A 1,1-di(indolyl)alkene compound, a preparation method and application thereof

Abstract

The application discloses a 1,1-di(indolyl)alkene compound and a preparation method and application thereof. The 1,1-di(indolyl)alkene compound is obtained by stirring reaction of a nickel catalyst, an indole compound, a phenylacetylene bromide compound and a solvent. The preparation method has the advantages of simple operation, easily obtained raw materials, low price, safe and simple operation, mild reaction, short reaction time, high yield, good regioselectivity, wide substrate applicability and the like. The method can efficiently construct various bioactive molecules and drug molecules, and has a good industrial application prospect in natural product molecule derivatization.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a 1,1-di(indolyl)alkene compound and a preparation method and application thereof. BACKGROUND

[0002] Indole and its derivatives have rich biological and pharmacological activities, and are a kind of widely used nitrogen-containing heterocyclic compounds. Among them, 1,1-di(indole) is a key skeleton in the synthesis of many natural products and drugs. This kind of novel 3,3'-biindolyl alkaloid with biological activity can be separated from some terrestrial and marine natural products. For example, arundine separated from Arundo donax roots was found to have strong carcinogenicity in 1994 (Chem. Nat. Compd. 1994, 30, 635-636), and vibrindole A separated from the culture medium of marine bacteria Vibrio parahemolyticus was found to have antibacterial activity in 1994 (J. Nat. Prod. 1994, 57, 1587-1590).

[0003] Recently, great progress has been made in the research on functional synthesis of indole and its derivatives, and many synthesis methods of novel skeletons and novel reaction modes have been developed. With the rapid development of transition metal-catalyzed indole functionalization, not only is it possible to make selective functionalization of multiple sites of indole, but also various metal-catalyzed strategies have their own unique reaction mechanisms. At present, there are more studies on the functionalization of a single indole, but the studies on the reaction involving a bi-indole molecule are relatively less, and the reactions have certain limitations, such as long reaction time (J. Org. Chem. 2016, 81, 11664-11670), severe reaction temperature (J. Org. Chem. 2016, 81, 11664-11670, Org. Lett. 2013, 15, 3622-3625), and expensive catalyst (Org. Lett. 2012, 14, 588-591). Considering the application prospect of 1,1-di(indole) skeleton in the fields of natural product research and medical biological application, it is worth paying attention to develop a method for efficiently, greenly and safely synthesizing 1,1-di(indole) by using cheap and readily available raw materials. SUMMARY

[0004] In view of the deficiencies in the prior art, the application provides a 1,1-di(indolyl)alkene compound and a preparation method and application thereof. The preparation method has the advantages that the raw materials are readily available and low in price, the operation is safe and simple, the reaction temperature is moderate, the reaction time is short, and the yield is good.

[0005] The principle of the present application is: using indole and aryl acetylene halide compound as raw materials, under the action of transition metal catalyst and reaction solvent, 1,1-di(indolyl)olefin compound is synthesized. All raw materials in the reaction are cheap and easy to obtain, the method is simple and easy to operate, safe, and thus has potential practical value.

[0006] The technical scheme adopted by the present application is:

[0007] A 1,1-di(indolyl)olefin compound preparation method comprises the following steps:

[0008] The nickel catalyst, indole compound, phenylacetylene bromide compound and solvent are stirred to obtain the 1,1-di(indolyl)olefin compound;

[0009] The reaction formula is as follows:

[0010]

[0011] Among them, R 1 One or more of H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl, eugenol formate group, menthol formate group, cinnamyl alcohol formate group, or form a C10-C15 aryl with the benzene ring;

[0012] R 2 Each is independently selected from H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl;

[0013] R 3 Each is independently selected from H, C1-C6 alkyl, C6-C15 aryl.

[0014] R 1 As a substituent on the benzene ring, the number is 5, each is independently selected from H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl, eugenol formate group, menthol formate group, cinnamyl alcohol formate group, or adjacent two form a C10-C15 aryl with the benzene ring;

[0015] R 2 As a substituent on the benzene ring, the number is 4, each is independently selected from H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl.

[0016] Preferably, R 1one of H, 3-Br, 4-Me, 4-Cl, 4-vanillin formate, 4-menthol formate, 4-cinnamyl alcohol formate, or forms 2-naphthalene with the benzene ring; R 2 each independently is one of H, 4-Me, 5-Cl, 5-NO2; R 3 each independently is one of H, Me, Ph.

[0017] Preferably, when R 2 is H and R 3 is Me, R 1 each independently is one of H, 3-Br, 4-Me, 4-Cl, 4-vanillin formate, 4-menthol formate, 4-cinnamyl alcohol formate, or forms 2-naphthalene with the benzene ring; when R 1 is H and R 3 is Me, R 2 each independently is one of H, 4-Me, 5-Cl, 5-NO2; when R 1 is H and R 2 is H, R 3 each independently is one of H, Me, Ph.

[0018] Preferably, the nickel catalyst is selected from one or more of palladium acetate, nickel triflate, nickel acetate, 1,3-bis(diphenylphosphinopropane) nickel dichloride, nickel (II) chloride bis-trihexylphosphite, bis(tricyclohexylphosphine) nickel (II) chloride, nickel (II) chloride ethylene glycol dimethyl ether complex, bis(triphenylphosphine) nickel (II) chloride, 1,2-bis(diphenylphosphino)ethane] nickel (II) dichloride, nickel chloride, nickel acetylacetonate.

[0019] Preferably, the solvent is at least one of methanol, ethanol, 1,1,1,3,3,3-hexafluoropropan-2-ol, trifluoroethanol, water, isopropanol, toluene.

[0020] Preferably, the volume ratio of the indole compound and the solvent is 1:1-0.025:1.

[0021] Preferably, the molar ratio of the nickel catalyst to the indole compound is 0.5:1-0.005:1.

[0022] Further preferably, the molar ratio of the nickel catalyst to the indole compound is 0.05:1-0.005:1.

[0023] Preferably, the molar ratio of the indole compound to the aryl acetylene bromide compound is 4:(2-4).

[0024] Preferably, the temperature of the reaction is 0℃-100℃, and the reaction time is 5min-10h.

[0025] Preferably, after the reaction, the solvent is removed by cooling and reducing pressure, and then purified by column chromatography.

[0026] Further preferably, the eluent of the column chromatography is petroleum ether and ethyl acetate, with a volume ratio of 10-3:1.

[0027] The 1,1-di(indolyl)alkene compound prepared by the preparation method.

[0028] The 1,1-di(indolyl)alkene compound in the preparation of 1,1-di(indolyl)alkane compounds or natural product molecular derivatization.

[0029] The structure of the 1,1-di(indolyl)alkane compound is as follows:

[0030]

[0031] Compared with the prior art, the 1,1-di(indolyl)alkene compound has the following beneficial effects:

[0032] The preparation method of the 1,1-di(indolyl)alkene compound is safe and simple to operate, the raw materials are easy to obtain, the price is low, the functional groups are adaptable, the substrates are adaptable, the environment is friendly, the reaction is mild, the reaction time is relatively short, and the yield is high. Through this synthesis method, various biologically active molecules and drug molecules can be efficiently constructed, and the method has good industrial application prospect.

[0033] The 1,1-di(indolyl)alkene compound can be used for preparing 1,1-di(indolyl)alkane compounds. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 and Figure 2 The hydrogen spectrum and the carbon spectrum of the target product (a) obtained in Example 1 are shown in Figures 1 and 2, respectively.

[0035] Figure 3 and Figure 4 The hydrogen spectrum and the carbon spectrum of the target product (b) obtained in Example 2 are shown in Figures 3 and 4, respectively.

[0036] Figure 5 and Figure 6 The hydrogen spectrum and the carbon spectrum of the target product (c) obtained in Example 3 are shown in Figures 5 and 6, respectively.

[0037] Figure 7 and Figure 8 The hydrogen spectrum and the carbon spectrum of the target product (d) obtained in Example 4 are shown in Figures 7 and 8, respectively.

[0038] Figure 9 and Figure 10are the1H NMR and13C NMR charts of the target product (e) obtained in Example 5, respectively.

[0039] Figure 11 and Figure 12 are the1H NMR and13C NMR charts of the target product (f) obtained in Example 6, respectively.

[0040] Figure 13 and Figure 14 are the1H NMR and13C NMR charts of the target product (g) obtained in Example 7, respectively.

[0041] Figure 15 and Figure 16 are the1H NMR and13C NMR charts of the target product (h) obtained in Example 8, respectively.

[0042] Figure 17 and Figure 18 are the1H NMR and13C NMR charts of the target product (i) obtained in Example 9, respectively.

[0043] Figure 19 and Figure 20 are the1H NMR and13C NMR charts of the target product (j) obtained in Example 10, respectively.

[0044] Figure 21 and Figure 22 are the1H NMR and13C NMR charts of the target product (k) obtained in Example 11, respectively.

[0045] Figure 23 and Figure 24 are the1H NMR and13C NMR charts of the target product (A) obtained in Example 12, respectively.

[0046] Figure 25 and Figure 26 are the1H NMR and13C NMR charts of the target product (B) obtained in Example 13, respectively.

[0047] Figure 27 and Figure 28 are the1H NMR and13C NMR charts of the target product (C) obtained in Example 14, respectively. DETAILED DESCRIPTION

[0048] The embodiments of the present application will be described in detail below with reference to Examples, but those skilled in the art will appreciate that the following Examples are for illustrative purposes only and should not be construed as limiting the scope of the present application. Unless otherwise specified, the specific conditions in the Examples were carried out according to the conventional conditions or the conditions recommended by the manufacturers. Unless otherwise specified, the reagents or instruments used were conventional products that can be commercially available.

[0049] It should be noted that:

[0050] In the present application, all the embodiments and preferred embodiments mentioned in the present application can be combined to form new technical solutions, if not otherwise specified.

[0051] In the present application, unless otherwise specified, each reaction or operation step can be carried out in sequence or in sequence. Preferably, the reaction method herein is carried out in sequence.

[0052] Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to that described can also be applied in the present application.

[0053] Example 1

[0054] Preparation of a

[0055]

[0056] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1-methylindole (0.4 mmol), phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography. The column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 60 mg of a was obtained, the yield was 85%.

[0057] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 1 and Figure 2 The structure characterization data are as follows:

[0058] 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 1H), 7.34 (t, J = 9.1 Hz, 2H), 7.27-7.09 (m, 7H), 7.06 (t, J = 7.4 Hz, 2H), 7.02-6.95 (m, 2H), 6.95-6.88 (m, 2H), 3.79 (s, 3H), 3.70 (s, 3H).

[0059] 13C NMR (101 MHz, CDC13) δ 138.9, 137.7, 137.0, 129.7, 129.2, 128.8, 128.7, 127.7, 127.2, 126.4, 125.4, 124.7, 121.8, 121.4, 121.4, 121.0, 119.7, 119.7, 119.1, 115.0, 109.4, 109.0, 32.8, 32.7.

[0060] HRMS (APCI) m / z: [M + H] + calcd for C 26 H 23 N2 363.1856, Found: 363.1855.

[0061] In combination with the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis results, it can be known that the product prepared in Example 1 is a.

[0062] Example 2

[0063] Preparation of b

[0064]

[0065] In the reaction bottle, Ni (dppp) Cl2 (0.02 mmol), 1-methylindole (0.4 mmol), 3-bromophenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 78 mg of b was obtained, the yield was 56%.

[0066] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 3 and Figure 4 The structure characterization data are as follows:

[0067] 1 H NMR (400MHz, CDC13) δ 7.78 (d, J = 8.0 Hz, 1 Hz), 7.36-7.31 (m, 2H), 7.27-7.13 (m, 4H), 7.13-7.07 (m, 2H), 7.03 (s, 1H), 7.02-6.91 (m, 3H), 6.90 (s, 1H), 6.84 (t, J = 7.9 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 3H).

[0068] 13C NMR (101 MHz, CDC13) δ 141.2, 137.7, 137.0, 131.6, 130.5, 130.1, 129.4, 129.1, 128.1, 126.9, 126.3, 122.7, 121.9, 121.8, 121.6, 121.3, 120.9, 119.9, 119.3, 114.5, 109.5, 109.1, 32.9, 32.8.

[0069] HRMS (APCI) m / z: [M + H] + calcd for C 26 H 22 BrN2 441.0961, Found: 441.0963.

[0070] In combination with the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis results, it can be known that the product prepared in Example 2 is b.

[0071] Example 3

[0072] Preparation of c

[0073]

[0074] In the reaction bottle, Ni (dppp) Cl2 (0.02 mmol), 1-methylindole (0.4 mmol), 4-methylphenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 62 mg of c was obtained, the yield was 83%.

[0075] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 5 and Figure 6 The structure characterization data are as follows:

[0076] 1 H NMR (400MHz, CDC13) δ 7.88 (d, J = 8.1 Hz, 1H), 7.43-7.37 (m, 2H), 7.34-7.25 (m, 3H), 7.23-7.15 (m, 2H), 7.13 (d, J = 7.7 Hz, 2H), 7.05-6.99 (m, 2H), 6.98-6.93 (m, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 2.31 (s, 3H).

[0077] 13C NMR (101 MHz, CDC13) δ 137.6, 137.0, 136.0, 135.0, 129.4, 129.0, 128.6, 128.5, 127.9, 127.3, 126.4, 124.9, 121.7, 121.4, 121.4, 121.0, 119.9, 119.6, 119.1, 115.2, 109.4, 108.9, 32.8, 32.7, 21.1.

[0078] HRMS (APCI) m / z: [M + H] + calcd for C 27 H 25 N2 377.2012, Found: 377.2013.

[0079] Based on the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 3 is c.

[0080] Example 4

[0081] Preparation of d

[0082]

[0083] In the reaction bottle, Ni (dppp) Cl2 (0.02 mmol), 1-methylindole (0.4 mmol), 4-chlorophenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 63 mg of d was obtained, the yield was 79%.

[0084] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 7 and Figure 8 The structure characterization data are as follows:

[0085] 1 H NMR (400MHz, CDC13) δ 7.76 (s, 1H), 7.37-7.31 (m, 1H), 7.28-7.07 (m, 5H), 7.08-7.02 (m, 3H), 7.02-6.98 (m, 2H), 6.94-6.01 (m, 2H), 6.88 (s, 1H), 3.78 (s, 3H), 3.68 (s, 3H).

[0086] 13C NMR (101 MHz, CDC13) δ 137.6, 137.0, 136.0, 135.0, 129.4, 129.0, 128.6, 128.5, 127.9, 127.3, 126.4, 124.9, 121.7, 121.4, 121.4, 121.0, 119.9, 119.6, 119.1, 115.2, 109.4, 108.9, 32.8, 32.7, 21.1.

[0087] HRMS (APCI) m / z: [M + H] + calcd for C 26 H 22 ClN2 397.1466, Found: 397.1470.

[0088] Based on the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 4 is d.

[0089] Example 5

[0090] Preparation of e

[0091]

[0092] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1-methylindole (0.4 mmol), 2-naphthalene acetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1, 59 mg of e was obtained, the yield was 71%.

[0093] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 9 and Figure 10 The structure characterization data are as follows:

[0094] 1H NMR (400 MHz, CDCb) d 7.85 (d, J = 8.1 Hz, 1H), 7.68 - 7.60 (m, 3H), 7.43 - 7.36 (m, 2H), 7.35 (s, 1H), 7.34 - 7.30 (m, 3H), 7.29 - 7.26 (m, 1H), 7.23 - 7.17 (m, 3H), 7.14 (t, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.93 (s, 1H), 6.90 (t, J = 7.5 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H).

[0095] 13 C NMR (101 MHz, CDCb) d 137.7, 137.1, 136.9, 133.6, 131.8, 129.8, 129.6, 129.3, 127.6, 127.6, 127.5, 127.4, 127.0, 126.7, 126.5, 125.6, 125.0, 124.7, 121.9, 121.5, 121.4, 121.1, 119.8, 119.6, 119.3, 114.9, 109.5, 109.0, 32.9, 32.8.

[0096] HRMS (APCI) m / z: [M + H] + calcd for C 30 H 25 N2 413.2012, Found: 413.2014.

[0097] Based on the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 5 is e.

[0098] Example 6

[0099] Preparation of f

[0100]

[0101] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1,4-dimethylindole (0.4 mmol), phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 53 mg of f, yield 68%.

[0102] The hydrogen spectrum and carbon spectrum of the obtained target product are as follows, respectivelyFigure 11 and Figure 12 The structure characterization data are as follows:

[0103] 1 H NMR (400 MHz, CDC13) δ 7.21 - 7.01 (m, 6H), 7.06 (t, J = 7.3 Hz, 2H), 7.03 - 6.92 (m, 2H), 6.85 (s, 1H), 6.81 - 6.74 (m, 3H), 3.72 (s, 3H), 3.62 (s, 3H), 2.67 (s, 3H), 2.34 (s, 3H).

[0104] 13C NMR (101 MHz, CDC13) δ 138.7, 137.9, 137.5, 132.1, 131.6, 130.7, 130.2, 130.1, 128.6, 128.3, 127.9, 126.5, 125.5, 124.8, 122.7, 122.3, 121.8, 121.7, 120.6, 116.3, 107.1, 106.8, 32.9, 21.6, 19.7.

[0105] HRMS (APCI) m / z: [M+H] + calcd for C 28 H 27 N2 391.2169, Found: 391.2168.

[0106] According to the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 6 is f.

[0107] Example 7

[0108] Preparation of g

[0109]

[0110] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1-methyl-5-bromoindole (0.4 mmol), phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring for 10 min at 50°C, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 51 mg of g was obtained, the yield was 60%.

[0111] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 13 and Figure 14 The structure characterization data are as follows:

[0112] 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (dd, J = 8.7, 5.5 Hz, 2H), 7.42 - 7.34 (m, 2H), 7.32 (s, 1H), 7.19 (dd, J = 8.6, 2.1 Hz, 1H), 7.15 - 7.05 (m, 5H), 7.05 - 6.99 (m, 2H), 7.05 - 6.99 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H).

[0113] 13 C NMR (101 MHz, DMSO) δ 138.1, 135.9, 135.3, 131.6, 131.4, 128.3, 127.9, 127.6, 127.2, 126.7, 125.8, 124.4, 124.2, 123.8, 121.4, 121.2, 119.1, 119.0, 118.2, 113.4, 111.9, 111.6, 32.8, 32.7.

[0114] HRMS (APCI) m / z: [M+H] + calcd for C 26 H 21 Cl2N2 431.1076, Found: 431.1078.

[0115] Based on the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 7 is g.

[0116] Example 8

[0117] Preparation of h

[0118]

[0119] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1-methyl-5-nitroindole (0.4 mmol), phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 5:1, 73 mg of h was obtained with a yield of 81%.

[0120] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 15 and Figure 16 respectively, and the structure characterization data are as follows:

[0121] 1 H NMR (400 MHz, CDC13) δ 8.52 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 9.1, 2.2 Hz, 1H), 8.10 (dd, J = 8.9, 2.2 Hz, 1H), 8.08 - 8.06 (m, 1H), 7.37 (t, J = 9.2 Hz, 2H), 7.20 (s, 1H), 7.17 - 7.05 (m, 7H), 3.87 (s, 3H), 3.82 (s, 3H).

[0122] 13 C NMR (101 MHz, DMSO) δ 141.0, 140.6, 140.1, 139.7, 137.6, 134.1, 133.4, 128.5, 128.0, 126.4, 126.1, 126.0, 125.2, 124.8, 120.7, 116.8, 116.6, 116.2, 111.0, 110.8, 33.2, 33.1.

[0123] HRMS (APCI) m / z: [M+H] + calcd for C 26 H 21 N4O4 453.1557, Found: 453.1559.

[0124] In combination with the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 8 is h.

[0125] Example 9

[0126] Preparation of i

[0127]

[0128] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), indole (0.4 mmol), phenylacetylenyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 7:1, 36 mg of i was obtained, the yield was 54%.

[0129] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 17 and Figure 18 The structure characterization data are as follows:

[0130] 1 H NMR (400 MHz, CDC13) δ 7.97 (s, 1H), 7.87 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.17 (s, 1H), 7.15 - 7.14 (m, 1H), 7.13 - 7.11 (s, 2H), 7.11 - 7.05 (m, 2H), 7.04 - 6.98 (m, 2H), 6.96 (d, J = 2.5 Hz, 1H), 6.94 - 6.89 (m, 1H), 6.88 (d, J = 2.6 Hz, 1H).

[0131] 13 C NMR (101 MHz, CDC13) δ 138.7, 136.8, 136.1, 128.9, 128.8, 127.8, 126.8, 125.8, 125.6, 125.5, 125.0, 124.6, 122.2, 121.9, 121.1, 120.9, 120.8, 120.1, 119.6, 116.3, 111.4, 111.0.

[0132] HRMS (APCI) m / z: [M+H] + calcd for C 24 H 19 N2 335.1543, Found: 335.1544.

[0133] Based on the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 9 is i.

[0134] Example 10

[0135] Preparation of j

[0136]

[0137] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1-phenylindole (0.4 mmol), phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 36 mg of j was obtained, the yield was 54%.

[0138] The hydrogen spectrum and carbon spectrum of the obtained target product are respectively as follows: Figure 19and Figure 20 The structural characterization data are as follows:

[0139] 1 H NMR (400 MHz, CDC13) δ 7.88 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 9.3 Hz, 2H), 7.49 - 7.42 (m, 8H), 7.34 - 7.27 (m, 6H), 7.25 (s, 1H), 7.23 (d, J = 3.5 Hz, 2H), 7.21 - 7.16 (m, 2H), 7.12 (t, J = 7.4 Hz, 2H), 7.08 - 7.02 (m, 1H), 6.99 (t, J = 7.5 Hz, 1H).

[0140] 13 C NMR (101 MHz, CDC13) δ 139.5, 139.4, 138.6, 136.9, 136.2, 129.5, 129.5, 128.9, 128.4, 128.4, 128.1, 128.0, 127.9, 127.3, 126.6, 126.4, 125.9, 124.5, 124.2, 122.7, 122.4, 121.6, 121.5, 121.2, 120.8, 120.3, 117.1, 110.8, 110.4.

[0141] HRMS (APCI) m / z: [M+H] + calcd for C 36 H 27 N2 487.2169, Found: 487.2172.

[0142] In combination with the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 10 is j.

[0143] Example 11

[0144] Preparation of k

[0145]

[0146] In a reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1,3-dimethylindole (0.4 mmol), phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 34 mg of k, yield 44%.

[0147] The hydrogen spectrum and carbon spectrum of the target product are shown in Figure 21 and Figure 22 The structural characterization data are as follows:

[0148] 1 H NMR (400 MHz, CDC13) δ 7.59 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.25 - 7.19 (m, 4H), 7.18 - 7.15 (m, 3H), 7.14 - 7.09 (m, 4H), 6.96 (s, 1H), 3.29 (d, J = 17.1 Hz, 6H), 2.36 (s, 3H), 1.91 (s, 3H).

[0149] 13 C NMR (101 MHz, CDC13) δ 138.1, 137.6, 137.4, 137.0, 136.8, 134.4, 128.7, 128.4, 128.4, 128.3, 127.7, 122.2, 122.1, 121.9, 119.1, 119.0, 118.9, 111.0, 110.4, 109.2, 109.0, 30.5, 30.3, 9.9, 9.2.

[0150] HRMS (APCI) m / z: [M+H] + calcd for C 28 H 27 N2 391.2169, Found: 391.2171.

[0151] In combination with the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 11 is k.

[0152] Example 12

[0153] Preparation of A

[0154]

[0155] In the reaction bottle, Ni (dppp) Cl2 (0.02 mmol), 1-methylindole (0.4 mmol), 4- syringic acid ester phenylacetylenyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in turn, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 4:1, 90 mg of A was obtained, the yield was 82%.

[0156] The hydrogen spectrum and carbon spectrum of the target product obtained are shown in Figure 23 and Figure 24 The structural characterization data are shown as follows:

[0157] 1 H NMR (400 MHz, CDCI3) δ 7.88 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.24 - 7.13 (m, 6H), 7.05 - 6.99 (m, 2H), 6.98 - 6.92 (m, 2H), 6.81 - 6.74 (m, 2H), 5.97 (ddt, J = 16.8, 9.9, 6.7 Hz, 1H), 5.14 - 5.06 (m, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.38 (d, J = 6.7 Hz, 2H);

[0158] 13 C NMR (101 MHz, CDCI3) δ 164.9, 151.1, 144.5, 138.8, 138.3, 137.8, 137.1, 137.1, 131.9, 130.5, 129.9, 129.5, 128.5, 127.1, 126.3, 125.7, 123.3, 122.7, 122.1, 121.7, 121.2, 121.0, 120.7, 120.1, 119.5, 119.5, 116.1, 114.7, 112.8, 109.6, 109.2, 55.9, 40.1, 33.0, 32.9.

[0159] HRMS (APCI) m / z: [M+H] + calcd for C 37 H 33 N2O3 553.2486, Found: 553.2485.

[0160] In combination with the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 12 is A.

[0161] Example 13

[0162] Preparation of B

[0163]

[0164] In a reaction flask, Ni(dppp)Cl2(0.02 mmol), 1-methylindole (0.4 mmol), 4-menthyl formate phenyl ethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were added in sequence. After stirring at 50 °C for 10 min, the heating and stirring were stopped, and the mixture was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the target product was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate (10:1, by volume) as the eluent. Yield: 30 mg of B, 20%.

[0165] The hydrogen spectrum and carbon spectrum of the target product obtained are shown in Figure 25 and Figure 26 The structural characterization data are as follows:

[0166] 1 H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.38 - 7.29 (mf, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.22 - 7.10 (m, 6H), 7.00 - 6.89 (m, 3H), 4.86 (td, J = 10.8, 4.3 Hz, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 2.09 (d, J = 11.8 Hz, 1H), 1.93 (dtd, J = 14.1, 6.9, 2.6 Hz, 1H), 1.69 (d, J = 11.5 Hz, 2H), 1.55 - 1.42 (m, 2H), 1.29 - 1.25 (m, 1H), 1.15 - 0.99 (m, 2H), 0.89 (t, J = 7.1 Hz, 6H), 0.76 (d, J = 6.9 Hz, 3H).

[0167] 13 C NMR (101 MHz, CDC13) δ 166.2, 143.7, 137.8, 137.1, 131.4, 130.4, 129.4, 129.1, 128.4, 127.2, 127.1, 126.3, 123.5, 122.0, 121.7, 121.2, 121.0, 120.0, 119.5, 114.7, 109.5, 109.1, 74.4, 47.2, 41.0, 34.3, 32.9, 32.8, 31.4, 26.4, 23.6, 22.0, 20.7, 16.5.

[0168] HRMS (APCI) m / z: [M + H] + calcd for C 37 H 41N2O2 545.3163, Found: 545.3164.

[0169] Based on the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 13 is B.

[0170] Example 14

[0171] Preparation of C

[0172]

[0173] In the reaction bottle, Ni(dppp)Cl2(0.02 mmol), 1-methylindole (0.4 mmol), 4-cinnamyl alcohol formate phenylacetylene bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were sequentially added, after stirring at 50°C for 10 min, the heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was separated and purified by column chromatography, the column chromatography eluent used was a mixture of petroleum ether: ethyl acetate with a volume ratio of 10:1, 21 mg of C was obtained, and the yield was 20%.

[0174] The hydrogen spectrum and carbon spectrum of the obtained target product are shown in Figure 27 and Figure 28 The structure characterization data are as follows:

[0175] 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.42-7.10 (m, 14H), 6.98 (s, 1H), 6.97-6.88 (m, 2H), 6.69 (d, J = 15.8 Hz, 1H), 6.36 (dt, J = 15.9, 6.3 Hz, 1H), 4.90 (dd, J = 6.3, 1.4 Hz, 2H), 3.79 (s, 3H), 3.70 (s, 3H).

[0176] 13 C NMR (101 MHz, CDCl3) δ 166.4, 144.1, 137.8, 137.1, 136.3, 133.9, 131.6, 130.5, 129.5, 129.2, 128.6, 128.4, 128.0, 127.0, 126.6, 126.4, 126.3, 123.5, 123.3, 122.0, 121.7, 121.2, 121.0, 120.0, 119.5, 119.4, 114.7, 109.6, 109.2, 65.2, 33.0, 32.9.

[0177] HRMS (APCI) m / z: [M + H] + calcd for C 36 H 31 N2O2 523.2380, Found:523.2383.

[0178] Based on the results of the above NMR spectra, carbon spectrum and high resolution mass spectrum analysis, it can be known that the product prepared in Example 14 is C.

[0179] Example 15

[0180] 1-methylindole and phenylacetylene bromide were reacted under different catalyst conditions (Table 1), and the preparation method was the same as that of Example 1, except that the catalysts were different.

[0181]

[0182] Table 1

[0183]

[0184]

[0185] Reaction conditions: 1a (0.4 mmol), 2a (0.3 mmol), catalyst (0.02 mmol), HFIP (1 mL), 50 °C for 10 min. The above are all isolated yields. n.d. = not detected.

[0186] Example 16

[0187] 1-methylindole and phenylacetylene were reacted under different catalyst conditions (Table 2), and the preparation method was the same as that of Example 1, except that the catalysts and phenylacetylene were different.

[0188]

[0189] Table 2

[0190]

[0191] Reaction conditions: 1a (0.4 mmol), 2a (0.3 mmol), catalyst (0.02 mmol), HFIP (1 mL), 50 °C for 10 min. n.d. = not detected.

[0192] Example 17

[0193] 1-methylindole and phenylacetylene bromide were reacted under different catalyst conditions (Table 1), and the preparation method was the same as that of Example 1, except that the catalysts were different.

[0194]

[0195] Table 3

[0196]

[0197]

[0198] Reaction conditions: 1a (0.4 mmol), 2a (0.3 mmol), Ni(dppp)Cl2, HFIP (1 mL) for 10 min. All the above yields are isolated yields.

[0199] Example 18

[0200] Preparation of i’

[0201]

[0202] In a 15 mL Schleck tube, 3,3'-(2-phenylvinyl-1,1-diyl)bis(1H-indole) i (0.01 mmol, 33.4 mg), Pd / C (0.001 mmol, 3.25 mg) and methanol (2 mL) were added in sequence, and hydrogenation was carried out at 50°C under normal pressure H2atmosphere for 24 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and then the target product was obtained by column chromatography separation and purification. The column chromatography eluent used was a mixture of petroleum ether and ethyl acetate with a volume ratio of 30:1, and 22.5 mg of i' was obtained with a yield of 68%.

Claims

1. A method for preparing a 1,1-di(indolyl)olefin compound, characterized in that, Includes the following steps: The 1,1-di(indole) olefin compound was obtained by stirring a nickel catalyst, an indole compound, a phenylacetylene bromide compound, and a solvent to give the 1,1-di(indole) olefin compound. The reaction formula is as follows: Among them, R 1 It is selected from one or more of H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl, eugenol formate, menthol formate, cinnamyl formate, or forms a C10-C15 aryl group with a benzene ring. R 2 Each is independently selected from H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, and C6-C15 aryl; R 3 Each is independently selected from H, C1-C6 alkyl, and C6-C15 aryl; The nickel catalyst is selected from one or both of nickel trifluoromethanesulfonate and 1,3-bis(diphenylphosphine)dichloride; the solvent is 1,1,1,3,3,3-hexafluoroprop-2-ol.

2. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: R 1 Selected from one of H, 3-Br, 4-Me, 4-Cl, 4-eugenol carboxylate, 4-menthol carboxylate, 4-cinnamyl carboxylate, or forming 2-naphthalene with a benzene ring; R 2 Each is independently selected from one of H, 4-Me, 5-Cl, and 5-NO2; R 3 Each is independently selected from one of H, Me, and Ph.

3. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: The volume ratio of the indole compound to the solvent is 1:1 to 0.025:

1.

4. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: The molar ratio of the nickel catalyst to the indole compound is 0.5:1 to 0.005:

1.

5. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: The molar ratio of the indole compound to the phenylacetylene bromide compound is 4:(2-4).

6. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: The temperature of the reaction is 0. C ~ 100 C, the reaction time is 5 min ~ 10 h.

7. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: After the reaction is complete, the solvent is removed by cooling and reducing the pressure, followed by purification by column chromatography.

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