CN115181054B - A kind of synthetic method of 3-benzylindole compound - Google Patents

A kind of synthetic method of 3-benzylindole compound Download PDF

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CN115181054B
CN115181054B CN202210981101.6A CN202210981101A CN115181054B CN 115181054 B CN115181054 B CN 115181054B CN 202210981101 A CN202210981101 A CN 202210981101A CN 115181054 B CN115181054 B CN 115181054B
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methylindole
benzylindole
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trimethylphenol
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李有桂
张昕
侯继承
王文斌
吴祥
朱成峰
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Hefei University of Technology
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract

本发明公开了一种3‑苄基吲哚类化合物的合成方法,以N‑甲基吲哚和2,4,6‑三甲基苯酚为反应原料,在氧化剂以及添加剂的存在下于溶剂中加热,进行交叉脱氢偶联反应,获得3‑苄基吲哚类化合物目标产物。本发明原料廉价易得,操作简单,底物适用性好,具有广阔的发展前景。The invention discloses a method for synthesizing 3-benzylindole compounds, wherein N-methylindole and 2,4,6-trimethylphenol are used as reaction raw materials, heated in a solvent in the presence of an oxidant and an additive, and a cross-dehydrogenation coupling reaction is performed to obtain a target product of the 3-benzylindole compound. The raw materials of the invention are cheap and readily available, the operation is simple, the substrate applicability is good, and the invention has broad development prospects.

Description

一种3-苄基吲哚类化合物的合成方法A kind of synthetic method of 3-benzylindole compound

技术领域Technical Field

本发明属于有机化学领域,具体涉及一种交叉脱氢偶联反应合成3-苄基吲哚类化合物的方法。The invention belongs to the field of organic chemistry, and specifically relates to a method for synthesizing 3-benzylindole compounds through a cross-dehydrogenation coupling reaction.

背景技术Background technique

在自然界中,特别是在生物体内,有许多贯穿整个生命活性的物质,其中一大类就是含有苯并五元杂环的化合物。在这些化合物中吲哚类化合物最为重要。In nature, especially in living organisms, there are many substances that run through the entire life activity, one of which is compounds containing benzo five-membered heterocycles. Among these compounds, indole compounds are the most important.

吲哚及其衍生物作为一类含氮杂环,是一类重要的生物碱。大多数都具有独特的生物活性和药理活性,因而广泛应用于医药行业。很多药物分子中都含有吲哚骨架。氟伐他汀(fluvastatin)是第一个全化学合成的降胆固醇药物,具有选择性高和不良反应发生率低等优点,是一种优良的降血脂药。利扎曲普坦(rizatriptan)和依立曲坦(eletriptan)是治疗偏头痛的特效药物,二者为偏头痛的药物治疗带来了革命性的进步。吲哚美辛(indometacin)可用于治疗风湿性疾病和多种关节炎。吲哚心安(pindolol)可用于治疗心律失常、心绞痛和高血压等病症。舍吲哚(sertindole)是新开发的非典型抗精神病药物。此外,长春新碱、长春碱等吲哚类生物碱对抗肿瘤具有良好的功效。As a class of nitrogen-containing heterocyclic rings, indole and its derivatives are an important class of alkaloids. Most of them have unique biological and pharmacological activities and are therefore widely used in the pharmaceutical industry. Many drug molecules contain indole skeletons. Fluvastatin is the first fully chemically synthesized cholesterol-lowering drug. It has the advantages of high selectivity and low incidence of adverse reactions and is an excellent lipid-lowering drug. Rizatriptan and eletriptan are specific drugs for the treatment of migraine, and both have brought revolutionary progress to the drug treatment of migraine. Indometacin can be used to treat rheumatic diseases and various arthritis. Pindolol can be used to treat arrhythmias, angina pectoris, hypertension and other diseases. Sertindole is a newly developed atypical antipsychotic drug. In addition, indole alkaloids such as vincristine and vinblastine have good anti-tumor effects.

近年来大量科学研究工作者一直致力于发展吲哚C-3位置的苄基化的方法。In recent years, a large number of scientific researchers have been committed to developing methods for the benzylation of the C-3 position of indole.

Isao Azumaya教授(J.Org.Chem.2013,78,23,12128–12135)首次在水溶性金(III)/TPPMS催化体系中发展了苯甲醇与吲哚的偶联反应,这是最高效、最环保的苄基化合成策略之一,多数情况下能得到中等产率的目标化合物。其中,Au(III)/TPPMS是强π亲核体1-甲基吲哚苄基化的有效催化剂,然而普通的路易斯酸是无效的。Professor Isao Azumaya (J.Org.Chem.2013,78,23,12128–12135) first developed the coupling reaction of benzyl alcohol and indole in a water-soluble gold(III)/TPPMS catalytic system, which is one of the most efficient and environmentally friendly benzylation synthetic strategies, and in most cases can obtain the target compound in moderate yield. Among them, Au(III)/TPPMS is an effective catalyst for the benzylation of the strong π nucleophile 1-methylindole, while ordinary Lewis acids are ineffective.

2015年,游书力等人(Chinese Journal ofCatalysis 2015,36,15-18)开发了一种用于Pd(0)催化吲哚苄基化的有效方法,该方法具有独特的区域选择性。当该反应在Pd(PPh3)4存在下进行时,它提供了在温和条件下以90%-99%的产率获得广泛的在其3位上带有二芳基甲烷的取代吲哚的途径。In 2015, You Shuli et al. (Chinese Journal of Catalysis 2015, 36, 15-18) developed an efficient method for Pd(0)-catalyzed benzylation of indoles with unique regioselectivity. When the reaction was carried out in the presence of Pd(PPh 3 ) 4 , it provided a pathway to a wide range of substituted indoles bearing diarylmethane at their 3-position in 90%-99% yields under mild conditions.

2020年,Amreen K.Bains等人(Chem.Commun.,2020,56,15442)报道了一种高效的镍催化剂,它可以有效地用多种醇对1H-吲哚进行选择性C3-烷基化。作者使用吲哚和苯甲醇为模型底物,当在110℃下加热吲哚(1mmol)、苄醇(2mmol)、镍催化剂(5mol%)和叔丁醇钾(0.7equiv)在甲苯(2mL)中的混合物时,能得到目标产物3-苄基吲哚。In 2020, Amreen K. Bains et al. (Chem. Commun., 2020, 56, 15442) reported an efficient nickel catalyst that can effectively selectively C3-alkylate 1H-indole with a variety of alcohols. The authors used indole and benzyl alcohol as model substrates, and when a mixture of indole (1 mmol), benzyl alcohol (2 mmol), nickel catalyst (5 mol%) and potassium tert-butoxide (0.7 equiv) in toluene (2 mL) was heated at 110 ° C, the target product 3-benzylindole was obtained.

目前报道的有关3-苄基吲哚类化合物的合成基本上都是使用昂贵的金属催化剂。因此对于开发仅使用廉价的氧化剂合成3-苄基吲哚类化合物有着重要意义。The synthesis of 3-benzylindole compounds reported so far basically uses expensive metal catalysts. Therefore, it is of great significance to develop a method for synthesizing 3-benzylindole compounds using only cheap oxidants.

发明内容Summary of the invention

本发明针对上述现有技术的不足之处,旨在提供一种3-苄基吲哚类化合物的合成方法。本发明通过交叉脱氢偶联反应合成3-苄基吲哚类化合物,具有原料廉价易得、操作简单、底物适用性广等优点,发展前景广阔。The present invention aims to provide a method for synthesizing 3-benzylindole compounds by cross-dehydrogenation coupling reaction, which has the advantages of cheap and readily available raw materials, simple operation, wide substrate applicability, etc., and has broad development prospects.

本发明3-苄基吲哚类化合物的合成方法,是以N-甲基吲哚和2,4,6-三甲基苯酚为反应原料,在氧化剂以及添加剂的存在下于溶剂中加热,进行交叉脱氢偶联反应,获得3-苄基吲哚类化合物目标产物。The method for synthesizing 3-benzylindole compounds of the present invention is to use N-methylindole and 2,4,6-trimethylphenol as reaction raw materials, heat them in a solvent in the presence of an oxidant and an additive, and perform a cross-dehydrogenation coupling reaction to obtain a target product of the 3-benzylindole compound.

具体包括如下步骤:The specific steps include:

将0.2mmol的N-甲基吲哚、1.0mmol的2,4,6-三甲基苯酚和0.08mmol的添加剂分别加入到1mL的溶剂中,而后加入氧化剂,在90~120℃下反应48~72h,得到目标产物。0.2 mmol of N-methylindole, 1.0 mmol of 2,4,6-trimethylphenol and 0.08 mmol of additive were added to 1 mL of solvent respectively, and then an oxidant was added, and the mixture was reacted at 90-120° C. for 48-72 hours to obtain the target product.

所述3-苄基吲哚类化合物的结构式如下式Ⅰ所示:The structural formula of the 3-benzylindole compound is shown in Formula I below:

其中R为苯环上不同位置的取代基团,如甲基(-CH3)、甲氧基(-OCH3)、各种卤素基团(-F、-Cl、-Br、-I)以及硝基(-NO2)、氰基(-CN)、苯基(-Ph)等。Wherein R is a substituent group at different positions on the benzene ring, such as methyl (-CH 3 ), methoxy (-OCH 3 ), various halogen groups (-F, -Cl, -Br, -I), nitro (-NO 2 ), cyano (-CN), phenyl (-Ph), and the like.

所述N-甲基吲哚的结构式如下式Ⅱ所示:The structural formula of the N-methylindole is shown in Formula II below:

所述2,4,6-三甲基苯酚的结构式如下式Ⅲ所示:The structural formula of the 2,4,6-trimethylphenol is shown in the following formula III:

反应路线如下所示:The reaction route is as follows:

其中R为苯环上不同位置的取代基团,如甲基(-CH3)、甲氧基(-OCH3)、各种卤素基团(-F、-Cl、-Br、-I)以及硝基(-NO2)、氰基(-CN)、苯基(-Ph)等。Wherein R is a substituent group at different positions on the benzene ring, such as methyl (-CH 3 ), methoxy (-OCH 3 ), various halogen groups (-F, -Cl, -Br, -I), nitro (-NO 2 ), cyano (-CN), phenyl (-Ph), and the like.

所述氧化剂包括二叔丁基过氧化物(DTBP)、过氧化氢叔丁醇(TBHP)、2,3-二氯-5,6-二氰基苯醌(DDQ)、氧化锌(ZnO)、氧化银(Ag2O)、过硫酸钾(K2S2O8)或二氧化锰(MnO2)。由于不同的氧化剂对反应的产率影响很大,通过对二叔丁基过氧化物(DTBP)、过氧化氢叔丁醇(TBHP)、2,3-二氯-5,6-二氰基苯醌(DDQ)、氧化锌(ZnO)、氧化银(Ag2O)、过硫酸钾(K2S2O8)、二氧化锰(MnO2)的研究,最终的产率分别为0%、0%、0%、12%、0%、18%、56%,所以本发明优选氧化剂为二氧化锰(MnO2)。The oxidant includes di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), zinc oxide (ZnO), silver oxide (Ag 2 O), potassium persulfate (K 2 S 2 O 8 ) or manganese dioxide (MnO 2 ). Since different oxidants have a great influence on the yield of the reaction, through the study of di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), zinc oxide (ZnO), silver oxide (Ag 2 O), potassium persulfate (K 2 S 2 O 8 ), and manganese dioxide (MnO 2 ), the final yields are 0%, 0%, 0%, 12%, 0%, 18%, and 56%, respectively. Therefore, the preferred oxidant of the present invention is manganese dioxide (MnO 2 ).

进一步,通过对添加剂3,4,5-三氟苯甲酸、2,4,6-三氟苯甲酸、2,3,6-三氟苯甲酸、2-溴-4,5-二氟苯甲酸的研究,最终的产率分别为56%、37%、43%、78%,所以本发明优选2-溴-4,5-二氟苯甲酸作为添加剂。Furthermore, through the study of additives 3,4,5-trifluorobenzoic acid, 2,4,6-trifluorobenzoic acid, 2,3,6-trifluorobenzoic acid, and 2-bromo-4,5-difluorobenzoic acid, the final yields were 56%, 37%, 43%, and 78%, respectively, so the present invention preferably uses 2-bromo-4,5-difluorobenzoic acid as the additive.

进一步,由于温度对反应产率有很大的影响,通过对90~120℃的筛选,最终的产率分别为39%(90℃)、51%(100℃)、78%(110℃)、49%(120℃),所以本发明优选110℃为最佳的反应温度。Furthermore, since temperature has a great influence on the reaction yield, through screening at 90-120°C, the final yields were 39% (90°C), 51% (100°C), 78% (110°C), and 49% (120°C), respectively. Therefore, the present invention prefers 110°C as the optimal reaction temperature.

进一步,通过对不同溶剂的筛选,如用四氢呋喃(THF)作溶剂时产率为0%、用二氯甲烷(DCM)作溶剂时产率为33%、用乙腈(MeCN)作溶剂时产率为57%、用1,2-二氯乙烷(DCE)作溶剂时产率为78%,所以溶剂优选为1,2-二氯乙烷(DCE)。Furthermore, by screening different solvents, for example, when tetrahydrofuran (THF) is used as the solvent, the yield is 0%, when dichloromethane (DCM) is used as the solvent, the yield is 33%, when acetonitrile (MeCN) is used as the solvent, the yield is 57%, and when 1,2-dichloroethane (DCE) is used as the solvent, the yield is 78%, so the solvent is preferably 1,2-dichloroethane (DCE).

同现有技术相比,本发明从吲哚衍生物出发,通过和廉价易得的2,4,6-三甲基苯酚发生偶联反应,得到3-苄基吲哚类化合物。因此,该反应符合绿色化学的要求,具有广阔的发展前景。Compared with the prior art, the present invention starts from indole derivatives and couples with cheap and readily available 2,4,6-trimethylphenol to obtain 3-benzylindole compounds. Therefore, the reaction meets the requirements of green chemistry and has broad development prospects.

具体实施方式Detailed ways

以下通过具体的实施例,对本发明的上述内容做进一步的详细说明,但不应该将此理解为对本发明保护主体的任何限制。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。The above contents of the present invention are further described in detail below through specific examples, but this should not be understood as any limitation to the subject of protection of the present invention. All technical solutions implemented based on the above contents of the present invention belong to the scope of the present invention. The present invention generally and/or specifically describes the materials and test methods used in the test.

实施例1:化合物Ⅰa的制备Example 1: Preparation of Compound Ia

依次将0.2mmol的N-甲基吲哚、1.0mmol的2,4,6-三甲基苯酚和0.08mmol的2-溴-4,5-二氟苯甲酸加入到烘箱烘干的10mL Schlenk管中,使用注射器在室温下将1mL1,2-二氯乙烷溶剂加入到Schlenk管中,然后再加入2.4mmol的MnO2,将Schlenk管密封,混合物加热到110℃反应72小时;反应结束后减压蒸发溶剂,以石油醚/乙酸乙酯=10/1~30/1(V/V)的混合液为流动相进行柱层析分离,得到产物3-苄基吲哚类化合物,产率为78%。0.2 mmol of N-methylindole, 1.0 mmol of 2,4,6-trimethylphenol and 0.08 mmol of 2-bromo-4,5-difluorobenzoic acid were sequentially added into a 10 mL Schlenk tube dried in an oven, 1 mL of 1,2-dichloroethane solvent was added into the Schlenk tube at room temperature using a syringe, and then 2.4 mmol of MnO 2 was added, the Schlenk tube was sealed, and the mixture was heated to 110° C. for reaction for 72 hours; after the reaction was completed, the solvent was evaporated under reduced pressure, and column chromatography was performed with a mixed solution of petroleum ether/ethyl acetate = 10/1 to 30/1 (V/V) as a mobile phase to obtain a product 3-benzylindole compound with a yield of 78%.

1H NMR(600MHz,CDCl3)δ7.58(d,J=8.0Hz,1H),7.31(dd,J=8.3,2.4Hz,1H),7.24(ddd,J=5.0,3.2,1.2Hz,1H),7.13–7.09(m,1H),6.93(s,2H),6.77(s,1H),4.51(s,1H),4.00(s,2H),3.74(s,3H),2.23(s,6H).13C NMR(151MHz,CDCl3)δ150.29,137.18,133.02,128.79,127.88,127.00,122.81,121.50,119.25,118.70,114.98,109.10,32.59,30.63,15.96.HRMS(ESI)m/z(M+H)+calculated for C18H19NO:266.1540,observed:266.1542. 1 H NMR (600 MHz, CDCl 3 )δ7.58 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.3, 2.4 Hz, 1H), 7.24 (ddd, J=5.0, 3.2, 1.2 Hz, 1H), 7.13–7.09 (m, 1H), 6.93 (s, 2H), 6.77 (s, 1H), 4.51 (s, 1H), 4.00 (s, 2H), 3.74 (s, 3H), 2.23 (s, 6H). 13 C NMR (151 MHz, CDCl 3 )δ150.29,137.18,133.02,128.79,127.88,127.00,122.81,121.50,119.25,118.70,114.98,109.10,32.59,30.63,15.96.HRMS(ESI)m/z(M+H) + calculated for C 18 H 19 NO:266.1540,observed:266.1542.

实施例2:化合物Ⅰb的制备Example 2: Preparation of Compound Ib

用底物Ⅱb代替Ⅱa,通过实施例1的方法,制备得到产物Ⅰb,产率44%。Substrate IIb Instead of IIa, product Ib was prepared by the method of Example 1 with a yield of 44%.

1H NMR(600MHz,CDCl3)δ7.37(s,1H),7.20(dd,J=8.6,2.4Hz,1H),7.07(ddd,J=8.3,3.5,1.7Hz,1H),6.93(s,2H),6.71(s,1H),4.51(s,1H),3.97(s,2H),3.71(s,3H),2.48(s,3H),2.24(s,6H).13C NMR(151MHz,CDCl3)δ150.26,135.61,133.13,128.76,128.08,127.88,127.15,123.12,122.78,118.81,114.33,108.81,32.62,30.54,21.52,15.96.HRMS(ESI)m/z(M+H)+calculated for C19H21NO:280.1696,observed:280.1692. 1 H NMR (600 MHz, CDCl 3 ) δ7.37 (s, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 7.07 (ddd, J = 8.3, 3.5, 1.7 Hz, 1H), 6.93 (s, 2H), 6.71 (s, 1H), 4.51 (s, 1H), 3.97 (s, 2H), 3.71 (s, 3H), 2.48 (s, 3H), 2.24 (s, 6H). 13 C NMR (151 MHz, CDCl 3 )δ150.26,135.61,133.13,128.76,128.08,127.88,127.15,123.12,122.78,118.81,114.33,108.81,32.62,30.54,21.52,15.96.HRMS(ESI)m/z(M+H) + calculated for C 19 H 21 NO:280.1696,observed:280.1692.

实施例3:化合物Ⅰc的制备Example 3: Preparation of Compound Ic

用底物Ⅱc代替Ⅱa,通过实施例1的方法,制备得到产物Ⅰc,产率78%。Substrate IIc Instead of IIa, product Ic was prepared by the method of Example 1 with a yield of 78%.

1H NMR(600MHz,CDCl3)δ7.42(d,J=8.4Hz,1H),7.27(d,J=1.9Hz,1H),7.03(dd,J=8.4,1.8Hz,1H),6.87(s,2H),6.74(s,1H),4.50(s,1H),3.93(s,2H),3.69(s,3H),2.21(s,6H).13CNMR(151MHz,CDCl3)δ150.36,137.56,132.57,128.68,127.62,127.58,126.40,122.86,120.15,119.36,115.23,109.15,32.67,30.48,15.95.HRMS(ESI)m/z(M+H)+calculated for C18H18ClNO:300.1150,observed:300.1151. 1 H NMR (600 MHz, CDCl 3 ) δ7.42 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.9 Hz, 1H), 7.03 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (s, 2H), 6.74 (s, 1H), 4.50 (s, 1H), 3.93 (s, 2H), 3.69 (s, 3H), 2.21 (s, 6H). 13 CNMR (151 MHz, CDCl 3 )δ150.36,137.56,132.57,128.68,127.62,127.58,126.40,122.86,120.15,119.36,115.23,109.15,32.67,30.48,15.95.HRMS(ESI)m/z(M+H) + calculated for C 18 H 18 ClNO:300.1150,observed:300.1151.

实施例4:化合物Ⅰd的制备Example 4: Preparation of Compound Id

用底物Ⅱd代替Ⅱa,通过实施例1的方法,制备得到产物Ⅰd,产率76%。Substrate IId Instead of IIa, product Id was prepared by the method of Example 1 with a yield of 76%.

1H NMR(600MHz,CDCl3)δ7.86(s,1H),7.44(dd,J=8.6,1.6Hz,1H),7.05(d,J=8.5Hz,1H),6.86(s,2H),6.68(s,1H),4.50(s,1H),3.89(s,2H),3.69(s,3H),2.21(s,6H).13C NMR(151MHz,CDCl3)δ150.38,132.41,130.36,129.75,128.67,128.00,127.81,126.90,122.88,114.42,111.18,82.29,32.71,30.31,15.95.HRMS(ESI)m/z(M+H)+calculated for C18H18INO:392.0506,observed:392.0501. 1 H NMR (600 MHz, CDCl 3 ) δ7.86 (s, 1H), 7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.86 (s, 2H), 6.68 (s, 1H), 4.50 (s, 1H), 3.89 (s, 2H), 3.69 (s, 3H), 2.21 (s, 6H). 13 C NMR (151 MHz, CDCl 3 )δ150.38,132.41,130.36,129.75,128.67,128.00,127.81,126.90,122.88,114.42,111.18,82.29,32.71,30.31,15.95.HRMS(ESI)m/z(M+H) + calculated for C 18 H 18 INO:392.0506,observed:392.0501.

实施例5:化合物Ⅰe的制备Example 5: Preparation of Compound Ie

用底物Ⅱe代替Ⅱa,通过实施例1的方法,制备得到产物Ⅰe,产率83%。Substrate II e Instead of IIa, the product Ie was prepared by the method of Example 1 with a yield of 83%.

1H NMR(600MHz,CDCl3)δ7.45(dd,J=7.9,1.0Hz,1H),7.32(dd,J=7.6,1.0Hz,1H),6.89–6.86(m,3H),6.69(s,1H),4.49(s,1H),4.09(s,3H),3.92(s,2H),2.21(s,6H).13CNMR(151MHz,CDCl3)δ150.37,133.45,132.39,130.96,130.07,128.69,126.51,122.85,119.91,118.60,114.79,103.83,36.51,30.35,15.96.HRMS(ESI)m/z(M+H)+calculatedfor C18H18BrNO:344.0645,observed:344.0642. 1 H NMR (600 MHz, CDCl 3 ) δ7.45 (dd, J=7.9, 1.0 Hz, 1H), 7.32 (dd, J=7.6, 1.0 Hz, 1H), 6.89–6.86 (m, 3H), 6.69 (s, 1H), 4.49 (s, 1H), 4.09 (s, 3H), 3.92 (s, 2H), 2.21 (s, 6H). 13 CNMR (151 MHz, CDCl 3 )δ150.37,133.45,132.39,130.96,130.07,128.69,126.51,122.85,119.91,118.60,114.79,103.83,36.51,30.35,15.96.HRMS( ESI )m/z(M+H) + calculatedfor C18H18BrNO :344.0645,observed:344.0642.

实施例6:化合物Ⅰf的制备Example 6: Preparation of Compound IF

用底物Ⅱf代替Ⅱa,通过实施例1的方法,制备得到产物Ⅰf,产率89%。Substrate II f Instead of IIa, the product If was prepared by the method of Example 1 with a yield of 89%.

1H NMR(600MHz,CDCl3)δ7.81(d,J=7.6Hz,1H),7.76(d,J=7.8Hz,1H),7.08(td,J=7.9,1.2Hz,1H),6.87(s,2H),6.83(s,1H),4.61(s,1H),3.96(s,2H),3.79(s,3H),2.22(s,6H).13CNMR(151MHz,CDCl3)δ150.57,132.91,131.82,131.76,128.66,128.49,128.09,125.40,123.07,119.79,117.93,116.24,37.19,30.15,15.98.HRMS(ESI)m/z(M+H)+calculated for C18H18N2O3:311.1390,observed:311.1392. 1 H NMR (600 MHz, CDCl 3 ) δ7.81 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.08 (td, J=7.9, 1.2 Hz, 1H), 6.87 (s, 2H), 6.83 (s, 1H), 4.61 (s, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 2.22 (s, 6H). 13 CNMR (151 MHz, CDCl 3 )δ150.57,132.91,131.82,131.76,128.66,128.49,128.09,125.40,123.07,119.79,117.93,116.24,37.19,30.15,15.98.HRMS(ESI)m/z(M+H) + calculated for C18H18N2O3 : 311.1390 ,observed: 311.1392 .

实施例7:化合物Ⅰg的制备Example 7: Preparation of Compound Ig

用底物Ⅱg代替Ⅱa,通过实施例1的方法,制备得到产物Ⅰg,产率42%。Substrate IIg Instead of IIa, the product Ig was prepared by the method of Example 1 with a yield of 42%.

1H NMR(600MHz,CDCl3)δ7.13–7.09(m,1H),6.93(s,2H),6.88(dd,J=8.2,1.3Hz,1H),6.49(d,J=7.2Hz,2H),4.45(s,1H),4.15(s,2H),3.90(s,3H),3.66(s,3H),2.22(s,6H).13CNMR(151MHz,CDCl3)δ155.09,150.03,138.76,134.22,129.06,126.90,125.69,122.54,122.21,115.92,102.51,99.05,55.10,32.79,32.08,15.97.HRMS(ESI)m/z(M+H)+calculated for C19H21NO2:296.1645,observed:296.1647。 1 H NMR (600 MHz, CDCl 3 )δ7.13–7.09 (m, 1H), 6.93 (s, 2H), 6.88 (dd, J=8.2, 1.3 Hz, 1H), 6.49 (d, J=7.2 Hz, 2H), 4.45 (s, 1H), 4.15 (s, 2H), 3.90 (s, 3H), 3.66 (s, 3H), 2.22 (s, 6H). 13 CNMR (151 MHz, CDCl 3 )δ155.09,150.03,138.76,134.22,129.06,126.90,125.69,122.54,122.21,115.92,102.51,99.05,55.10,32.79,32.08,15.97. HRMS (ESI) m/z (M+H) + calculated for C 19 H 21 NO 2 :296.1645, observed:296.1647.

Claims (6)

1. A synthetic method of 3-benzyl indole compounds is characterized in that:
n-methylindole and 2,4, 6-trimethylphenol are used as reaction raw materials, and are heated in a solvent 1, 2-dichloroethane in the presence of an oxidant manganese dioxide and an additive 2-bromo-4, 5-difluorobenzoic acid to carry out cross dehydrogenation coupling reaction, so that a 3-benzylindole compound target product is obtained;
the structural formula of the 3-benzyl indole compound is shown as the following formula I:
the structural formula of the N-methylindole is shown as the following formula II:
the structural formula of the 2,4, 6-trimethylphenol is shown as the following formula III:
wherein R is substituent groups at different positions on the benzene ring, including methyl, methoxy, halogen groups, nitro, cyano and phenyl.
2. The synthesis method according to claim 1, wherein:
the molar amount of the oxidant added is 12 equivalents of the molar amount of N-methylindole.
3. The synthesis method according to claim 1, wherein:
the molar amount of the additive added is 40% of the molar amount of the N-methylindole.
4. The synthesis method according to claim 1, wherein:
the reaction temperature is 90-120 ℃.
5. The method of synthesis according to claim 4, wherein:
the reaction temperature was 110 ℃.
6. The synthesis method according to claim 1, wherein:
the molar ratio of N-methylindole to 2,4, 6-trimethylphenol was 1:5.
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