A process for the preparation of a polysubstituted indole compound

Abstract

The application discloses a preparation method of a polysubstituted indole compound and belongs to the technical field of organic synthesis. In an inert gas atmosphere and an organic solvent, a cheap copper salt is used as a catalyst, 2-ethynyl aniline and a diazonium compound are used as raw materials, a coupling / cyclization / indole 3,3 rearrangement series reaction is realized by one-pot method, and a series of polysubstituted indole compounds are generated. The raw materials and the catalyst used in the application are cheap and easy to obtain, the substrate adaptability is wide, the functional group tolerance is strong, the reaction condition is mild, the step economy and the atom economy are high, the steroid indole compound can be obtained, and the application provides an effective new method for the synthesis and modification of a pharmaceutical intermediate.

Description

Technical Field

[0001] This invention relates to a method for preparing polysubstituted indole compounds, specifically using 2-ethynylaniline and diazo compounds as raw materials to prepare polysubstituted indole compounds, belonging to the field of pharmaceutical intermediates and organic synthesis technology. Background Technology

[0002] Indole compounds are compounds formed by the fusion of benzene and pyrrole rings. Their skeletal structures are widely found in alkaloids, marine natural products, and circadian rhythm regulators, such as serotonin, which is present in neurons of the human central nervous system and participates in sleep and body temperature control. Due to their high biological activity, indole drugs are widely used in fields such as antitumor, antihypertensive, analgesic, antibacterial, antiviral, and anti-inflammatory applications.

[0003] Correspondingly, the synthesis of multisubstituted indole compounds has always been an important research topic in the fields of drug molecule design and organic synthesis. Examples include the synthesis of alkaloids such as (±)-Aspidospermidine, (+)-Strictamine, alkaloids containing N-bridged ring structures, benzodiazepines containing indole rings, the natural anticancer drug Dictyodendrin B, the natural alkaloid (±)-Arborisidine, and the synthesis of enantioselective polysubstituted indoles (Xia, G.; Han, X.; Lu, X. Org. Lett. 2014, 16, 2058-2061.; Gao, B.; Yao, F.; Zhang, Z.; Ding, H. Angew. Chem. Int. Ed. 2021, 60, 10603-10607.; Hashimoto, Y.; Harada, S.; Kato, R.; Ikeda, K.; Nonnhoff, J.; H.; Nemoto, T. ACS Catal. 2022, 12, 14990-14998.; Chiu, J-W.; Chu, T-Y.; Barve, I-J.; Sun, C-M. Org. Lett. 2023, 25, 6246-6250.; Okui, Y.; Mori, A.; Okano, K. Org. Lett. 2023, 25, 2669-2673.; Liu, Y.; Li, G.; Ma, W.; Bao, G.; Li, Y.; He, Z.; Xu, Z.; Wang, R.; Sun, W. Chem. Sci. 2024, 15, 11099-11107.; Drennhaus, T.; Leifert, D.; Lammert, J.; Drennhaus, J. P.; Bergander, K.; Daniliuc, C. G.; Studer, A. J. Am. Chem. Soc. 2023, 145, 8665-8676.).

[0004] Traditional methods for indole synthesis include the reaction of nitrobenzene with Grignard reagent to obtain indole, the reaction of o-vinylphenyl isocyanide, tributyltin hydride and triethylborane through a radical process to obtain indole, etc. (Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129-2132.; Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127-3128.; Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791-3792.). Although many chemical methods for the synthesis of indole compounds have been reported, the above methods have the characteristics of harsh reaction conditions, the use of highly toxic and flammable and explosive reagents, and poor reaction selectivity. In recent years, with the development of transition metal catalysis and metal carbene migration reactions, researchers have applied highly reactive metal carbene to the synthesis of indole. The metal carbene generated in situ from transition metal and o-vinyl aniline through coupling / cyclization can efficiently synthesize indole compounds (Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 968-971.; Xiao, T.; Dong, X.; Zhou, L. Org. Biomol. Chem. 2013, 11, 1490-1497.; Liu, G.; Xu, G.; Li, J.; Ding, D.; Sun, J. Org. Biomol. Chem. 2014, 12, 1387-1390.). At the same time, it has also been reported that the 3-position of indole can be selectively functionalized through 3,3-rearrangement initiated by the catalyst (Zhao, F.; Zhang, D.; Nian, Y.; Zhang, L.; Yang, W.; Liu, H. Org. Lett. 2014, 16, 5124-5127.; Wu, C.; Zhao, F.; Du, Y.; Zhao, L.; Chen, L.; Wang, J.; Liu, H. RSC Adv. 2016, 6, 70682-70690.; Rong, M.-G.; Qin, T.-Z.; Zi, W. Org. Lett. 2019, 21, 5421-5425.; Tsubata, S.; Tsubouchi, A.; Saito, A. Org. Chem. Front. 2023, 10, 2618-2623.).But the reported metal carbene coupling / cyclization process is limited to introducing functional groups at C2 position of indole, and the reported 3,3 rearrangement of indole mostly uses expensive catalysts, and has limitations in introducing functional groups at C2 and C3 positions of indole simultaneously, so the method combining the above methods to synthesize the functionalized indole compound has further development value. SUMMARY

[0005] In view of the problems in the prior art synthesis method of indole compounds, the present application provides a preparation method for synthesizing a polysubstituted indole compound by coupling / cyclization / rearrangement reaction of 2-ethynylaniline and diazocompound under the action of a transition metal catalyst, which has the advantages of easy raw materials, wide substrate adaptability, mild reaction conditions, high economy and atom economy of steps. The structural formula of the indole compound is shown as formula III:

[0006]

[0007] Among them:

[0008] R 1 is one or more of alkyl, cycloalkyl, alkoxy, phenyl, benzyl, alkoxyphenyl, halogenated phenyl, polycyclic aryl, heterocyclic group, F, Cl, Br, I, cyano, nitro, hydroxyl, sulfonyl, and is at any position on the benzene ring;

[0009] R 2 is one of alkyl, allyl, alkynyl, phenyl, benzyl, sulfonyl, p-toluenesulfonyl;

[0010] R 3 is one of allyl, alkynyl, acyl, sulfonyl, 1-phenylallyl;

[0011] R 4 is one of H, phenyl, benzyl, alkoxyphenyl, halogenated phenyl, borane phenyl;

[0012] R 5 is one of acyl, ester, amide, phenyl, benzyl, fluoroalkyl, trimethylsilyl.

[0013] A preparation method of a polysubstituted indole, comprising the following steps: adding 2-ethynylaniline, diazocompound and catalyst into a solvent, heating the reaction in an inert atmosphere, then performing vacuum distillation, concentration and column chromatography separation and purification on the reaction system to obtain the polysubstituted indole compound.

[0014] As an embodiment of the present application, the molar ratio of the 2-ethynylaniline, diazocompound, catalyst, base and solvent is 1:(1-2):(0.01-0.2):(10-100).

[0015] As an embodiment of the present application, the catalyst is one of CuCl, CuBr, CuI, Cu(MeCN)4PF6, CuBr2.

[0016] As an embodiment of the present application, the solvent is at least one of tetrahydrofuran (THF), chloroform, 1,2-dichloroethane (DCE), acetonitrile (MeCN), 1,4-dioxane, toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA).

[0017] As an embodiment of the present application, the protective atmosphere is argon or nitrogen.

[0018] As an embodiment of the present application, the temperature of heating is 40-100℃, and the time of heating is 3-24h.

[0019] In an embodiment of the present application, the structure of the 2-ethynylaniline is shown as formula I:

[0020]

[0021] Wherein:

[0022] R 1 is one or several of alkyl, cycloalkyl, alkoxy, phenyl, benzyl, alkoxyphenyl, halogenated phenyl, polycyclic aryl, heterocyclic group, F, Cl, Br, I, cyano, nitro, hydroxyl, sulfonyl, and the position is any position on the benzene ring;

[0023] R 2 is one of alkyl, allyl, alkynyl, phenyl, benzyl, sulfonyl, p-toluenesulfonyl;

[0024] R 3 is one of allyl, alkynyl, acyl, sulfonyl, cinnamyl.

[0025] In an embodiment of the present application, the structure of the diazo compound is shown as formula II:

[0026]

[0027] Wherein:

[0028] R 4 is one of H, phenyl, benzyl, alkoxyphenyl, halogenated phenyl, borane phenyl;

[0029] R 5 is one of acyl, ester, amide, phenyl, benzyl, fluoroalkyl, trimethylsilyl.

[0030] Compared with the prior art, the present application has the following advantages:

[0031] (1) The present application uses 2-ethynylaniline and diazonium compound as raw materials, which are easy to synthesize, and a cheap copper salt as a catalyst, and a one-pot coupling / cyclization / rearrangement series reaction is carried out in a simple reaction system to generate a polysubstituted indole compound.

[0032] (2) The method for synthesizing the polysubstituted indole compound constructed in the present application has the advantages of mild reaction conditions, simple operation, wide substrate adaptability, strong functional group tolerance for different substituent diazonium compounds, and a highest yield of up to 91%.

[0033] (3) The synthesis reaction system of the polysubstituted indole compound established in the present application has the advantages of wide substrate adaptability, mild reaction conditions, economic and atomic economy, and provides a new efficient and simple method for the synthesis and modification of drug intermediates. DETAILED DESCRIPTION

[0034] The present application will be further described in detail below in combination with specific embodiments, but the protection scope of the present application is not limited to the content described, and the specific technology or condition not noted in the examples is carried out according to the technology or condition described in the literature in the art or according to the product instruction, and the reagent or instrument not noted by the manufacturer is a conventional product that can be purchased.

[0035] Example 1

[0036] Synthesis of polysubstituted indole compound 2-(3-allyl-1-methyl-1H-indol-2-yl) ethyl acetate 3a:

[0037] Under an argon atmosphere, N-allyl-2-ethynylaniline 1a (0.2 mmol), diazoethyl acetate 2a (0.3 mmol), CuI (0.01 mmol), MeCN (10 mmol) were added to a test tube, then after stirring at 60°C for 12h, the reaction product was concentrated by reduced pressure distillation to obtain a crude product, which was purified by 200-300 mesh silica gel column chromatography column (ethyl acetate: petroleum ether = 1:100) and then the solvent was removed by reduced pressure distillation to obtain 2-(3-allyl-1-methyl-1H-indol-2-yl) ethyl acetate 3a, yellow liquid, yield 65%, the reaction equation is shown in the following formula:

[0038]

[0039] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0040] 1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.12 - 7.04 (m, 1H), 6.04 - 5.90 (m, 1H), 5.10 - 5.02 (m, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 3.71 (s, 3H), 3.52 (d, J = 6.0 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 170.01, 137.37, 137.14, 129.48, 127.54, 121.61, 119.10, 118.92, 114.71, 111.15, 109.12, 61.30, 31.17, 30.04, 28.94, 14.29. HRMS (ESI) calcd for [C 16 H 20 NO2] + ([M+H + ): 258.1489, found 258.1485.

[0041] Example 2

[0042] Synthesis of polysubstituted indole compound phenethyl 2-(1-methyl-1H-indol-2-yl)pent-4-enoate 3b:

[0043] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), phenethyl diazoacetate 2c (0.4 mmol), CuCl (0.02 mmol), chloroform (15 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 60 °C for 10 h, and the crude product was purified by column chromatography on 200-300 mesh silica gel (ethyl acetate: petroleum ether = 1:50) and the solvent was removed by distillation under reduced pressure to obtain phenethyl 2-(1-methyl-1H-indol-2-yl)pent-4-enoate 3b as a yellow liquid with a yield of 56%, and the reaction equation is shown in the following formula:

[0044]

[0045] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0046] 1H NMR (500 MHz, Chloroform-d) δ 7.54 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.18 - 7.13 (m, 3H), 7.09 (d, J = 7.4 Hz, 1H), 7.06 - 7.00 (m, 2H), 6.04 - 5.81 (m, 1H), 5.10 - 4.86 (m, 2H), 4.30 (t, J = 6.8 Hz, 2H), 3.76 (s, 2H), 3.58 (s, 3H), 3.48 (d, J = 6.1 Hz, 2H), 2.87 (t, J = 6.8 Hz, 2H); 13 C NMR (126 MHz, Chloroform-d) δ 169.79, 137.84, 137.45, 129.38, 128.95, 128.63, 127.83, 126.70, 121.72, 119.24, 119.05, 114.70, 111.49, 109.17, 65.66, 35.30, 31.24, 29.87, 29.00. HRMS (ESI) calcd for [C 22 H 24 NO2] + ([M+H + ]): 334.1802, found 334.1801.

[0047] Example 3

[0048] Synthesis of polysubstituted indole compound 2-(3-allyl-l-methyl-lH-indol-2- yl)acetic acid 2-methylallyl ester 3c:

[0049] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), ethyl 2-methylallyl diazoacetate 2d (0.3 mmol), CuI (0.02 mmol), DCE (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 50 °C for 6 h, the crude product was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:100), and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)acetic acid 2-methylallyl ester 3c, dark red liquid, yield 70%, the reaction equation is shown in the following formula:

[0050]

[0051] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0052] 1H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.03 - 5.89 (m, 1H), 5.10 - 5.02 (m, 1H), 5.01 - 4.95 (m, 1H), 4.90 (d, J = 7.5 Hz, 2H), 4.50 (s, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 3.53 (d, J = 5.7 Hz, 2H), 1.70 (s, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 169.79, 137.84, 137.45, 129.38, 128.95, 128.63, 127.83, 126.70, 121.72, 119.24, 119.05, 114.70, 111.49, 109.17, 65.66, 35.30, 31.24, 29.87, 29.00. HRMS (ESI) calcd for [C 18 H 22 NO2] + ([M+H + ]): 284.1645, found 284.1646.

[0053] Example 4

[0054] Synthesis of 2-(3-allyl-l-methyl-lH-indol-2-yl)acetic acid furan-2-ylmethyl ester 3d:

[0055] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), diazoacetic acid furan-2- methyl ester 2e (0.3 mmol), CuI (0.01 mmol), DMF (8 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 60 °C for 10 h, the crude product was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:100), and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)acetic acid furan-2-ylmethyl ester 3d, dark red liquid, yield 36%, the reaction equation is shown in the following formula:

[0056]

[0057] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0058] 1H NMR (500 MHz, Chloroform-d) δ 7.54 (d, J = 7.9 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.11 - 7.05 (m, 1H), 6.42 - 6.31 (m, 2H), 5.99 - 5.85 (m, 1H), 5.07 (s, 2H), 5.05 - 4.99 (m, 1H), 4.97 - 4.90 (m, 1H), 3.82 (s, 2H), 3.67 (s, 3H), 3.49 (d, J = 6.1 Hz, 2H); 13 C NMR (151 MHz, Chloroform-d) δ 169.65, 149.17, 143.46, 137.27, 137.07, 129.01, 127.40, 121.64, 119.08, 118.91, 114.72, 111.26, 111.09, 110.73, 109.14, 58.75, 30.87, 29.99, 28.88. HRMS (ESI) calcd for [C 19 H 20 NO3] + ([M+H + ]): 310.1438, found 310.1442.

[0059] Example 5

[0060] Synthesis of polysubstituted indole compound 2-(3-allyl-l-methyl-lH-indol-2- yl)acetic acid cyclohexyl ester 3e:

[0061] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), diazoacetic acid cyclohexyl ester 2f (0.2 mmol), CuBr2(0.01 mmol), MeCN (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 80 °C for 12 h, the crude product was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:50) and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)acetic acid cyclohexyl ester 3e, yellow liquid, yield 53%, the reaction equation is shown in the following formula:

[0062]

[0063] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0064] 1H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.09 - 5.85 (m, 1H), 5.14 - 5.02 (m, 1H), 5.01 - 4.93 (m, 1H), 4.82 - 4.68 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.52 (d, J = 6.1 Hz, 2H), 1.92 - 1.75 (m, 2H), 1.73 - 1.61 (m, 2H), 1.55 - 1.46 (m, 1H), 1.41 - 1.30 (m, 4H), 1.26 - 1.19 (m, 1H); 13 CNMR (151 MHz, Chloroform-d) δ 169.49, 137.39, 137.05, 129.73, 127.50, 121.48, 119.00, 118.87, 114.72, 110.96, 109.09, 73.73, 31.62, 31.49, 30.05, 28.90, 25.38, 23.77. HRMS (ESI) calcd for [C 20 H 26 NO2] + ([M+H + ]): 312.1958, found 312.1965.

[0065] Example 6

[0066] Synthesis of polysubstituted indole compound 2-(3-allyl-l-methyl-lH-indol-2- yl)acetic acid 2-phenylpropyl ester 3f:

[0067] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), 2-phenylpropyl-2-diazoacetate 2b (0.3 mmol), Cu(MeCN)4PF6(0.01 mmol), chloroform (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 100 °C for 4 h, the crude product was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)acetic acid 2-phenylpropyl ester 3f, yellow liquid, yield 50%, the reaction equation is shown in the following formula:

[0068]

[0069] Product NMR spectra and high resolution mass spectrometry characterization data:

[0070] 1 H NMR (600 MHz, Chloroform-d) δ 7.54 (d, J = 7.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.19 - 7.13 (m, 3H), 7.12 - 7.01 (m, 3H), 5.97 - 5.85 (m, 1H), 5.01 (d, J = 17.0 Hz, 1H), 4.95 (d, J = 9.9 Hz, 1H), 4.23 - 4.11 (m, 2H), 3.73 (s, 2H), 3.51 (s, 3H), 3.46 (d, J = 4.3 Hz, 2H), 3.02 (q, J = 6.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 3H); 13 C NMR (151 MHz, Chloroform-d) δ 169.87, 142.96, 137.32, 136.99, 129.23, 128.55, 127.43, 127.31, 126.76, 121.53, 119.04, 118.88, 114.68, 110.99, 109.15, 70.07, 38.93, 31.04, 29.79, 28.86, 18.03. HRMS (ESI) calcd for [C 23 H 26 NO2] + ([M+H + ]): 348.1958, found 348.1966.

[0071] Example 7

[0072] Synthesis of polysubstituted indole compound 2-(3-allyl-1-methyl-1H-indol-2-yl)-N,N- diethylacetamide 3g:

[0073] N-allyl-2-ethynyl-N-methylaniline 1a (0.2 mmol), 2-diazo-N,N-diethylacetamide 2g (0.3 mmol), CuCl (0.03 mmol), 1,4-dioxane (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 80 °C for 16 h, the crude product was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:20), then the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-1-methyl-1H-indol-2-yl)-N,N-diethylacetamide 3g, yellow liquid, yield 75%, the reaction equation is shown in the following formula:

[0074]

[0075] Product NMR spectra and high resolution mass spectrometry characterization data:

[0076] 1 H NMR (600 MHz, Chloroform-d) δ 7.52 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.05 - 5.87 (m, 1H), 5.11 - 5.02 (m, 1H), 5.01 - 4.95 (m, 1H), 3.82 (s, 2H), 3.70 (s, 3H), 3.50 (d, J = 5.7 Hz, 2H), 3.38 (q, J = 6.8 Hz, 4H), 1.16 - 1.09 (m, 6H); 13 C NMR (151 MHz, Chloroform-d) δ 168.37, 137.40, 137.16, 131.08, 127.54, 121.23, 118.84, 118.69, 114.76, 109.83, 109.03, 42.33, 40.78, 30.80, 30.32, 29.07, 14.39, 13.16. HRMS (ESI) calcd for [C 18 H 25 N2O] + ([M+H + ]): 285.1961, found 285.1966.

[0077] Example 8

[0078] Synthesis of polysubstituted indole compound butyl 2-(3-allyl-l-methyl-lH-indol-2- yl)acetate 3h:

[0079] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), diazoacetic acid n-butyl ester 2h (0.2 mmol), CuI (0.01 mmol), chloroform (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 50 °C for 12 h, the crude product was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:200) and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)acetate 3h, yellow liquid, yield 65%, the reaction equation is shown in the following formula:

[0080]

[0081] Product NMR spectra and high resolution mass spectrometry characterization data:

[0082] 1 H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.06 - 5.85 (m, 1H), 5.11 - 5.02 (m, 1H), 5.01 - 4.93 (m, 1H), 4.08 (t, J = 6.7 Hz, 2H), 3.79 (s, 2H), 3.72 (s, 3H), 3.59 - 3.46 (m, 2H), 1.58 (q, J = 7.4 Hz, 2H), 1.37 - 1.29 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13 C NMR (151 MHz, Chloroform-d) δ 170.15, 137.35, 137.05, 129.47, 127.46, 121.57, 119.06, 118.89, 114.71, 111.04, 109.12, 65.23, 31.12, 30.66, 30.04, 28.92, 19.18, 13.80.

[0083] Example 9

[0084] Synthesis of poly-substituted indole compound cinnamyl 2-(3-allyl-1- methyl-1H-indol-2-yl)acetate 3i:

[0085] N-allyl-2-ethynyl-N-methylaniline 1a (0.2 mmol), diazo cinnamyl acetate 2i (0.3 mmol), CuBr (0.01 mmol), THF (10 mmol) were added into a test tube under argon atmosphere, then after stirring at 80 °C for 6 h, the reaction product was concentrated by distillation under reduced pressure to obtain a crude product, which was purified by 200-300 mesh silica gel chromatography column (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain cinnamyl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3i as a colorless liquid with a yield of 73%, the reaction equation is shown in the following formula:

[0086]

[0087] Product NMR spectra and high resolution mass spectrometry characterization data:

[0088] 1H NMR (600 MHz, Chloroform-d) δ 7.55 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 4.4 Hz, 3H), 7.29 - 7.25 (m, 2H), 7.24 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 6.27 - 6.20 (m, 1H), 6.03 - 5.89 (m, 1H), 5.10 - 5.02 (m, 1H), 5.00 - 4.93 (m, 1H), 4.74 (d, J = 6.4 Hz, 2H), 3.85 (s, 2H), 3.72 (s, 3H), 3.53 (d, J = 5.9 Hz, 2H); 13 C NMR (151 MHz, Chloroform-d) δ 169.79, 137.30, 137.08, 136.12, 134.48, 129.24, 128.74, 128.26, 127.45, 126.73, 122.73, 121.66, 119.13, 118.95, 114.79, 111.21, 109.18, 65.78, 31.12, 30.10, 28.94. HRMS (ESI) calcd for [C 23 H 23 NNaO2] + ([M+Na + ]): 368.1621, found 368.1628.

[0089] Example 10

[0090] Synthesis of 2-(3-allyl-l-methyl-lH-indol-2-yl)-2-phenylacetic acid ethyl ester 3j:

[0091] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), diazophenylacetic acid ethyl ester 2l (0.4 mmol), CuBr2(0.02 mmol), toluene (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 100 °C for 6 h, the crude product was purified by 200-300 mesh silica column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)-2-phenylacetic acid ethyl ester 3j, yellow liquid, yield 57%, the reaction equation is shown in the following formula:

[0092]

[0093] Product NMR spectra and high resolution mass spectrometry characterization data:

[0094] 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 7.9 Hz, 1H), 7.33 - 7.26 (m, 3H), 7.25 (s, 1H), 7.24 - 7.20 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.13 - 7.09 (m, 1H), 6.02 - 5.91 (m, 1H), 5.52 (s, 1H), 5.10 - 5.03 (m, 1H), 5.01 - 4.95 (m, 1H), 4.34 - 4.18 (m, 2H), 3.64 - 3.50 (m, 2H), 3.48 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 171.39, 137.64, 137.35, 136.85, 132.28, 128.70, 128.07, 127.56, 127.27, 121.94, 119.20, 114.95, 112.31, 109.24, 61.63, 47.93, 31.37, 29.02, 14.32. HRMS (ESI) calcd for [C 22 H 24 NO2] + ([M+H + ]): 334.1802, found 334.1809.

[0095] Example 11

[0096] Synthesis of polysubstituted indole compound 2-(3-allyl-l-methyl-lH-indol-2-yl)-3- phenylpropionic acid ethyl ester 3k:

[0097] N-allyl-2-ethynyl-N-methylaniline la (0.2 mmol), 2-diazo-3-phenylpropionic acid ethyl ester 2m (0.3 mmol), CuBr (0.03 mmol), MeCN (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 80 °C for 12 h to obtain the crude product, which was purified by 200-300 mesh silica gel column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain 2-(3-allyl-l-methyl-lH-indol-2-yl)-3-phenylpropionic acid ethyl ester 3k, yellow liquid, yield 36%, the reaction equation is shown in the following formula:

[0098]

[0099] Product NMR spectra and high resolution mass spectrometry characterization data:

[0100] 1 H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 7.9 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.22 - 7.18 (m, 3H), 7.14 - 7.08 (m, 1H), 7.08 - 7.02 (m, 2H), 5.92 - 5.82 (m, 1H), 5.12 - 4.91 (m, 2H), 4.23 - 4.15 (m, 2H), 4.15 - 4.07 (m, 1H), 3.65 - 3.60 (m, 1H), 3.58 (s, 3H), 3.50 - 3.37 (m, 2H), 3.16 - 3.07 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, Chloroform-d) δ 172.27, 139.09, 137.10, 136.96, 132.94, 129.00, 128.38, 128.34, 127.62, 126.47, 121.43, 118.96, 118.91, 114.72, 110.90, 109.01, 107.90, 61.28, 44.79, 37.43, 30.21, 28.57, 14.08. HRMS (ESI) calcd for [C 23 H 26 NO2] + ([M+H + ]): 348.1958, found 348.1953.

[0101] Example 12

[0102] Synthesis of poly-substituted indole compound ethyl 2-(1,3-diallyl-1H-indol-2- yl)acetate 3l:

[0103] N,N-diallyl-2-ethynylaniline 1b (0.2 mmol), ethyl diazoacetate 2a (0.3 mmol), CuCl (0.01 mmol), chloroform (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 100 °C for 4 h, the crude product was purified by 200-300 mesh silica column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain ethyl 2-(1,3-diallyl-1H-indol-2-yl)acetate 3l as a yellow liquid with a yield of 68%, the reaction equation is shown in the following formula:

[0104]

[0105] Product NMR spectra and high resolution mass spectrometry characterization data:

[0106] 1 H NMR (600 MHz, Chloroform-d) δ 7.56 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 3.9 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.08 - 5.77 (m, 2H), 5.15 - 5.02 (m, 2H), 4.99 (d, J = 10.0 Hz, 1H), 4.81 (d, J = 17.4 Hz, 3H), 4.11 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 3.53 (d, J = 5.9 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, Chloroform-d) δ 170.10, 137.25, 136.51, 133.69, 129.17, 127.68, 121.68, 119.22, 118.98, 116.17, 114.77, 111.53, 109.52, 61.35, 45.73, 31.08, 28.92, 14.27. HRMS (ESI) calcd for [C 18 H 22 NO2] + ([M+H + ]): 284.1645, found 284.1643.

[0107] Example 13

[0108] Synthesis of poly-substituted indole compound ethyl 2-(1,3-diallyl-5-methyl-1H- indol-2-yl)acetate 3m:

[0109] N,N-diallyl-2-ethynyl-4-methylaniline 1d (0.2 mmol), diazoacetic acid ethyl ester 2a (0.3 mmol), CuCl (0.04 mmol), MeCN (5 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 100 °C for 12 h, the crude product was purified by 200-300 mesh silica chromatography column (ethyl acetate: petroleum ether = 1:50) and the solvent was removed by distillation under reduced pressure to obtain 2-(1,3-diallyl-5-methyl-1H-indol-2-yl)acetate 3m as a colorless liquid with a yield of 22%, the reaction equation is shown in the following formula:

[0110]

[0111] Product NMR spectra and high resolution mass spectrometry characterization data:

[0112] 1 H NMR (600 MHz, Chloroform-d) δ 7.33 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.06 - 5.84 (m, 2H), 5.14 - 4.94 (m, 3H), 4.84 - 4.72 (m, 3H), 4.10 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 3.50 (d, J = 5.9 Hz, 2H), 2.44 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, Chloroform-d) δ 170.15, 137.36, 134.91, 133.79, 129.23, 128.47, 127.86, 123.23, 118.63, 116.05, 114.69, 110.98, 109.24, 61.31, 45.74, 31.12, 28.87, 21.63, 14.26. HRMS (ESI) calcd for [C 19 H 24 NO2] + ([M+H + ]): 298.1802, found 298.1800.

[0113] Example 14

[0114] Synthesis of 2-(1,3-diallyl-5-cyano-1H-indol-2-yl)acetic acid ethyl ester 3n:

[0115] Under argon atmosphere, 4-(diallylamino)-3-ethynylbenzonitrile 1e (0.2 mmol), diazomethane 2a (0.3 mmol), CuCl (0.04 mmol), chloroform (10 mmol) were added into a test tube, then after stirring at 100 °C for 12 h, the reaction product was concentrated by distillation under reduced pressure to obtain the crude product, which was purified by 200-300 mesh silica gel column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain 2-(1,3-diallyl-5-cyano-1H-indol-2-yl)acetic acid ethyl ester 3n, colorless liquid, yield 26%, the reaction equation is shown in the following formula:

[0116]

[0117] Product NMR spectra and high resolution mass spectrometry characterization data:

[0118] 1 H NMR (600 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 6.02 - 5.87 (m, 1H), 5.85 - 5.67 (m, 1H), 5.17 (s, 1H), 5.16 - 5.12 (m, 1H), 5.07 (d, J = 10.2 Hz, 1H), 4.93 - 4.78 (m, 2H), 4.75 (d, J = 17.1 Hz, 1H), 4.20 - 4.06 (m, 2H), 3.82 (t, J = 7.6 Hz, 1H), 2.97 - 2.88 (m, 1H), 2.73 - 2.65 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (151 MHz, Chloroform-d) δ 171.47, 139.74, 138.50, 134.41, 132.43, 127.52, 126.08, 124.69, 120.92, 118.07, 116.91, 110.55, 102.84, 101.57, 61.63, 45.69, 43.52, 36.17, 14.23. HRMS (ESI) calcd for [C 19 H 21 N2O2] + ([M+H + ]): 309.1958, found 309.1957.

[0119] Example 15

[0120] Synthesis of polysubstituted indole compound ethyl 2-(1-methyl-3-(2- methyallyl)-1H-indol-2-yl)acetate 3o:

[0121] Under argon atmosphere, 2-ethynyl-N-methyl-N-(2-methylallyl)aniline 1g (0.2 mmol), diazoacetic acid ethyl ester 2a (0.3 mmol), Cu(MeCN)4PF6(0.01 mmol), DMA (10 mmol) were added into a test tube, then after stirring at 40 °C for 10 h, the reaction product was concentrated by distillation under reduced pressure to obtain the crude product, which was purified by 200-300 mesh silica gel column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain 2-(1-methyl-3-(2-methylallyl)-1H-indol-2-yl)acetate 3o, yellowish liquid, yield 91%, the reaction equation is shown in the following formula:

[0122]

[0123] Product NMR spectra and high resolution mass spectrometry characterization data:

[0124] 1 H NMR (500 MHz, Chloroform-d) δ 7.58 - 7.52 (m, 1H), 7.32 - 7.25 (m, 1H), 7.22 - 7.15 (m, 1H), 7.10 - 7.04 (m, 1H), 4.78 - 4.69 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 3.71 (s, 3H), 3.46 (s, 2H), 1.70 (d, J = 1.3 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 170.00, 144.90, 137.16, 129.90, 127.99, 121.51, 119.12, 119.08, 111.18, 110.87, 109.03, 61.24, 33.15, 31.13, 30.03, 22.38, 14.28. HRMS (ESI) calcd for [C 17 H 22 NO2] + ([M+H + ]): 272.1645, found 272.1644.

[0125] Example 16

[0126] Synthesis of polysubstituted indole compound ethyl 2-(1-methyl-3-(1- phenylallyl)-1H-indol-2-yl)acetate 3p:

[0127] N-cinnamyl-2-ethynyl-N-methylaniline 1h (0.2 mmol), diazoacetic acid ethyl ester 2a (0.2 mmol), CuCl (0.01 mmol), chloroform (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 80 °C for 12 h, the crude product was purified by 200-300 mesh silica column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain 2-(1-methyl-3-(1-phenylallyl)-1H-indol-2-yl)acetate 3p, yellowish liquid, yield 66%, the reaction equation is shown in the following formula:

[0128]

[0129] Product NMR spectra and high resolution mass spectrometry characterization data:

[0130] 1H NMR (500 MHz, Chloroform-d) δ 7.37 - 7.32 (m, 1H), 7.32 - 7.27 (m, 3H), 7.25 (d, J = 2.2 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.19 - 7.13 (m, 2H), 6.99 - 6.93 (m, 1H), 6.53 - 6.40 (m, 1H), 5.26 - 5.15 (m, 1H), 5.13 - 5.00 (m, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.78 (s, 2H), 3.72 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 169.82, 143.07, 139.95, 137.34, 129.71, 128.36, 128.27, 126.73, 126.17, 121.52, 120.23, 119.12, 115.95, 114.59, 109.22, 61.32, 46.16, 31.39, 30.04, 14.23. HRMS (ESI) calcd for [C 22 H 24 NO2] + ([M+H + ]): 334.1802, found 334.1808.

[0131] Example 17

[0132] Synthesis of polysubstituted indole compound (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3q:

[0133] N-allyl-2-ethynyl-N-methylaniline 1a (0.2 mmol), (1R,2S,5R)-2-isopropyl-5- methylcyclohexyl 2-diazoacetate 2n (0.3 mmol), CuBr (0.02 mmol), DCE (10 mmol) were added into a test tube under argon atmosphere, then the reaction product was concentrated by distillation under reduced pressure after stirring at 100 °C for 24 h, the crude product was purified by 200-300 mesh silica column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(3-allyl-1-methyl-1H-indol-2- yl)acetate 3q, yellow liquid, yield 71%, the reaction equation is shown in the following formula:

[0134]

[0135] Product NMR spectra and high resolution mass spectrometry characterization data:

[0136] 1 H NMR (500 MHz, Chloroform-d) δ 7.58 - 7.51 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.11 - 7.05 (m, 1H), 6.03 - 5.88 (m, 1H), 5.14 - 5.03 (m, 1H), 5.01 - 4.94 (m, 1H), 4.74 - 4.61 (m, 1H), 3.80 - 3.75 (m, 2H), 3.70 (s, 3H), 3.55 - 3.47 (m, 2H), 1.98 - 1.92 (m, 1H), 1.71 - 1.61 (m, 3H), 1.50 - 1.40 (m, 1H), 1.35 - 1.26 (m, 1H), 1.06 - 0.90 (m, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H), 0.67 (d, J = 6.9 Hz, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 169.63, 137.41, 137.16, 129.69, 127.60, 121.52, 119.03, 118.92, 114.73, 111.10, 109.05, 75.29, 47.20, 40.94, 34.32, 31.52, 31.44, 29.99, 28.96, 26.28, 23.48, 22.11, 20.81, 16.34. HRMS (ESI) calcd for [C 24 H 34 NO2] + ([M+H + ]): 368.2584, found 368.2590.

[0137] Example 18

[0138] Synthesis of polysubstituted indole compound (2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3r:

[0139] In an argon atmosphere, N-allyl-2-ethynyl-N-methyl aniline la (0.2 mmol), (2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-diazoacetate 2o (0.3 mmol), CuBr (0.01 mmol), THF (10 mmol) were added into a test tube, then after stirring at 80 °C for 24 h, the reaction product was concentrated by distillation under reduced pressure to obtain a crude product, which was purified by a 200-300 mesh silica gel column (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain (2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3r, yellow liquid, yield 65%, the reaction equation is shown in the following formula:

[0140]

[0141] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0142] 1 H NMR (500 MHz, Chloroform-d) δ 7.57-7.52 (m, 1H), 7.30-7.25 (m, 1H), 7.22-7.15 (m, 1H), 7.10-7.04 (m, 1H), 6.03-5.91 (m, 1H), 5.10-5.03 (m, 1H), 5.01-4.95 (m, 1H), 4.92-4.86 (m, 1H), 3.79 (d, J = 18.5 Hz, 2H), 3.72 (d, J = 13.8 Hz, 3H), 3.57-3.48 (m, 2H), 2.37-2.27 (m, 1H), 1.79-1.64 (m, 3H), 1.38-1.07 (m, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.78-0.76 (m, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 170.30, 137.44, 129.69, 127.64, 121.56, 119.08, 118.93, 114.77, 111.09, 109.06, 109.01, 81.08, 48.96, 48.01, 45.03, 36.91, 31.43, 30.05, 28.97, 28.15, 27.18, 19.79, 18.94, 13.61. HRMS (ESI) calcd for [C 24 H 32 NO2] + ([M+H + ]): 366.2428, found 366.2423.

[0143] Example 19

[0144] Synthesis of poly-substituted indole compound (E)-3,7-dimethyl-2,6-octadien-1-yl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3s:

[0145] Under argon atmosphere, N-allyl-2-ethynyl-N-methylaniline 1a (0.2 mmol), (E)-3,7-dimethyloct-2,6-dien-1-yl 2-diazoacetate 2p (0.3 mmol), CuCl (0.01 mmol), MeCN (10 mmol) were added into a test tube, then after stirring at 80 °C for 24 h, the reaction product was concentrated by distillation under reduced pressure to obtain the crude product, which was purified by 200-300 mesh silica column chromatography (ethyl acetate: petroleum ether = 1:100) and the solvent was removed by distillation under reduced pressure to obtain (E)-3,7-dimethyl-2,6-octadien-1-yl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3s, yellow liquid, yield 59%, the reaction equation is shown in the following formula:

[0146]

[0147] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0148] 1 H NMR (500 MHz, Chloroform-d) δ 7.59 - 7.50 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.11 - 7.02 (m, 1H), 6.02 - 5.90 (m, 1H), 5.36 - 5.27 (m, 1H), 5.12 - 5.02 (m, 2H), 5.01 - 4.94 (m, 1H), 4.60 (d, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.71 (s, 3H), 3.55 - 3.49 (m, 2H), 2.12 - 2.00 (m, 4H), 1.69 - 1.65 (m, 6H), 1.59 (d, J = 1.3 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 169.99, 142.78, 137.41, 137.20, 131.98, 129.51, 127.60, 123.87, 121.60, 119.10, 118.94, 118.19, 114.70, 111.22, 109.10, 62.23, 39.65, 31.18, 30.03, 28.96, 26.46, 25.78, 17.81, 16.60. HRMS (ESI) calcd for [C 24 H 31 NNaO2] + ([M+Na + ): 388.2247, found 388.2249.

[0149] Example 20

[0150] Synthesis of polysubstituted indole compound (3S,8S,9S,10R,14R,17R)-10-methyl- 17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetrahydro- 1H-cyclopenta-3-yl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3t:

[0151] N-allyl-2-ethynyl-N-methylaniline 1a (0.2 mmol), 1-diazo-3-(((3S,8S,9S,10R,14R,17R)- 10-methyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17- tetrahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)propan-2-one 2q (0.3 mmol), CuCl (0.04 mmol), DMF (10 mmol) were added into a test tube, then after stirring at 100 °C for 24 h, the reaction product was concentrated by distillation under reduced pressure to obtain the crude product, which was purified by 200-300 mesh silica gel column chromatography (ethyl acetate: petroleum ether = 1:50) and the solvent was removed by distillation under reduced pressure to obtain (3S,8S,9S,10R,14R,17R)-10-methyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetrahydro-1H-cyclopenta-3-yl 2-(3-allyl-1-methyl-1H-indol-2-yl)acetate 3t, brown liquid, yield 37%, the reaction equation is shown in the following formula:

[0152]

[0153] Product nuclear magnetic resonance spectrum and high resolution mass spectrometry characterization data:

[0154] 1 H NMR (500 MHz, Chloroform-d) δ 7.57 - 7.51 (m, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.23 - 7.16 (m, 1H), 7.12 - 7.05 (m, 1H), 6.04 - 5.89 (m, 1H), 5.38 - 5.31 (m, 1H), 5.10 - 5.02 (m, 1H), 5.01 - 4.95 (m, 1H), 4.66 - 4.55 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.61 - 3.38 (m, 2H), 2.34 - 2.23 (m, 2H), 2.03 - 1.93 (m, 2H), 1.86 - 1.79 (m, 3H), 1.57 - 1.55 (m, 1H), 1.52 - 1.41 (m, 5H), 1.39 - 1.30 (m, 4H), 1.28 - 1.20 (m, 2H), 1.16 - 1.10 (m, 5H), 0.99 (s, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.90 - 0.83 (m, 8H), 0.67 (s, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 169.42, 139.61, 137.44, 137.20, 129.70, 127.64, 122.98, 121.57, 119.09, 118.94, 114.76, 111.16, 109.12, 56.88, 56.36, 50.22, 42.51, 39.92, 39.70, 38.21, 37.11, 36.75, 36.37, 35.95, 32.07, 32.04, 31.53, 30.08, 28.96, 28.37, 28.17, 27.90, 24.44, 24.01, 22.95, 22.71, 21.21, 19.46, 18.89, 12.02. HRMS (ESI) calcd for [C 40 H 57 NO2] + ([M+H + ]): 584.4462, found 584.4495.

[0155] The above is only part of the embodiments of the application, and does not limit the application in any form. Any simple modification, equivalent change and modification made according to the technical essence of the application to the above embodiments are within the scope of the technical solution of the application.

Claims

1. A process for the preparation of a polysubstituted indole, characterized in that, A 2-ethynylaniline as described in formula I, a diazonium compound as described in formula II and a catalyst are added into a solvent, heated in an inert atmosphere, then the reaction system is concentrated, and a polysubstituted indole compound as described in formula III is obtained after column chromatography separation and purification: Wherein: R 1 is alkyl, and the position is any position on the phenyl ring; R 2 is alkyl; R 3 is one of allyl, 1-phenylallyl; R 4 is H; R 5 is one of ester group, amide group; The catalyst is one of CuCl, CuBr, CuI, Cu(MeCN)4PF6, CuBr2; the heating temperature is 40-100 DEG C, and the heating time is 3-24 h.

2. The method for preparing the polysubstituted indole compound according to claim 1, characterized in that, The molar ratio of the 2-ethynylaniline, the diazonium compound, the catalyst, the solvent is 1:(1-2):(0.01-0.2):(10-100).

3. The method for preparing the polysubstituted indole compound according to claim 1, characterized in that, at least one of tetrahydrofuran, chloroform, 1,2-dichloroethane, acetonitrile, 1,4-dioxane, toluene, N,N - dimethylformamide, N,N - dimethylacetamide.

4. The method for preparing the polysubstituted indole compound according to claim 1, characterized in that, The inert atmosphere is one of argon, nitrogen.

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