129.2, 128.3, 124.4, 121.5, 119.7, 113.1, 112.3, 110.7, 32.7, 30.6.HRMS(EI-TOF): Anal Calcd. For. C 16H 13 79Br 81BrN: 378.9394, Found: 378.9398. Anal Calcd. For. C 16H 13 81Br 2N: 380.9374, Found: 380.9383.IR (neat, cm -1): υ 3072, 2913, 1663, 1473, 1420, 1284, 1069, 1008, 864, 784, 718, 659。
实施例二十五。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛1a（0.5 mmol），碘（0.05 mmol），吲哚2c（0.5 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。white solid, 90 % yield. mp: 104-105 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.36-7.31 (m, 1H), 7.30-7.24 (m, 2H), 7.22-7.16 (m, 1H), 7.15-7.07 (m, 1H), 7.04-6.96 (m, 3H), 3.97 (s, 2H), 3.56 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl 3) δ 140.8, 136.5, 133.5, 131.2, 129.9, 127.6, 120.6, 119.2, 118.9, 118.0, 109.0, 108.5, 29.7, 29.4, 10.2.HRMS(EI-TOF): Anal Calcd. For. C 17H 16 79BrN: 313.0461, Found: 313.0476. Anal Calcd. For. C 17H 16 81BrN: 315.0441, Found: 315.0451.IR (neat, cm -1): υ 3056, 2911, 1612, 1480, 1369, 1329, 1191, 1001, 776, 728, 659。
实施例二十六。
。
空气中，向具有磁力搅拌子的试管中，依次添加醛2m（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），HFIP（2.0 mL）。将试管用封口膜密封，并在25℃下搅拌16 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。yellow solid, 96 % yield. mp: 153 – 155 ℃. 1H NMR (400 MHz, DMSO- d 6) δ 7.87 – 7.65 (m, 4H), 7.47 – 7.42 (m, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.22 (dd, J = 8.4, 5.2 Hz, 1H), 7.17 (dd, J = 9.3, 2.5 Hz, 1H), 7.14 – 7.06 (m, 2H), 7.04 – 6.94 (m, 3H), 6.74 (ddd, J = 9.4, 8.4, 2.5 Hz, 1H), 3.99 (d, J = 20.3 Hz, 4H), 3.70 (s, 3H), 2.82 (s, 3H), 2.23 (s, 3H). 13C NMR (100 MHz, DMSO- d 6) δ 168.97, 163.81, 161.38, 148.46, 146.73 (d, J = 9.1 Hz), 146.36, 140.19, 139.34, 138.77, 138.39, 136.77, 131.36 (d, J = 2.5 Hz), 130.10, 129.94, 129.32, 127.46, 127.20, 123.90, 123.28 (d, J = 9.6 Hz), 121.29, 121.10, 118.68, 118.41, 113.01, 110.60 (d, J = 23.0 Hz), 109.55, 106.11 (d, J = 23.7 Hz), 43.10, 32.15, 30.76, 30.16, 10.32. 19F NMR (376 MHz, DMSO- d 6) δ -113.18.HRMS (ESI-TOF): Anal Calcd. For. C 36H 30FNO 3S[M+Na] +: 598.1823, Found: 598.1795. IR (neat, cm -1): υ 3037, 2919, 1745, 1602, 1503, 1466, 1317, 1198, 1134, 1044, 1012, 907, 808, 734, 665。
实施例二十七。
。
空气中，向具有磁力搅拌子的试管中，依次添加酮2n（0.5 mmol），碘（0.05 mmol），N-甲基吲哚2（0.75 mmol），三乙基硅烷（1.0 mmol），MeCN（5.0 mL）。将试管用封口膜密封，并在50℃下搅拌36 h，然后将反应液用无水硫酸钠干燥后，利用旋转蒸发仪除去溶剂后硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得C3-烷基化吲哚。brown solid, 80 % yield. mp: 133 – 135 ℃. 1H NMR (400 MHz, Chloroform- d) δ 7.59 – 7.46 (m, 2H), 7.42 (s, 1H), 7.34 – 7.30 (m, 2H), 7.29 – 7.25 (m, 1H), 7.24 – 7.20 (m, 1H), 7.16 – 7.09 (m, 3H), 7.00 (d, J = 2.5 Hz, 1H), 6.96 – 6.91 (m, 3H), 6.88 (d, J = 9.0 Hz, 1H), 6.79 – 6.76 (m, 1H), 6.66 (dd, J = 9.1, 2.5 Hz, 1H), 4.63 (s, 2H), 4.27 (q, J = 7.1 Hz, 1H), 3.76 (s, 1H), 3.68 – 3.66 (m, 6H), 2.37 (s, 3H), 1.61 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl 3) δ 168.9, 168.0, 164.5, 156.3, 143.5, 139.2, 137.2, 136.2, 134.2, 133.4, 131.0, 130.7, 130.0, 129.0, 127.7, 126.9, 125.8, 121.4, 119.8, 119.5, 119.5, 118.5, 115.2, 111.6, 111.4, 109.0, 101.0, 63.0, 55.5, 36.2, 32.4, 30.0, 22.2, 13.1.HRMS(EI-TOF): Anal Calcd. For. C 38H 34 35ClN 3O 5: 647.2182, Found: 647.2191. Anal Calcd. For. C 38H 34 37ClN 3O 5: 649.2152, Found: 649.2145. IR (neat, cm -1): υ 3348, 3052, 2956, 2928, 1736, 1676, 1532, 1477, 1366, 1315, 1226, 1152, 1072, 1035, 925, 835, 737。

Claims (10)

  1. 一种C3-烷基化吲哚的制备方法，其特征在于，以吲哚和羰基化合物为反应底物，在硅烷、碘存在下，反应得到C3-烷基化吲哚。
  2. 根据权利要求1所述C3-烷基化吲哚的制备方法，其特征在于：所述C3-烷基化吲哚的化学结构式为：
    所述羰基化合物的化学结构通式为： ；
    所述吲哚化合物的化学结构通式为： ；
    所述硅烷的结构通式为： ；
    上述化学结构式中，R 1和R 2独立的选自氢、烷基、芳基、取代芳基、杂芳香基、取代杂芳香基、酯基或者羰基；R 3选自苯基或者甲基；R 4选自氢、烷基、酯基；R 5选自氢、氨基、硼基、烷基、烷氧基、氰基、酯基或者卤素；R 6、R 7、R 8独立的选自氢、烷基、芳基或者烷氧基。
  3. 根据权利要求1所述C3-烷基化吲哚的制备方法，其特征在于：所述反应的温度为15～80℃，反应的时间为12～48小时。
  4. 根据权利要求1所述C3-烷基化吲哚的制备方法，其特征在于：所述碘的用量为羰基化合物摩尔量的5～20%；吲哚化合物用量为羰基化合物摩尔量的1～1.5倍；硅烷的用量为羰基化合物摩尔量的1.5～2.5倍。
  5. 根据权利要求1所述C3-烷基化吲哚的制备方法，其特征在于：反应在有机溶剂中进行。
  6. 根据权利要求5所述C3-烷基化吲哚的制备方法，其特征在于：所述有机溶剂为六氟异丙醇、1,2-二氯乙烷、乙腈、硝基甲烷、甲苯、三氟乙醇中的一种或几种。
  7. 根据权利要求1所述C3-烷基化吲哚的制备方法制备的C3-烷基化吲哚。
  8. 硅烷和碘在以吲哚和羰基化合物为反应底物制备C3-烷基化吲哚中的应用。
  9. 吲哚和羰基化合物为反应底物在制备C3-烷基化吲哚中的应用。
  10. 根据权利要求8或者9所述的应用，其特征在于，制备C3-烷基化吲哚的方法无金属或者金属化合物参与。
PCT/CN2022/079805 2022-01-25 2022-03-08 一种 c3- 烷基化吲哚的制备方法 WO2023142231A1 (zh)

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