A 2-cyanoindole-substituted geminal difluoroolefin compound and its preparation method and application

Abstract

The present invention relates to the technical field of organic synthesis, and in particular to a 2-cyanoindole-substituted gem-difluoroolefin compound and its preparation method and application. The compound preparation method comprises: using trifluoromethylindolemethanol compounds and trimethylsilyl cyanide as raw materials, and heating the reaction in a solvent under the action of a Lewis acid catalyst and an inorganic base to obtain the 2-cyanoindole-substituted gem-difluoroolefin compound. The present invention provides a 2-cyanoindole-substituted gem-difluoroolefin compound and its preparation method. The method uses trifluoromethylindolemethanol compounds and trimethylsilyl cyanide, which are easily available, as raw materials, and does not require the use of explosive diazo compounds. It has the advantages of mild reaction conditions, simple operation, high yield, and a wide range of reaction substrates.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a 2-cyanoindole-substituted gem-difluoroolefin compound, a preparation method and an application thereof. Background Art

[0002] Gem-difluoroolefin compounds are widely used in pharmaceuticals, pesticides, insecticides, and functional materials. Gem-difluoroolefins are considered to be biological isoelectronic versions of carbonyl compounds. Many biologically active natural products and drugs can significantly enhance their physiological and pharmacological activities by introducing gem-difluoroolefin units. For example, artemisinin derivatives containing gem-difluoroolefins have shown superior biological activity. In addition, gem-difluoroolefin compounds are also a very important class of organic synthesis intermediates that can be used to synthesize various fluorine-containing and non-fluorine-containing functional molecules. For example, gem-difluoroolefins can be easily converted into monofluoro-substituted alkenes and difluoroalkyl-substituted functional molecules.

[0003] Indoles are a very important class of alkaloids with extensive applications in medicinal chemistry, organic synthesis, pesticides, functional materials, and other fields. Meanwhile, cyano compounds are not only widely present in many important natural products and best-selling pharmaceuticals, but also have important applications in agrochemicals and polymer materials. Furthermore, cyano compounds are also a very important class of organic synthesis intermediates, which can be used to prepare carboxylic acids, aldehydes, ketones, amines, amides, and heterocyclic compounds through functional group transformation. Therefore, the synthesis of cyanoindole-substituted gem-difluoroolefins is of great significance.

[0004] At present, there are many methods for the synthesis of geminal difluoroolefins, such as the classic Wittig-type reaction. However, the method of indole-substituted geminal difluoroolefins is very rare (Angew.Chem.Int.Ed.2020,59,5572–5576). These prior art methods usually require the use of explosive azo compounds, and the substrate reaction is relatively limited, usually limited to N-alkylated electron-rich indole substrates, while those with electron-withdrawing functional groups such as ester groups and cyano groups cannot react. However, there are currently no literature reports on 2-cyanoindole-substituted geminal difluoroolefin compounds and their synthesis methods. Summary of the Invention

[0005] Based on the above content, the present invention provides a 2-cyanoindole substituted gem-difluoroolefin compound and a preparation method and application thereof, filling the technical gap in 2-cyanoindole substituted gem-difluoroolefin compounds.

[0006] One of the technical solutions of the present invention is a 2-cyanoindole-substituted geminal difluoroolefin compound, the structural formula of which is shown in formula (1):

[0007]

[0008] Among them, R 1 、R 2 、R 3 are independent groups, R 1 is selected from one of hydrogen, halogen, hydroxy, cyano, ester, methyl, ethyl or methoxy; R 2 R is selected from one of hydrogen, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, C1-C6 branched alkyl, benzyl or allyl; 3 One selected from phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl or thienyl.

[0009] The second technical solution of the present invention is a method for preparing the above-mentioned 2-cyanoindole-substituted gem-difluoroolefin compound, comprising the following steps: using trifluoromethylindolemethanol compounds and trimethylsilyl cyanide as raw materials, heating the reaction in a solvent in the presence of a Lewis acid catalyst and an inorganic base to obtain the 2-cyanoindole-substituted gem-difluoroolefin compound.

[0010] Specific reaction equation:

[0011]

[0012] Furthermore, the method further includes tracking the reaction by thin plate chromatography during the heating reaction until the reaction is complete, and post-reaction treatment: cooling to room temperature after the reaction is completed, filtering to remove insoluble matter, and then concentrating by rotary evaporation. The crude product is chromatographed on a 200-300 mesh silica gel column, and gradient elution is performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 5:1 as an eluent to obtain a 2-cyanoindole-substituted gem-difluoroolefin compound.

[0013] Furthermore, the trifluoromethyl indole methanol compound is a compound represented by formula (2):

[0014] Among them, R 1 、R 2 、R 3 are independent groups, R 1 is selected from one of hydrogen, halogen, hydroxy, cyano, ester, methyl, ethyl or methoxy; R 2 R is selected from one of hydrogen, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, C1-C6 branched alkyl, benzyl or allyl; 3 One selected from phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl or thienyl.

[0015] The molar ratio of the trifluoromethylindolemethanol compound to trimethylsilyl cyanide is 1:2-3.

[0016] Furthermore, the Lewis acid catalyst is scandium trifluoromethanesulfonate, and the molar ratio of the trifluoromethylindolemethanol compound to scandium trifluoromethanesulfonate is 1:0.05 to 1:0.2.

[0017] Furthermore, the inorganic base is any one of calcium oxide, magnesium oxide, barium oxide, zinc oxide or aluminum oxide, and the molar ratio of the inorganic base to the trifluoromethylindole methanol compound is 10:1.

[0018] The purpose of adding the base in the present invention is to neutralize the hydrogen fluoride produced in the reaction, which is beneficial to the reaction.

[0019] Furthermore, the inorganic base is magnesium oxide;

[0020] Furthermore, the solvent is any one of chlorobenzene, toluene, acetonitrile or dichloroethane, and the concentration of the trifluoromethylindole carbinol compound in the solvent is 0.05-0.5 mol / L.

[0021] Furthermore, the solvent is chlorobenzene, which has the best yield;

[0022] Furthermore, the heating reaction temperature is 80-140° C., and the heating reaction time is 6-24 hours.

[0023] The third technical solution of the present invention is the use of the above-mentioned 2-cyanoindole-substituted gem-difluoroolefin compound as an organic synthesis intermediate.

[0024] Furthermore, the 2-cyanoindole-substituted gem-difluoroolefin compound and methylthiophenol are subjected to an addition reaction under the catalysis of tetramethylguanidine to synthesize a sulfide compound.

[0025] Furthermore, the 2-cyanoindole-substituted gem-difluoroolefin compound and methylthiophenol are catalyzed by cobalt dichloride to synthesize an amino compound through a substitution reaction.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention provides a 2-cyanoindole-substituted gem-difluoroolefin compound and a preparation method thereof. This method uses readily available trifluoromethylindolemethanol compounds and trimethylsilyl cyanide as raw materials, eliminating the need for explosive diazo compounds. It has the advantages of mild reaction conditions, simple operation, high yield, and a wide range of reaction substrates.

[0028] The 2-cyanoindole-substituted gem-difluoroolefin compound developed and prepared by the present invention has indole, gem-difluoroolefin and cyano functional groups, can undergo various chemical transformations, and is an important organic synthesis intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0030] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound 1a prepared in Example 1 of the present invention;

[0031] Figure 2 This is the carbon NMR spectrum of compound 1a prepared in Example 1 of the present invention;

[0032] Figure 3 This is the NMR fluorine spectrum of compound 1a prepared in Example 1 of the present invention;

[0033] Figure 4 This is the single crystal diffraction pattern of compound 1a prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0034] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0035] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any intermediate value within a stated value or stated range and any other stated value or intermediate value within the stated range is also encompassed by the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0036] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0037] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0038] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0039] Example 1:

[0040] The reaction equation is:

[0041]

[0042] To a 25 mL round-bottom flask, trifluoromethylindolemethanol 2a (87.4 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) were added in sequence and stirred at 120°C for 12 h (the reaction was monitored by thin-layer chromatography until completion). After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 10:1 to obtain the target product 1a (63.1 mg, white solid, 75% yield).

[0043] Figure 1 This is the H NMR spectrum of compound 1a prepared in this example;

[0044] Figure 2 This is the carbon NMR spectrum of compound 1a prepared in this example;

[0045] Figure 3 This is the NMR fluorine spectrum of compound 1a prepared in this example;

[0046] Figure 4 Single crystal diffraction pattern of compound 1a prepared in this example

[0047] 1 H NMR (600MHz, CDCl3) δ8.93 (s, 1H), 7.73–7.30 (m, 7H), 7.24 (d, J = 8.2Hz, 1H), 7.13 (td, J = 7.9, 0.8Hz, 1H); 13C NMR(151MHz, CDCl3) δ154.0(dd,J=299.0,294.5Hz),136.7,132.6(dd,J=4.5,3.0Hz),128.8(dd,J=4.5,3.0Hz),128.6,12 7.9,126.6,125.5(d,J=3.0Hz),121.9,121.3,120.6(dd,J=4.5,3.0Hz),113.2,112.0,106.4,87.5(dd,J=22.7,19.6Hz); 19 F NMR(565MHz, CDCl3)δ-81.76(d,J=22.7Hz),-85.46(d,J=22.7Hz); HRMS(ESI)calcd for C 17 H 10 F2N2Na[M+Na] + :303.0704;found:303.0700.

[0048] Example 2

[0049] The reaction equation is:

[0050]

[0051] To a 25 mL round-bottom flask, trifluoromethylindolemethanol 2b (91.6 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) were added in sequence and stirred at 120°C for 8 hours (the reaction was monitored by thin plate chromatography until the reaction was complete). After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 10:1 as the eluent to obtain the target product 1b (70.6 mg, white solid, 80% yield).

[0052] 1 H NMR (400MHz, CDCl3) δ8.98 (s, 1H), 7.36–7.30 (m, 6H), 7.22 (d, J = 8.5Hz, 1H), 7.05 (s, 1H), 2.37 (s, 3H); 13C NMR(101MHz, CDCl3) δ153.9(dd,J=296.9,293.9Hz),135.2,132.7(dd,J=5.1,3.0Hz),128.8(dd,J=4.0,3.0Hz),128.6128.5,127. 8,125.8(d,J=2.0Hz),120.3,120.0(dd,J=5.1,2.0Hz),113.5,111.7,106.2(dd,J=3.0,2.0Hz),87.5(dd,J=22.2,20.2Hz),21.4; 19 F NMR(565MHz, CDCl3)δ-82.70(d,J=23.1Hz),-84.47(d,J=22.9Hz); HRMS(ESI)calcd for C 18 H 12 F2N2Na[M+Na] + :317.0861;found:317.0851.

[0053] Example 3

[0054] The reaction equation is:

[0055]

[0056] To a 25 mL round-bottom flask, trifluoromethylindolemethanol 2c (104.8 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) were added in sequence and stirred at 120°C for 24 h (the reaction was monitored by thin-layer chromatography until completion). After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was concentrated by rotary evaporation to remove the solvent. Gradient elution was performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1 to obtain the target product 1c (52.8 mg, white solid, 52% yield).

[0057] 1 H NMR (600MHz, CDCl3) δ9.41 (s, 1H), 8.08–8.06 (m, 2H), 7.45 (d, J = 9.3Hz, 1H), 7.36–7.29 (m, 5H), 3.90 (s, 3H); 13C NMR (151MHz, CDCl3) δ 167.5, 154.0 (dd, J = 299.0, 293.7Hz), 139.1, 132.3 (dd, J = 4.6, 3.0Hz), 128.7 (t, J = 3.5Hz), 128.6, 128. 1,127.3,125.2(d,J=1.9Hz),124.2,123.9,121.9(dd,J=4.7,2.8Hz),112.6,112.1,108.0,87.0(dd,J=22.4,20.2Hz),52.3; 19 F NMR(565MHz, CDCl3)δ-80.97(d,J=21.4Hz),-84.46(d,J=21.3Hz); HRMS(ESI)calcd for C 19 H 12 F2N2NaO2[M+Na] + :361.0759;found:361.0746.

[0058] Example 4

[0059] The reaction equation is:

[0060]

[0061] To a 25 mL round-bottom flask, trifluoromethylindolemethanol 2d (96.4 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) were added in sequence and stirred at 120°C for 12 hours (the reaction was monitored by thin-layer chromatography until completion). After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 8:1 to obtain the target product 1d (87.5 mg, white solid, 94% yield).

[0062] 1 H NMR (600MHz, CDCl3) δ9.06 (s, 1H), 7.48–7.28 (m, 5H), 7.06 (d, J = 8.9Hz, 1H), 6.82 (d, J = 1.2Hz, 1H), 6.78 (dd, J = 8.9, 1.6Hz, 1H), 3.84 (s, 3H); 13CNMR(151MHz,CDCl3)δ159.7,153.9(dd,J=297.8,293.8Hz),138.0,132.7(dd,J=4.5,3.0Hz),128.9(dd,J=4.5,3.0Hz),128 .5,127.9,122.0,120.9(dd,J=4.7,3.0Hz),119.8(d,J=2.5Hz),113.9,113.5,104.7,93.8,87.6(dd,J=22.0,20.1Hz),55.5; 19 F NMR(565MHz, CDCl3)δ-81.88(d,J=23.1Hz),-85.68(d,J=23.0Hz); HRMS(ESI)calcd for C 18 H 12 F2N2NaO[M+Na] + :333.0810;found:333.0802.

[0063] Example 5

[0064] The reaction equation is:

[0065]

[0066] A 25 mL round-bottom flask was charged with trifluoromethylindolemethanol 2e (92.8 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL). The mixture was stirred at 120 ° C for 12 hours (the reaction was monitored by thin plate chromatography until the reaction was complete). After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was concentrated to remove the solvent and gradient elution was performed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 10:1 to obtain the target product 1e (87.5 mg, white solid, yield 94%).

[0067] 1 H NMR (600MHz, CDCl3) δ8.92(s,1H),7.46–7.29(m,5H),7.14(dd,J=8.9,5.2Hz,1H),7.09(dd,J=9.0,2.1Hz,1H),6.89(td,J=9.1,2.2Hz,1H); 13C NMR (151MHz, CDCl3) δ162.4 (d, J = 245.2Hz), 154.0 (dd, J = 298.1, 294.2Hz), 137.0 (d, J = 13.0Hz), 132.4 (dd, J = 4.3, 3.3Hz), 128.8 (t, J = 3. 5Hz), 128.6, 128.0, 122.6 (d, J = 9.8Hz), 122.1, 121.0, 113.2, 111.5 (d, J = 25.4Hz), 106.5, 98.2 (d, J = 26.6Hz), 87.4 (dd, J = 22.2, 20.0Hz); 19 FNMR(565MHz, CDCl3)δ-81.44(d,J=21.8Hz),-85.03(d,J=21.8Hz),-113.64–-113.69(m); HRMS(ESI)calcd for C 17 H 10 F3N2[M+H] + :299.0791;found:299.0790.

[0068] Example 6

[0069] The reaction equation is:

[0070]

[0071] A 25 mL round-bottom flask was added with trifluoromethylindolemethanol 2f (116.8 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) in sequence. The mixture was stirred at 120 ° C for 12 hours (the reaction was monitored by thin plate chromatography until the reaction was complete). After the reaction was completed, it was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was concentrated by rotary evaporation to remove the solvent and gradient elution was performed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 10:1 as the eluent to obtain the target product 1f (105.5 mg, light yellow solid, yield 93%).

[0072] 1 H NMR (600MHz, CDCl3) δ8.84(s,1H),7.60(s,1H),7.58(d,J=7.5Hz,1H),7.50(d,J=7.7Hz,1H),7.47(t, J=7.7Hz,1H),7.04(d,J=8.9Hz,1H),6.84(d,J=2.0Hz,1H),6.81(dd,J=8.9,2.2Hz,1H),3.85(s,3H); 13C NMR (151MHz, CDCl3) δ159.8,154.2(dd,J=298.9,295.0Hz),138.1,133.7(t,J=3.9Hz),132.2,131.0(q,J=32.3Hz),129.1,126.6,125.5(dd,J=7.1 ,3.3Hz),124.7,124.6(q,J=4.5Hz),122.9,121.6,121.1,119.8(t,4.2Hz ),119.5(d,1.6Hz),113.8,104.8,93.9,87.1(dd,J=21.4,20.0Hz),55.4; 19 F NMR(565MHz, CDCl3)δ62.70(s,3F),-79.88–-79.96(m,1F),-84.09–-84.13(m,1F); HRMS(ESI)calcd forC 19 H 11 F5N2NaO[M+Na] + :401.0684;found:401.0680.

[0073] Example 7

[0074] The reaction equation is:

[0075]

[0076] Take a 25mL round-bottom flask and add 2g (100.6mg, 0.3mmol) of trifluoromethylindolemethanol, magnesium oxide (3mmol), scandium trifluoromethanesulfonate (0.06mmol), trimethylsilyl cyanide (0.9mmol), and anhydrous chlorobenzene (3mL) in sequence. Stir at 120°C for 8 hours (trace the reaction by thin plate chromatography until the reaction is complete). After the reaction is completed, cool to room temperature and filter to remove insoluble matter. The filtrate is rotary concentrated to remove the solvent and gradient elution is performed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 10:1 as the eluent to obtain 1g (96.3mg, white solid, yield 99%) of the target product.

[0077] 1 H NMR (400MHz, CDCl3) δ8.90(s,1H),7.35(d,J=7.0Hz,1H),7.30–7.21(m,3H),7.14–7.11(m,1H),6.80–6.77(m,2H),3.84(s,3H),2.22(s,3H); 13C NMR (101MHz, CDCl3) δ159.5,153.2(dd,J=297.1,292.2Hz),137.9,137.6(d,J=1.7Hz),130.8,130.6,128.6,12 5.9,121.9(d,J=2.6Hz),119.4(d,J=1.4Hz),113.9,113.4,103.9,93.7,87.1(dd,J=27.1,18.4Hz),55.5,19.7; 19 F NMR(376MHz, CDCl3)δ-83.76(d,J=22.6Hz),-84.07(d,J=22.8Hz); HRMS(ESI)calcd for C 19 H 14 F2N2NaO[M+Na] + :347.0966;found:347.0954.

[0078] Example 8

[0079] The reaction equation is:

[0080]

[0081] Take a 25 mL round-bottom flask and add trifluoromethylindolemethanol 2h (111.4 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) in sequence. Stir at 120 ° C for 15 hours (trace the reaction by thin plate chromatography until the reaction is complete). After the reaction is completed, cool to room temperature and filter to remove insoluble matter. The filtrate is rotary concentrated to remove the solvent and gradient elution is performed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 10:1 as the eluent to obtain the target product 1h (100.5 mg, white solid, yield 93%).

[0082] 1 H NMR (400MHz, CDCl3) δ8.80 (s, 1H), 7.90–7.87 (m, 3H), 7.64 (d, J = 7.0Hz, 1H) ,7.53–7.42(m,3H),7.16(d,J=8.9Hz,1H),6.75–6.70(m,2H),3.79(s,3H); 13C NMR (101MHz, CDCl3) δ159.4,153.8(dd,J=297.7,292.8Hz),137.9,133.8,131.7(d,J=1.8Hz),129.6(dd,J=3.3,2.7Hz),129.3,129.2,128.6,126.7, 126.0,125.2,124.6,121.7(d,J=2.7Hz),121.4(dd,J=4.1,2.7Hz),119.1 (d,J=1.9Hz),114.0,113.4,103.8,93.6,86.3(dd,J=26.8,19.5Hz),55.2; 19 F NMR(376MHz, CDCl3)δ-82.17(d,J=20.8Hz),-82.68(d,J=21.0Hz); HRMS(ESI)calcd for C 22 H 14 F2N2NaO[M+Na] + :383.0966;found:383.0953.

[0083] Example 9

[0084] The reaction equation is:

[0085]

[0086] To a 25 mL round-bottom flask, trifluoromethylindolemethanol 2i (98.2 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) were added in sequence and stirred at 120 ° C for 24 hours (the reaction was monitored by thin plate chromatography until the reaction was complete). After the reaction was completed, it was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 9:1 as the eluent to obtain the target product 1i (62.6 mg, light yellow solid, yield 66%).

[0087] 1 H NMR (600MHz, CDCl3) δ8.66(s,1H),7.32(d,J=4.9Hz,1H),7.25(d,J=8.9Hz,1H),6. 99(t,J=4.1Hz,1H),6.95(s,1H),6.85(d,J=7.9Hz,1H),6.84(s,1H),3.87(s,3H); 13C NMR (151MHz, CDCl3) δ159.8,153.5(dd,J=300.6,293.4Hz),137.9,134.5(d,J=6.7Hz),127.2(t,J=5.0Hz),127.1,126.0(dd ,J=5.7,2.8Hz),121.8,119.7(d,J=1.8Hz),119.6(dd,J=5.0,2.7Hz),113.7,104.7,93.8,83.5(dd,J=24.9,23.4Hz),55.5; 19 F NMR(565MHz, CDCl3)δ-80.24(d,J=17.9Hz),-83.87(d,J=17.9Hz); HRMS(ESI)calcdfor C 16 H 10 F2N2NaOS[M+Na] + :339.0374;found:339.0363.

[0088] Example 10

[0089] The reaction equation is:

[0090]

[0091] A 25 mL round-bottom flask was charged with trifluoromethylindolemethanol 2j (119.2 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) in sequence. The mixture was stirred at 120 ° C for 8 hours (the reaction was monitored by thin plate chromatography until the reaction was complete). After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was concentrated by rotary evaporation to remove the solvent. Gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 15:1 as the eluent to obtain the target product 1j (77.7 mg, white solid, yield 67%).

[0092] 1 H NMR (600MHz, CDCl3) δ7.62 (t, J = 7.7Hz, 1H), 7.56–7.52 (m, 3H), 7.40–7.31 (m, 5H), 7. 12(d,J=8.9Hz,1H),6.81(dd,J=8.9,2.2Hz,1H),6.73(d,J=2.1Hz,1H),3.77(s,3H); 13C NMR (151MHz, CDCl3) δ 159.9, 154.0 (dd, J = 298.1, 294.0Hz), 139.1, 136.0, 132.6 (dd, J = 4.5, 3.2Hz), 130.0, 128.9 (t, J = 3.6Hz), 128 .6,127.9,126.6,122.2,121.4(dd,J=4.6,2.9Hz),119.9(d,J=2.5Hz),113.6,112.7,109.1,93.2,87.6(dd,J=22.0,20.1Hz),55.6; 19 F NMR(565MHz, CDCl3)δ-81.41(d,J=22.2Hz),-85.25(d,J=22.2Hz); HRMS(ESI)calcd for C 24 H 17 F2N2O[M+H] + :387.1303;found:387.1296.

[0093] Example 11

[0094] The reaction equation is:

[0095]

[0096] A 25 mL round-bottom flask was charged with trifluoromethylindolemethanol 2k (123.4 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL). The mixture was stirred at 120 ° C for 15 hours (the reaction was monitored by thin plate chromatography until the reaction was complete). After the reaction was completed, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 15:1 as the eluent to obtain the target product 1k (94.9 mg, white solid, yield 79%).

[0097] 1 H NMR (400MHz, CDCl3) δ7.38–7.29(m,8H),7.20(d,J=6.8Hz,2H),7.08(d,J=8.9Hz, 1H),6.76(dd,J=8.9,2.2Hz,1H),6.68(d,J=2.1Hz,2H),5.45(s,2H),3.78(s,3H); 13C NMR (151MHz, CDCl3) δ 159.6, 153.9 (dd, J = 297.7, 293.7Hz), 138.6, 135.7, 132.7 (dd, J = 4.4, 3.4Hz), 129.0, 128.8 (t, J = 3.6Hz), 128.5, 128 .1,127.8,126.7,122.4,120.1(d,J=2.5Hz),119.9(dd,J=4.5,3.1Hz),113.0,112.9,108.9,92.9,87.7(dd,J=22.0,20.1Hz),55.5,49.1; 19 F NMR(376MHz, CDCl3)δ-81.75(d,J=23.1Hz),-85.69(d,J=23.0Hz); HRMS(ESI)calcd for C 25 H 19 F2N2O[M+H] + :401.1460;found:401.1451.

[0098] Example 12

[0099] The reaction equation is:

[0100]

[0101] To a 25 mL round-bottom flask, trifluoromethylindolemethanol 2l (108.4 mg, 0.3 mmol), magnesium oxide (3 mmol), scandium trifluoromethanesulfonate (0.06 mmol), trimethylsilyl cyanide (0.9 mmol), and anhydrous chlorobenzene (3 mL) were added in sequence and stirred at 120 ° C for 15 hours (the reaction was tracked by thin plate chromatography until the reaction was complete). After the reaction was completed, it was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 15:1 as the eluent to obtain the target product 1l (86.2 mg, white solid, yield 82%).

[0102] 1H NMR (600MHz, CDCl3) δ7.38–7.29(m,5H),7.08(d,J=8.9Hz,1H),6.76(dd,J=8.9,2.2Hz,1H),6.68(d,J=2.1Hz,2H),6.01(ddt,J =17.0,10.3,5.1Hz,1H),5.29(dd,J=10.3,0.6Hz,1H),5.10(dd,J=17.1,0.5Hz,1H),4.87(dt,J=5.0,1.5Hz,2H),3.86(s,3H); 13 C NMR (151MHz, CDCl3) δ 159.5, 153.9 (dd, J = 297.7, 293.5Hz), 138.4, 132.8 (dd, J = 4.4, 3.3Hz), 131.6, 128.8 (t, J = 3.5Hz), 128.5, 127 .8,122.3,119.9(d,J=2.7Hz),119.7(dd,J=4.4,3.2Hz),118.0,113.0,112.7,108.6,92.6,87.7(dd,J=21.8,20.2Hz),55.5,47.7; 19 F NMR(565MHz, CDCl3)δ-81.96(d,J=23.3Hz),-85.82(d,J=23.2Hz); HRMS(ESI)calcdfor C 21 H 17 F2N2O[M+H] + :351.1303;found:351.1290.

[0103] Example 13

[0104] To verify the practicality of the present invention, we also conducted gram-scale scale-up experiments with good results. Furthermore, when the starting material, trifluoromethylindolemethanol 2a, was scaled up to 4 mmol, the reaction still produced the desired product in an ideal yield, fully demonstrating the practicality of the present invention.

[0105] The reaction equation is:

[0106]

[0107] To a 100 mL round-bottom flask, trifluoromethylindolemethanol 2a (1.165 g, 4 mmol), magnesium oxide (40 mmol), scandium trifluoromethanesulfonate (0.8 mmol), trimethylsilyl cyanide (12 mmol), and anhydrous chlorobenzene (40 mL) were added in sequence and stirred at 120°C for 12 h (the reaction was monitored by thin-layer chromatography until completion). After the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration. The filtrate was rotary concentrated to remove the solvent and gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 10:1 as the eluent to obtain the target product 1a (695 mg, 62% yield).

[0108] Example 14

[0109] The 2-cyanoindole-substituted geminal difluoroolefin compound prepared in Example 1-13 simultaneously has indole, vinyl difluoroethylene, and cyano groups, and can be synthesized into other compounds through functional group conversion reactions. It is an important organic synthesis intermediate.

[0110] Taking the 2-cyanoindole-substituted gem-difluoroolefin compound 1a prepared in Example 13 as an example, the 2-cyanoindole-substituted gem-difluoroolefin compound 1a can be reacted with p-methylthiophenol in the presence of tetramethylguanidine to synthesize a thioether through an addition reaction, as shown in the following reaction formula:

[0111]

[0112] To a 10 mL round-bottom flask, 2-cyanoindole-substituted gem-difluoroolefin compound 1a (0.2 mmol), p-methylthiophenol (0.4 mmol), and tetramethylguanidine (0.04 mmol) were added in sequence, followed by dichloroethane (1 mL). The mixture was stirred at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed by rotary concentrator. Gradient elution was performed using a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 10:1 as the eluent to obtain the target product 4 (56.6 mg, white solid, 70% yield).

[0113] 1 H NMR (600MHz, CDCl3) δ8.75(s,1H),7.83(d,J=8.3Hz,1H),7.58(d,J=7.6Hz,2H),7.44(d,J= 8.1Hz,2H),7.38–7.21(m,6H),7.16(d,J=7.9Hz,1H),5.17(d,J=16.3Hz,1H),2.35(s,3H); 13C NMR (151MHz, CDCl3) δ140.3, 137.0, 136.3, 135.4, 129.8, 129.6 (d, J = 284.2Hz), 129.5, 127.8, 126. 4,125.0,123.6,122.8,121.9(t,J=2.8Hz),121.8,113.7,112.0,106.6,52.0(t,J=24.8Hz),21.2; 19 F NMR(565MHz, CDCl3)δ-71.39(dd,J=206.2,16.6Hz),-72.01(dd,J=206.2,14.3Hz); HRMS(ESI)calcd for C 24 H 19 F2N2S[M+H] + :405.1232; found:405.1237.

[0114] The 2-cyanoindole-substituted gem-difluoroolefin compound 1a can also be converted into an amino compound by reduction with sodium borohydride in the presence of cobalt dichloride as the catalyst. The reaction formula is:

[0115]

[0116] To a 10 mL round-bottom flask, 2-cyanoindole-substituted gem-difluoroolefin compound 1a (0.2 mmol), cobalt dichloride (0.4 mmol), and di-tert-butyl dicarbonate (0.8 mmol) were added in sequence, followed by methanol (3 mL). Sodium borohydride was added portionwise over ten minutes under an ice bath. The mixture was allowed to react at room temperature. After completion of the reaction, the solvent was removed by rotary concentrator. Gradient elution was performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 25:1 to 10:1 as the eluent to obtain the desired product 5 (56.9 mg, white solid, 74% yield).

[0117] 1 H NMR (600MHz, CDCl3) δ9.22(s,1H),7.38–7.25(m,6H),7.18(d,J=7.5Hz,2H),7.03(t,J=7.5Hz,1H),4.89(s,1H),4.22(d,J=6.3Hz,2H),1.48(s,3H); 13C NMR(151MHz,CDCl3)δ157.5,153.8(dd,J=297.9,288.4Hz),135.6,134.4,128.6,128.4,127 .3,127.1,122.4,119.9,119.6,111.2,105.5,88.4(dd,J=20.7,17.3Hz),80.3,36.3,28.4, 19 F NMR(565MHz, CDCl3)δ-84.11(d,J=31.1Hz),-88.52(dd,J=31.1Hz); HRMS(ESI)calcd forC 22 H 23 F2N2O2[M+H] + :385.1722; found:385.1717.

[0118] 2-Cyanoindole-substituted geminal difluoroolefin compound 1a can also react with Grignard reagent to synthesize 3-fluoro-β-carboline compounds. The reaction formula is:

[0119]

[0120] A 25 mL round-bottom flask was charged with a 2-cyano-substituted gem-difluoroolefin (0.2 mmol). Anhydrous tetrahydrofuran (2 mL) was added under a nitrogen atmosphere. Allylmagnesium bromide (1 mmol / mL, 0.8 mL) was added dropwise at 0°C. After half an hour, the mixture was stirred at room temperature for 15 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride (5 mL). The mixture was extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in a rotary evaporator. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20 / 1 to 10 / 1, v / v) to obtain the desired product (36.9 mg, white solid, 61% yield).

[0121] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.61–7.45(m,7H),7.40(d,J=8.1Hz,1H),7.04–6.97(m,1H),6.22(ddt,J=1 6.7,10.0,6.6Hz,1H),5.39(dd,J=17.1,1.6Hz,1H),5.31(dd,J=10.0,1.4Hz,1H),3.92(dt,J=6.6,1.3Hz,2H); 13C NMR (101MHz, CDCl3) δ153.9 (d, J = 225.9Hz), 141.9, 138.1 (d, J = 15.5Hz), 134.2, 133.1 (d, J = 2.0Hz), 132.7 (d, J = 3.3Hz), 13 1.8(d,J=4.7Hz),130.0,128.7,128.6,128.4,123.5,121.5(d,J=5.7Hz),119.7,117.8,114.2(d,J=35.5Hz),111.6,39.1; 19 F NMR(376MHz, CDCl3)δ-87.23(s); HRMScalcd for C 22 H 20 FN2[M+H] + :331.1605;found:331.1599; 1 HRMS calcd for C 20 H 16 FN2[M+H] + :303.1292;found:303.1283.

[0122] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A 2-cyanoindole-substituted geminal difluoroolefin compound, characterized in that: The structural formula is shown in formula (1): （1）； Among them, R 1 、R 2 、R 3 are independent groups, R 1 is selected from one of hydrogen, halogen, hydroxy, cyano, methyl, ethyl or methoxy; R 2 R is selected from one of hydrogen, phenyl, halogen-substituted phenyl, C1-C6 branched alkyl, benzyl or allyl; 3 One selected from phenyl, halogen-substituted phenyl, naphthyl or thienyl.

2. A method for preparing a 2-cyanoindole-substituted gem-difluoroolefin compound according to claim 1, characterized in that: The following steps are involved: Using trifluoromethylindolemethanol compounds and trimethylsilyl cyanide as raw materials, a heating reaction is carried out in a solvent under the action of a Lewis acid catalyst and an inorganic base to obtain the 2-cyanoindole-substituted gem-difluoroolefin compound.

3. The method for preparing a 2-cyanoindole-substituted gem-difluoroolefin compound according to claim 2, wherein: The trifluoromethyl indole methanol compound is a compound represented by formula (2): （2）； The molar ratio of the trifluoromethylindole carbinol compound and trimethylsilyl cyanide is 1:2-3; wherein R 1 、R 2 、R 3 are independent groups, R 1 is selected from one of hydrogen, halogen, hydroxy, cyano, ester, methyl, ethyl or methoxy; R 2 R is selected from one of hydrogen, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, C1-C6 branched alkyl, benzyl or allyl; 3 One selected from phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl or thienyl.

4. The method for preparing a 2-cyanoindole-substituted gem-difluoroolefin compound according to claim 2, wherein: The Lewis acid catalyst is scandium trifluoromethanesulfonate, and the molar ratio of the trifluoromethylindolemethanol compound to scandium trifluoromethanesulfonate is 1:0.05 to 1:0.

2.

5. The method for preparing a 2-cyanoindole-substituted gem-difluoroolefin compound according to claim 2, wherein: The inorganic base is any one of calcium oxide, magnesium oxide, barium oxide, zinc oxide or aluminum oxide, and the molar ratio of the inorganic base to the trifluoromethylindole methanol compound is 10:

1.

6. The method for preparing a 2-cyanoindole-substituted gem-difluoroolefin compound according to claim 2, wherein: The solvent is any one of chlorobenzene, toluene, acetonitrile or dichloroethane, and the concentration of the trifluoromethyl indole methanol compound in the solvent is 0.05-0.5 mol / L; The heating reaction temperature is 80-140° C., and the heating reaction time is 6-24 hours.

7. Use of the 2-cyanoindole substituted gem-difluoroolefin compound according to claim 1 as an organic synthesis intermediate.

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