1, 1-bis (indolyl) olefin compound as well as preparation method and application thereof

Abstract

The invention discloses a 1, 1-bis (indolyl) olefin compound as well as a preparation method and application thereof. A nickel catalyst, an indole compound, a phenylacetylene bromide compound and a solvent are stirred to react to obtain the 1, 1-bis (indolyl) olefin compound. The preparation method provided by the invention has the advantages of simple operation, easily available 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 a variety of bioactive molecules and drug molecules, and has good industrial application prospects in natural product molecule derivatization.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a 1,1-bis(indolyl)olefin compound, a preparation method thereof, and an application thereof. Background Art

[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-bis(indole) is a key skeleton in the synthesis of many natural products and drugs. Such novel 3,3'-bisindolyl alkaloids with biological activities can be isolated from some terrestrial and marine natural products. For example, arundine isolated from the roots of Arundo donax was found to have strong carcinogenicity in 1994 (Chem. Nat. Compd. 1994, 30, 635–636), while vibrindole A isolated from the culture medium of the marine bacterium 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 the functionalization synthesis of indole and its derivatives, and many synthesis methods with novel skeletons and new reaction modes have been developed. With the rapid development of transition metal-catalyzed indole functionalization, not only has it made the multi-site selective functionalization of indole possible, but also various metal-catalyzed strategies have their own unique reaction mechanisms. At present, there are many studies on the functionalization of a single indole, but the research on the reaction involving bisindole molecules is relatively less, and the reactions all have certain limitations, such as too long reaction time (J. Org. Chem. 2016, 81, 11664-11670), relatively harsh reaction temperature (J. Org. Chem. 2016, 81, 11664-11670, Org. Lett. 2013, 15, 3622–3625), expensive catalysts (Org. Lett. 2012, 14, 588-591), etc. Considering the application prospects of the 1,1-bis(indole) skeleton in the fields of natural product research and pharmaceutical biology, it is worthy of attention to develop a method for efficiently, greenly, and safely synthesizing 1,1-bis(indole) using cheap and easily available raw materials. Summary of the Invention

[0004] Aiming at the deficiencies of the existing technology, the present invention provides a 1,1-bis(indolyl)olefin compound, a preparation method thereof, and an application thereof. The preparation method has easily available raw materials, low price, safe and simple operation, moderate reaction temperature, short reaction time, and good yield.

[0005] The principle of the present invention is as follows: Using indole and arylacetylene halide compounds as raw materials, 1,1-bis(indolyl) olefin compounds are synthesized under the action of a transition metal catalyst and a reaction solvent. All raw materials in this reaction are cheap and easily available, the method is simple and feasible, and the operation is safe, so it has potential practical value.

[0006] The technical solution adopted in the present invention is as follows:

[0007] A preparation method of 1,1-bis(indolyl) olefin compounds, comprising the following steps:

[0008] A nickel catalyst, an indole compound, a phenylacetylene bromide compound and a solvent are stirred and reacted to obtain the 1,1-bis(indolyl) olefin compound;

[0009] The reaction formula is as follows:

[0010]

[0011] Wherein, R 1 is selected from one or more of H, halogen, NO 2 , CF 3 , CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl, eugenol formate, menthol formate, cinnamyl alcohol formate, or forms a C10-C15 aryl with the benzene ring;

[0012] R 2 are each independently selected from H, halogen, NO 2 , CF 3 , CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl;

[0013] R 3 are each independently selected from one of H, C1-C6 alkyl, C6-C15 aryl.

[0014] R 1 is a substituent on the benzene ring, with a number of 5, and each is independently selected from H, halogen, NO 2 , CF 3 , CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl, eugenol formate, menthol formate, cinnamyl alcohol formate, or two adjacent ones form a C10-C15 aryl with the benzene ring;

[0015] R 2 is a substituent on the benzene ring, with a number of 4, and each is independently selected from H, halogen, NO 2 , CF 3 , CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl.

[0016] Preferably, R 1 is selected from one of H, 3-Br, 4-Me, 4-Cl, 4-eugenol formate, 4-menthol formate, 4-cinnamyl alcohol formate, or forms 2-naphthalene with the benzene ring; R 2 are each independently selected from one of H, 4-Me, 5-Cl, 5-NO 2 ; R 3 are each independently selected from one of H, Me, Ph.

[0017] Preferably, when R 2 is H and R 3 is Me, R 1 are each independently selected from one of H, 3-Br, 4-Me, 4-Cl, 4-eugenol 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 are each independently selected from one of H, 4-Me, 5-Cl, 5-NO 2 ; when R 1 is H and R 2 is H, R 3 are each independently selected from one of H, Me, Ph.

[0018] Preferably, the nickel catalyst is selected from one or more of palladium acetate, nickel trifluoromethanesulfonate, nickel acetate, 1,3-bis(diphenylphosphine propane) nickel dichloride, chloro-bis(trihexylphosphine) nickel(II) salt, bis(tricyclohexylphosphine) nickel(II) chloride, nickel(II) chloride ethylene glycol dimethyl ether complex, bis(triphenylphosphine) nickel(II) chloride, 1,2-bis(diphenylphosphine) 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 to 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] More 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 arylacetylene bromide compound is 4:(2 - 4).

[0024] Preferably, the temperature of the reaction is 0 °C to 100 °C, and the reaction time is 5 min to 10 h.

[0025] Preferably, after the reaction, it is cooled, the solvent is removed under reduced pressure, and purified by column chromatography.

[0026] More preferably, the eluent for column chromatography is petroleum ether and ethyl acetate, and the volume ratio is 10 to 3:1.

[0027] 1,1-Bis(indolyl)olefin compounds prepared by the above preparation method.

[0028] Use of the above 1,1-bis(indolyl)olefin compounds in the preparation of 1,1-bis(indolyl)alkane compounds or the derivatization of natural product molecules.

[0029] The structural formula of the 1,1-bis(indolyl)alkane compound is as follows:

[0030]

[0031] Compared with the prior art, the beneficial effects of the present invention are:

[0032] The preparation method of the 1,1-bis(indolyl)olefin compound provided by the present invention is safe and simple to operate, the raw materials are easy to obtain, the price is low, it has good adaptability to functional groups, wide adaptability to substrates, is environmentally friendly, and the reaction is mild, the reaction time is relatively short, and the yield is high. Through this synthetic method, a variety of bioactive molecules and drug molecules can be efficiently constructed, and it has good industrial application prospects.

[0033] The 1,1-bis(indolyl)olefin compound provided by the present invention can be used to prepare 1,1-bis(indolyl)alkane compounds. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

[0038] Figure 9 and Figure 10 are the hydrogen spectrum and carbon spectrum of the target product (e) obtained in Example 5, respectively.

[0039] Figure 11 and Figure 12 are the hydrogen spectrum and carbon spectrum of the target product (f) obtained in Example 6, respectively.

[0040] Figure 13 and Figure 14 are the hydrogen spectrum and carbon spectrum of the target product (g) obtained in Example 7, respectively.

[0041] Figure 15 and Figure 16 are the hydrogen spectrum and carbon spectrum of the target product (h) obtained in Example 8, respectively.

[0042] Figure 17 and Figure 18 are the hydrogen spectrum and carbon spectrum of the target product (i) obtained in Example 9, respectively.

[0043] Figure 19 and Figure 20 are the hydrogen spectrum and carbon spectrum of the target product (j) obtained in Example 10, respectively.

[0044] Figure 21 and Figure 22 are the hydrogen spectrum and carbon spectrum of the target product (k) obtained in Example 11, respectively.

[0045] Figure 23 and Figure 24 are the hydrogen spectrum and carbon spectrum of the target product (A) obtained in Example 12, respectively.

[0046] Figure 25 and Figure 26 are the hydrogen spectrum and carbon spectrum of the target product (B) obtained in Example 13, respectively.

[0047] Figure 27 and Figure 28 are the hydrogen spectrum and carbon spectrum of the target product (C) obtained in Example 14, respectively. Detailed implementation manners

[0048] The embodiments of the present invention will be described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those not specified in the examples, the operations are carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments not specified in the manufacturer are all conventional products that can be obtained through commercial purchase.

[0049] It should be noted that:

[0050] In the present invention, unless otherwise specified, all the embodiments and preferred implementation methods mentioned herein can be combined with each other to form a new technical solution.

[0051] In the present invention, unless otherwise indicated, each reaction or operation step can be carried out out of order or in sequence. Preferably, the reaction methods herein are carried out in sequence.

[0052] Unless otherwise specified, the professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods or materials similar or equivalent to the described content can also be applied to the present invention.

[0053] Example 1

[0054] Preparation of a

[0055]

[0056] Ni(dppp)Cl (0.02 mmol), 1-methylindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were successively added to a reaction flask. After stirring at 50 °C for 10 min, heating and stirring were stopped, and it was 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 mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 60 mg of a was obtained with a yield of 85%. 2 (0.02 mmol), 1-methylindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were successively added to a reaction flask. After stirring at 50 °C for 10 min, heating and stirring were stopped, and it was 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 mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 60 mg of a was obtained with a yield of 85%.

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

[0058] 1 H NMR (400 MHz, CDCl 3 ) 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] 13 C NMR (101 MHz, CDCl 3)δ138.9,137.7,137.0,129.7,129.2,128.8,128.7,127.7,127.2,126.4,125.4,124.7,121.8,121.4,121.4,121.0,119.7,119.7,119.1,115.0,109.4,109.0,32.8,32.7.

[0060] HRMS(APCI)m / z:[M+H] + calcd for C 26 H 23 N 2 363.1856,Found:363.1855.

[0061] Combined with the above results of 1H NMR, 13C NMR spectra and high-resolution mass spectrometry analysis, it can be seen that the product obtained in Example 1 is a.

[0062] Example 2

[0063] Preparation of b

[0064]

[0065] Ni(dppp)Cl was successively added to the reaction flask 2 (0.02 mmol), 1-methylindole (0.4 mmol), 3-bromophenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring at 50 °C for 10 min, heating and stirring were stopped, and the mixture was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 78 mg of b was obtained with a yield of 56%.

[0066] The 1H NMR spectrum and 13C NMR spectrum of the obtained target product are respectively as Figure 3 and Figure 4 shown, and the structure characterization data are as follows:[[]]END]]

[0067] 1 H NMR(400MHz,CDCl 3 )δ7.78(d,J = 8.0Hz,1Hz),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 = 7.9Hz,1H),3.77(s,3H),3.67(s,3H).

[0068] 13 C NMR (101 MHz, CDCl 3 )δ141.2,137.7,137.0,131.6,130.5,130.1,129.4,129.1,128.1,126.9,126.3,122. 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] + Calculate for C 26 H 22 Bn 2 441.0961,Found:441.0963.

[0070] Combining the results of the above H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrometry analysis, it can be seen that the product obtained in Example 2 is b.

[0071] Example 3

[0072] Preparation of c

[0073]

[0074] Add Ni(dppp)Cl 2 (0.02mmol), 1-methylindole (0.4mmol), 4-methylphenylethynyl bromide (0.3mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1mL) were stirred at 50°C for 10min, then heating and stirring were stopped, the mixture was 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 eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1, 62mg c, and the yield was 83%.

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

[0076] 1 H NMR (400 MHz, CDCl 3)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] 13 C NMR (101 MHz, CDCl 3 )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 N 2 377.2012, Found: 377.2013.

[0079] Combined with the results of the above nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high-resolution mass spectrometry analysis, it can be seen that the product prepared in Example 3 is c.

[0080] Example 4

[0081] Preparation of d

[0082]

[0083] Ni(dppp)Cl was successively added to the reaction flask 2 (0.02 mmol), 1-methylindole (0.4 mmol), 4-chlorophenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring at 50 °C for 10 min, heating and stirring were stopped, cooled to room temperature, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 63 mg of d was obtained with a yield of 79%.

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

[0085] 1 H NMR (400 MHz, CDCl 3 )δ7.76(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] 13 C NMR (101 MHz, CDCl 3 )δ137.6,137.0,136.0,135.0,129.4,129.0,128.6,128.5,127.9,127.3,126.4,124.9, 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] + Calculate for C 26 H 22 C1N 2 397.1466,Found:397.1470.

[0088] Combining the results of the above H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrometry analysis, it can be seen that the product obtained in Example 4 is d.

[0089] Example 5

[0090] Preparation of e

[0091]

[0092] Add Ni(dppp)Cl 2 (0.02mmol), 1-methylindole (0.4mmol), 2-naphthylethynyl bromide (0.3mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1mL) were stirred at 50°C for 10min, then heating and stirring were stopped, the mixture was 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 eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1, 59mg e, and the yield was 71%.

[0093] The hydrogen spectrum and carbon spectrum of the obtained target product are as follows: Figure 9 and Figure 10As shown, the structural characterization data is as follows:

[0094] 1 H NMR(400MHz,CDCl 3 )δ7.85(d,J=8.1Hz,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=7.5Hz,1H),6.99(s,1H),6.93(s,1H),6.90(t,J=7.5Hz,1H),3.78(s,3H),3.71(s,3H).

[0095] 13 C NMR(101MHz,CDCl 3 )δ137.7,137.1,136.9,133.6,131.8,129.8,129.6,129.3,127.6,127.6,127.5,127.4,127.0,126.7,126.5,125.6,125.0,124.7,121.9,121.5,121.4,121.1,119.8,119.6,119.3,114.9,109.5,109.0,32.9,32.8.

[0096] HRMS(APCI)m / z:[M+H] + calcd for C 30 H 25 N 2 413.2012,Found:413.2014.

[0097] Combined with the above results of 1H NMR, 13C NMR spectra and high-resolution mass spectrometry analysis, the product obtained in Example 5 is e.

[0098] Example 6

[0099] Preparation of f

[0100]

[0101] Ni(dppp)Cl was successively added to the reaction flask 2(0.02 mmol), 1,4 - dimethylindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3 - hexafluoroisopropanol (1 mL). After stirring at 50 °C for 10 min, heating and stirring were stopped, and it was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 53 mg of f was obtained with a yield of 68%.

[0102] The 1H NMR spectrum and 13C NMR spectrum of the obtained target product are shown in Figure 11 and Figure 12 respectively, and the structure characterization data are as follows:

[0103] 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 N 2 391.2169, Found: 391.2168.

[0106] Combined with the above results of 1H NMR, 13C NMR spectra and high - resolution mass spectrometry analysis, the product prepared in Example 6 is f.

[0107] Example 7

[0108] Preparation of g

[0109]

[0110] In the reaction flask, Ni(dppp)Cl was added successively2 (0.02 mmol), 1-methyl-5-bromoindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring the reaction at 50 °C for 10 min, heating and stirring were stopped, and the mixture was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, 51 mg, and the yield was 60%.

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

[0112] 1 H NMR (400 MHz, DMSO-d 6 ) 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 Cl 2 N 2 431.1076, Found: 431.1078.

[0115] Combined with the above results of 1H NMR, 13C NMR spectra and high-resolution mass spectrometry analysis, the product prepared in Example 7 is g.

[0116] Example 8

[0117] Preparation of h

[0118]

[0119] Ni(dppp)Cl was added successively into the reaction flask 2 (0.02 mmol), 1-methyl-5-nitroindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring at 50 °C for 10 min, heating and stirring were stopped, and it was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography. The target product was obtained. The eluent for column chromatography used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 5:1, 73 mg h, and the yield was 81%.

[0120] The 1H NMR spectrum and 13C NMR spectrum of the obtained target product are respectively as shown in Figure 15 and Figure 16 shown below, and the structure characterization data are as follows:

[0121] 1 1H NMR (400 MHz, CDCl 3 ) 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 13C 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 N 4 O 4 453.1557, Found: 453.1559.

[0124] Combined with the above results of 1H NMR, 13C NMR spectra and high-resolution mass spectrometry analysis, it can be seen that the product prepared in Example 8 is h.

[0125] Example 9

[0126] Preparation of i

[0127]

[0128] Ni(dppp)Cl was successively added into a reaction flask 2 (0.02 mmol), indole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring at 50 °C for 10 min, heating and stirring were stopped, and the mixture was cooled to room temperature. The solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography. The target product was obtained. The eluent used for column chromatography was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 7:1, and 36 mg of i was obtained with a yield of 54%.

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

[0130] 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 N 2 335.1543, Found: 335.1544.

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

[0134] Example 10

[0135] Preparation of j

[0136]

[0137] Ni(dppp)Cl (0.02 mmol), 1-phenylindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were successively added to a reaction flask. After stirring at 50 °C for 10 min, heating and stirring were stopped, and the mixture was 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 mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 36 mg of j was obtained with a yield of 54%. 2 (0.02 mmol), 1-phenylindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL) were successively added to a reaction flask. After stirring at 50 °C for 10 min, heating and stirring were stopped, and the mixture was 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 mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 36 mg of j was obtained with a yield of 54%.

[0138] The proton nuclear magnetic resonance spectrum and carbon spectrum of the obtained target product are respectively as Figure 19 and Figure 20 shown, and the structural characterization data are as follows:

[0139] 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 C36 H 27 N 2 487.2169, Found: 487.2172.

[0142] Combined with the results of the above nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high-resolution mass spectrometry analysis, it can be seen that the product obtained in Example 10 is j.

[0143] Example 11

[0144] Preparation of k

[0145]

[0146] Ni(dppp)Cl was successively added to the reaction flask 2 (0.02 mmol), 1,3-dimethylindole (0.4 mmol), phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring at 50 °C for 10 min, 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 eluent used for column chromatography was a mixed solvent of petroleum ether: ethyl acetate with a volume ratio of 10:1, and 34 mg of k was obtained with a yield of 44%.

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

[0148] 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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] + Calculate for C 28 H 27 N 2 391.2169,Found:391.2171.

[0151] Combining the results of the above H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrometry analysis, it can be seen that the product obtained in Example 11 is k.

[0152] Example 12

[0153] Preparation of A

[0154]

[0155] Add Ni(dppp)Cl 2 (0.02mmol), 1-methylindole (0.4mmol), 4-eugenol formate phenylethynyl bromide (0.3mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1mL) were stirred at 50°C for 10min, then heating and stirring were stopped, the mixture was 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 eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1, 90mg A, and the yield was 82%.

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

[0157] 1 H NMR (400 MHz, CDCl 3 )δ7.88(d,J=8.1Hz,2H),7.83(d,J=8.0Hz,1H),7.39–7.32(m,2H),7.27(t,J=7.5Hz,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=16.8,9.9,6.7Hz,1H),5.14–5.0 6(m,2H),3.81(s,3H),3.77(s,3H),3.71(s,3H),3.38(d,J=6.7Hz,2H);

[0158] 13 C NMR (101 MHz, CDCl 3)δ164.9,151.1,144.5,138.8,138.3,137.8,137.1,137.1,131.9,130.5,129.9,129.5,128.5,127.1,126.3,125.7,123.3, 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] + Calculate for C 37 H 33 N 2 O 3 553.2486,Found:553.2485.

[0160] Combining the results of the above H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrometry analysis, it can be seen that the product obtained in Example 12 is A.

[0161] Embodiment 13

[0162] Preparation of B

[0163]

[0164] Add Ni(dppp)Cl 2 (0.02mmol), 1-methylindole (0.4mmol), 4-menthol formate phenylethynyl bromide (0.3mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1mL) were stirred at 50°C for 10min, then heating and stirring were stopped, the mixture was 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 eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1, 30mg B, and a yield of 20%.

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

[0166] 1 H NMR (400 MHz, CDCl 3)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, CDCl 3 )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 41 N 2 O 2 545.3163, Found: 545.3164.

[0169] Combined with the results of the above 1H NMR, 13C NMR spectra and high-resolution mass spectrometry analysis, it can be seen that the product prepared in Example 13 is B.

[0170] Example 14

[0171] Preparation of C

[0172]

[0173] In the reaction flask, Ni(dppp)Cl was added successively 2(0.02 mmol), 1-methylindole (0.4 mmol), 4-cinnamoylformate phenylethynyl bromide (0.3 mmol) and 1,1,1,3,3,3-hexafluoroisopropanol (1 mL). After stirring the reaction at 50 °C for 10 min, 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 mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 10:1, and 21 mg of C was obtained with a yield of 20%.

[0174] The proton NMR spectrum and carbon NMR spectrum of the obtained target product are respectively as Figure 27 and Figure 28 shown, and the structure characterization data are as follows:

[0175] 1 H NMR (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 N 2 O 2 523.2380, Found: 523.2383.

[0178] Combined with the above results of proton NMR, carbon NMR spectra and high-resolution mass spectrometry analysis, it can be seen that the product prepared in Example 14 is C.

[0179] Example 15

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

[0181]

[0182] Table 1

[0183]

[0184]

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

[0186] Example 16

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

[0188]

[0189] Table 2

[0190]

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

[0192] Example 17

[0193] 1-Methylindole and phenylethynyl bromide were reacted under different catalyst dosages and reaction temperature conditions (Table 3). The preparation method was the same as that of Example 1, except for the different catalyst dosages and reaction temperatures.

[0194]

[0195] Table 3

[0196]

[0197]

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

[0199] Example 18

[0200] Preparation of i'

[0201]

[0202] In a 15 mL Schleck tube, sequentially add 3,3'-(2-phenylethylene-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), and carry out a hydrogenation reaction at 50 °C under an atmosphere of H 2 for 24 hours. After the reaction is completed, remove the solvent by rotary evaporation under reduced pressure, and then separate and purify by column chromatography. The target product is obtained. The eluent used for column chromatography is a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 30:1. 22.5 mg of i', and the yield is 68%.

Claims

1. A method for preparing 1,1-di(indolyl)olefin compounds, characterized in that: The following steps are involved: The nickel catalyst, the indole compound, the phenylacetylene bromide compound and the solvent are stirred for reaction to obtain the 1,1-di(indolyl)olefin compound; The reaction formula is as follows: Among them, R 1 One or more selected from H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl, eugenol formate, menthol formate, cinnamyl formate, or forming a C10-C15 aryl with a benzene ring; R 2 Each is independently selected from H, halogen, NO2, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C6-C15 aryl; R 3 Each is independently selected from one of H, C1-C6 alkyl, and C6-C15 aryl.

2. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: R 1 R is selected from one of H, 3-Br, 4-Me, 4-Cl, 4-eugenol formate, 4-menthol formate, 4-cinnamyl formate, or forms 2-naphthalene with the benzene ring; 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 nickel catalyst is selected from one or more of nickel trifluoromethanesulfonate, nickel acetate, 1,3-bis(diphenylphosphinopropane)nickel dichloride, chlorobistrihexyl phosphate nickel(II) salt, 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, and nickel acetylacetonate.

4. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: The solvent is at least one of methanol, ethanol, 1,1,1,3,3,3-hexafluoropropan-2-ol, trifluoroethanol, water, isopropanol, and toluene; The volume ratio of the indole compound to the solvent is 1:1-0.025:

1.

5. 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 0.5:1-0.005:

1.

6. 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 arylacetylene bromide compound is 4:(2-4).

7. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: The reaction temperature is 0°C to 100°C, and the reaction time is 5 minutes to 10 hours.

8. The method for preparing 1,1-di(indolyl)olefin compounds according to claim 1, characterized in that: After the reaction is completed, the solution is cooled, the solvent is removed under reduced pressure, and the solution is purified by column chromatography.

9. 1,1-di(indolyl)olefin compounds prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the 1,1-di(indolyl)olefin compound according to claim 9 in the preparation of 1,1-di(indolyl)alkane compounds or the derivatization of natural product molecules.

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