Process for the preparation of indole compounds based on n-arylsulfonyl ortho-alkynylanilines

Abstract

The application discloses a preparation method of an indole compound based on N-aromatic sulfonyl ortho-alkynyl aniline. Under the protection of inert gas, the compound (I), a base and an additive are mixed and reacted in an aprotic solvent, then saturated ammonium chloride solution is added for quenching, filtration, washing and vacuum evaporation, and column chromatography separation is performed to obtain the indole compound. When the additive is 18-crown-6, the mixing ratio of the compound (I), the base and the additive is 1:3:6, and the obtained indole compound is product (II). When the additive is N,N-diethylethylenediamine, the mixing ratio is 1:4:12, and the obtained indole compound is product (III). Ar and Ar are any one of a phenyl group, a substituted phenyl group, a naphthyl group and an aromatic heterocyclic group, and R is any one of a methyl group, an aryl group, a methoxy group and a halogen. 1 and Ar 2 The application realizes selective synthesis of two kinds of indole compounds by using simple and easily obtained N-aromatic sulfonyl ortho-alkynyl aniline as raw material under the condition of a base and different additives.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing indole compounds based on N-aromatic sulfonyl o-alkynyl aniline. Background Technology

[0002] 2-Diarylmethane- or benzyl-substituted indoles are the core structures found in many bioactive substances with anticancer, antibacterial, and antimalarial properties, and have wide applications in medicinal chemistry. 2-Diarylmethane-indoles can be prepared via nucleophilic addition (as shown in reaction a) of aryl Grignard reagents with indole esters, or via Friedel-Crafts alkylation (as shown in reaction b). However, both methods have limited substrate versatility due to the limitations of the reaction conditions. The traditional synthetic method for 2-benzyl-3-arylindoles is the Fischer indole synthesis (as shown in reaction c). However, this method requires the aryl group of 1,3-diarylacetone to have a symmetrical structure; otherwise, the product will be a mixture of two products, which greatly limits the diversity of 2-benzyl-3-arylindoles.

[0003] a) Nucleophilic addition

[0004]

[0005] b) Friedel-Crafts alkylation

[0006]

[0007] c) Fischer indole synthesis

[0008]

[0009] In summary, 2-diarylmethaneindole and 2-benzyl-3-arylindole compounds are skeletal structures with important physiological activities. However, the synthesis methods for these compounds have many problems, such as cumbersome operation, pre-preparation of complex substrates, poor substrate universality, and limited product variety. Summary of the Invention

[0010] To address the shortcomings of existing technologies, this invention provides a method for the highly selective preparation of 2-diarylmethaneindole and 2-benzyl-3-arylindole using N-aromaticsulfonyl-o-ynylaniline as a starting material. This method is highly atom-economical, has no transition metal catalysis, and is simple to operate.

[0011] The technical solution adopted in this invention is as follows:

[0012] A method for preparing indole compounds based on N-aromatic sulfonyl o-alkynyl aniline involves reacting the compound shown in formula (Ⅰ), a base, and an additive in an aprotic solvent under inert gas protection. After the reaction is complete, a saturated ammonium chloride solution is added to quench the reaction, followed by filtration, washing, and evaporation under reduced pressure. The indole compounds are then separated by column chromatography.

[0013] When the additive is 18-crown-6, the mixing ratio of the compound shown in formula (Ⅰ), the base and the additive is 1:3:6, and the resulting indole compound is product (Ⅱ).

[0014] When the additive is N,N-diethylethylenediamine, the mixing ratio of the compound shown in formula (Ⅰ), the base and the additive is 1:4:12, and the resulting indole compound is product (Ⅲ).

[0015]

[0016] Among them, Ar 1 and Ar 2 Each of the following groups is selected from phenyl, substituted phenyl, naphthyl, and aromatic heterocyclic groups, and R is selected from methyl, aryl, methoxy, and halogen groups.

[0017] Furthermore, the aprotic solvent is selected from any one of ethylene glycol dimethyl ether, tetrahydrofuran, cyclopentyl methyl ether, and dioxane, which helps to improve the yield.

[0018] Furthermore, the alkali is hexamethyldisilamide potassium, which helps to improve the yield.

[0019] Furthermore, silica gel powder is added for filtration after quenching.

[0020] Further, it was washed with ethyl acetate.

[0021] Furthermore, in column chromatography, the PE:EA ratio of 30:1 to 5:1 eluent results in the best separation effect.

[0022] Furthermore, the additive used to prepare product (II) is 6 equivalents of 18-crown-6, and the additive used to prepare product (III) is 12 equivalents of N,N-diethylethylenediamine.

[0023] Furthermore, the reaction temperature for preparing product (II) is room temperature, and the reaction time is 12–18 hours; the reaction temperature for preparing product (III) is 80–100℃, and the reaction time is 12–18 hours, so that the reaction is complete and sufficient, and the preparation efficiency of products (II) and (III) is improved.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] This invention enables the selective synthesis of 2-diarylmethaneindole and 2-benzyl-3-arylindole compounds under metal-free conditions and with readily available N-aromatic sulfonyl o-alkynyl aniline as a raw material, under alkaline conditions and with different additives. This makes the synthesis of these two types of indole compounds simpler and more efficient. Detailed Implementation

[0026] The present invention will be described in detail below with reference to preferred embodiments, and the objectives and effects of the present invention will become clearer. The present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0027] Example 1

[0028] Preparation and characterization of compound II-1:

[0029]

[0030] Under nitrogen protection, the compound shown in I-1 (34.7 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran solvent. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by silica gel column chromatography (PE:EA = 30:1) to give product II-1 in 78% yield. 1 H NMR (500MHz, CDCl3): δ7.68(s,1H),7.48(d,J=7.7Hz,1H),7.32–7.26(m,4H),7.25–7.21( m,2H),7.21–7.15(m,5H),7.11–7.07(m,1H),7.06–7.02(m,1H),6.07(s,1H),5.54(s,1H).

[0031] Example 2

[0032] Preparation and characterization of compound II-2:

[0033]

[0034] Under nitrogen protection, I-2 (41.5 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-2 in 48% yield. 1 H NMR (500MHz, DMSO–d6): δ11.07(s,1H),7.64(d,J=7.8Hz,1H),7.60–7.56(m,2H),7.53(d,J=7.6Hz,1H),7.43(d,J=7.9Hz,1H), 7.38–7.33(m,2H),7.31–7.26(m,2H),7.25–7.22(m,2H),7.05–7.00(m,1H),6.96–6.92(m,1H),5.93–5.88(m,1H),5.84(s,1H).

[0035] Example 3

[0036] Preparation and characterization of compound II-3:

[0037]

[0038] Under nitrogen protection, I-3 (43.1 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-3 in 75% yield. 1H NMR (500MHz, CDCl3): δ7.74(s,1H),7.50(d,J=7.8Hz,1H),7.34–7.26(m,3H),7.24– 7.17(m,5H),7.17–7.10(m,3H),7.08–7.04(m,1H),6.12–6.04(m,1H),5.57(s,1H).

[0039] Example 4

[0040] Preparation and characterization of compound II-4:

[0041]

[0042] Under nitrogen protection, I-4 (38.2 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-4 in 72% yield. 1 H NMR (500MHz, CDCl3): δ7.71 (s, 1H), 7.49 (d, J = 7.8Hz, 1H), 7.35–7.23 (m, 5H), 7.22– 7.15(m,3H),7.14–7.10(m,3H),7.08–7.04(m,1H),6.08–6.02(m,1H),5.52(s,1H).

[0043] Example 5

[0044] Preparation and characterization of compound II-5:

[0045]

[0046] Under nitrogen protection, I-5 (42.4 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-5 in 70% yield. 1 H NMR (500MHz, CDCl3): δ7.74(s,1H),7.57–7.49(m,5H),7.43–7.38(m,2H),7.34–7.29(m,3H),7.28–7.22( m,5H),7.22–7.19(m,1H),7.13–7.09(m,1H),7.06(td,J=7.5,1.1Hz,1H),6.15–6.09(m,1H),5.59(s,1H).

[0047] Example 6

[0048] Preparation and characterization of compound II-6:

[0049]

[0050] Under nitrogen protection, I-6 (39.8 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-6 in 94% yield. 1H NMR (500MHz, CDCl3): δ7.84–7.74(m,3H),7.73–7.69(m,1H),7.59(s,1H),7.51(d,J=7.8Hz,1H),7.47–7.41(m,2H),7.36(dd,J=8.5,1.8 Hz,1H),7.34–7.29(m,2H),7.29–7.23(m,3H),7.22–7.19(m,1H),7.14–7.10(m,1H),7.08–7.04(m,1H),6.18–6.09(m,1H),5.73(s,1H).

[0051] Example 7

[0052] Preparation and characterization of compound II-7:

[0053]

[0054] Under nitrogen protection, I-7 (39.8 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-7 in 78% yield. 1 H NMR (500MHz, CDCl3): δ7.99(d,J=8.4Hz,1H),7.84(d,J=7.7Hz,1H),7.76(d,J=8.2Hz,1H),7.67(s,1H),7.46(d,J=7.7Hz,1H),7.43–7.40(m,1H) ,7.39–7.35(m,1H),7.34–7.31(m,1H),7.29–7.21(m,3H),7.20–7.17(m, 2H),7.13(d,J=7.9Hz,1H),7.10–7.01(m,3H),6.28(s,1H),6.06(s,1H).

[0055] Example 8

[0056] Preparation and characterization of compound II-8:

[0057]

[0058] Under nitrogen protection, I-8 (34.8 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 5:1) to give product II-8 in 67% yield. 1 H NMR (500MHz, CDCl3): δ8.47(d,J=3.3Hz,2H),8.33(s,1H),7.56–7.48(m,2H),7.36–7.31(m,2H),7.30–7.27(m,1 H),7.26–7.23(m,2H),7.22–7.18(m,2H),7.15–7.11(m,1H),7.09–7.05(m,1H),6.07–6.05(m,1H),5.59(s,1H).

[0059] Example 9

[0060] Preparation and characterization of compound II-9:

[0061]

[0062] Under nitrogen protection, I-9 (35.4 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-9 in 41% yield; ¹H NMR (500MHz, DMSO–d6): δ 11.06 (s, 1H), 7.45–7.41 (m, 2H), 7.37–7.32 (m, 4H), 7.30–7.26 (m, 2H), 7.04–6.98 (m, 2H), 6.95–6.92 (m, 1H), 6.88–6.84 (m, 1H), 6.11–6.06 (m, 1H), 5.88 (s, 1H).

[0063] Example 10

[0064] Preparation and characterization of compound II-10:

[0065]

[0066] Under nitrogen protection, I-10 (36.5 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-10 in 32% yield. 1 H NMR (500MHz, CDCl3): δ7.76(s,1H),7.34–7.30(m,4H),7.28–7.24(m,2H),7.22–7.18( m,4H),7.12(td,J=9.3,3.4Hz,2H),6.88–6.83(m,1H),6.08–6.03(m,1H),5.57(s,1H).

[0067] Example 11

[0068] Preparation and characterization of compound II-11:

[0069]

[0070] Under nitrogen protection, I-11 (36.2 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-11 in 74% yield. 1H NMR (500MHz, CDCl3): δ7.54(s,1H),7.23–7.18(m,5H),7.18–7.14(m,2H),7.12–7.09(m,4H) ,7.00(d,J=8.2Hz,1H),6.85(dd,J=8.3,1.3Hz,1H),5.92(s,1H),5.46(s,1H),2.32(s,3H).

[0071] Example 12

[0072] Preparation and characterization of compound II-12:

[0073]

[0074] Under nitrogen protection, I-12 (42.4 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-12 in 67% yield. 1 H NMR (500MHz, DMSO–d6): δ11.05(s,1H),7.67–7.64(m,1H),7.60–7.56(m,2H),7.40– 7.35(m,2H),7.34–7.27(m,6H),7.25–7.19(m,7H),5.96–5.90(m,1H),5.64(s,1H).

[0075] Example 13

[0076] Preparation and characterization of compound II-13:

[0077]

[0078] Under nitrogen protection, I-13 (37.7 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-13 in 52% yield. 1 H NMR (500MHz, CDCl3): δ7.67(s,1H),7.32–7.28(m,4H),7.26–7.22(m,2H),7.21–7.18(m,4H),7.08(d,J =8.8Hz,1H),6.97(d,J=2.4Hz,1H),6.77(dd,J=8.8,2.5Hz,1H),6.02(s,1H),5.54(s,1H),3.79(s,3H).

[0079] Example 14

[0080] Preparation and characterization of compound II-14:

[0081]

[0082] Under nitrogen protection, I-14 (41.2 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-14 in 92% yield. 1 H NMR (500MHz, CDCl3): δ7.78–7.73(m,1H),7.74(d,J=8.5Hz,1H),7.70–7.65(m,2H),7.56(s,1H),7.48(d,J=7.7H z,1H),7.43–7.38(m,2H),7.33(dd,J=8.5,1.8Hz,1H),7.15–7.02(m,7H),6.10(s,1H),5.62(s,1H),2.31(s,3H).

[0083] Example 15

[0084] Preparation and characterization of compound II-15:

[0085]

[0086] Under nitrogen protection, I-15 (47.4 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was then separated by column chromatography (PE:EA = 30:1) to give product II-15 in 80% yield. ¹H NMR (500 MHz, CDCl₃): δ 7.83–7.74 (m, 3H), 7.73–7.69 (m, 1H), 7.62 (s, 1H), 7.57–7.50 (m, 5H), 7.46–7.37 (m, 5H), 7.33–7.28 (m, 3H), 7.19 (d, J = 8.1 Hz, 1H), 7.14–7.10 (m, 1H), 7.09–7.05 (m, 1H), 6.17 (s, 1H), 5.73 (s, 1H).

[0087] Example 16

[0088] Preparation and characterization of compound II-16:

[0089]

[0090] Under nitrogen protection, I-16 (42.8 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 20:1) to give product II-16 in 93% yield. 1H NMR (500MHz, CDCl3): δ7.82–7.72(m,3H),7.71–7.67(m,1H),7.56(s,1H),7.49(d,J=7.7Hz,1H),7.45–7.40(m,2H),7.34 (dd,J=8.5,1.8Hz,1H),7.19–7.08(m,4H),7.07–7.03(m,1H),6.85–6.81(m,2H),6.11(s,1H),5.65(s,1H),3.75(s,3H).

[0091] Example 17

[0092] Preparation and characterization of compound II-17:

[0093]

[0094] Under nitrogen protection, I-17 (41.6 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-17 in 87% yield. 1 H NMR (500MHz, CDCl3): δ7.81–7.73(m,2H),7.70–7.62(m,2H),7.53(s,1H),7.49(d,J=7.7Hz,1H),7.45–7.39(m,2H),7.30(d d,J=8.5,1.8Hz,1H),7.18–7.12(m,3H),7.12–7.08(m,1H),7.07–7.03(m,1H),6.99–6.93(m,2H),6.08(s,1H),5.63(s,1H).

[0095] Example 18

[0096] Preparation and characterization of compound II-18:

[0097]

[0098] Under nitrogen protection, I-18 (45.8 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 10:1) to give product II-18 in 95% yield. 1 H NMR (500MHz, CDCl3): δ7.79(s,1H),7.77–7.70(m,2H),7.68–7.63(m,1H),7.57(s,1H),7.48(d,J=7.6Hz,1H),7.41–7.36(m,2H),7 .33(dd,J=8.5,1.7Hz,1H),7.12–7.01(m,3H),6.41(d,J=2.2Hz,2H),6.36(t,J=2.2Hz,1H),6.15(s,1H),5.58(s,1H),3.63(s,6H).

[0099] Example 19

[0100] Preparation and characterization of compound II-19:

[0101]

[0102] Under nitrogen protection, I-19 (41.5 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-19 in 84% yield; ¹H NMR (500MHz, CDCl₃): δ 7.82–7.73 (m, 3H), 7.71–7.66 (m, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.8Hz, 1H), 7.46–7.40 (m, 2H), 7.35 (dd, J = 8.5, 1.8Hz, 1H), 7.27–7.21 (m, 1H), 7.19–7.16 (m, 1H), 7.13–7.02 (m, 5H), 6.16–6.10 (m, 1H), 6.02 (s, 1H).

[0103] Example 20

[0104] Preparation and characterization of compound II-20:

[0105]

[0106] Under nitrogen protection, I-20 (42.4 mg, 0.1 mmol, 1.0 equiv) and 18-crown-6 (158.4 mg, 0.6 mmol, 6.0 equiv) were dissolved in 1 mL of tetrahydrofuran. Hexamethyldisilamide potassium (1.0 mol / L inTHF, 0.3 mL, 0.3 mmol, 3.0 equiv) was added with stirring, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product II-20 in 72% yield; 1H NMR (500MHz, CDCl3): δ7.81–7.74(m,2H),7.74–7.65(m,2H),7.57(s,1H),7.49 (d,J=7.7Hz,1H),7.45–7.39(m,2H),7.36–7.31(m,3H),7.20–7.15(m,3H),7.1 2–7.08(m,1H),7.08–7.03(m,1H),6.68(dd,J=17.6,10.9Hz,1H),6.14–6.09(m ,1H),5.71(dd,J=17.6,0.7Hz,1H),5.67(s,1H),5.22(dd,J=10.9,0.6Hz,1H).

[0107] Example 21

[0108] Preparation and characterization of compound III-1:

[0109]

[0110] Under nitrogen protection, I-1 (34.7 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was then separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-1 in 80% yield. ¹H NMR (500MHz, CDCl₃): δ 7.71–7.65 (m, 1H), 7.61 (s, 1H), 7.55–7.49 (m, 2H), 7.44–7.38 (m, 2H), 7.32–7.22 (m, 3H), 7.22–7.16 (m, 1H), 7.15–7.06 (m, 5H), 4.14 (s, 2H).

[0111] Example 22

[0112] Preparation and characterization of compound III-2:

[0113]

[0114] Under nitrogen protection, I-2 (41.5 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was then separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-2 in 37% yield. ¹H NMR (500MHz, CDCl₃): δ 7.90 (s, ¹H), 7.83 (s, ¹H), 7.75–7.70 (m, ¹H), 7.66 (d, J = 7.8Hz, ¹H), 7.61–7.56 (m, 2H), 7.37–7.26 (m, 4H), 7.23–7.15 (m, 4H), 4.24 (s, 2H).

[0115] Example 23

[0116] Preparation and characterization of compound III-3:

[0117]

[0118] Under nitrogen protection, I-3 (43.1 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-3 in 63% yield. 1 H NMR (500MHz, CDCl3): δ7.86(s,1H),7.68(d,J=7.9Hz,1H),7.59–7.55(m,2H),7.39–7.26(m,6H),7.24–7.19(m,3H),7.19–7.14(m,1H),4.24(s,2H).

[0119] Example 24

[0120] Preparation and characterization of compound III-5:

[0121]

[0122] Under nitrogen protection, I-5 (42.4 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-5 in 87% yield. 1 H NMR (500MHz, CDCl3): δ7.82 (d, J=7.6Hz, 2H), 7.78–7.68 (m, 6H), 7.55–7.50 (m, 2H), 7. 43–7.36(m,3H),7.34–7.30(m,2H),7.29–7.26(m,2H),7.26–7.19(m,2H),4.32(s,2H).

[0123] Example 25

[0124] Preparation and characterization of compound III-6:

[0125]

[0126] Under nitrogen protection, I-6 (39.8 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-6 in 71% yield. 1 H NMR (500MHz, CDCl3): δ7.96(d,J=0.7Hz,1H),7.91(d,J=8.5Hz,1H),7.87–7.81(m,2H),7.78(s,1H),7.75–7.72(m,1H) ,7.70(dd,J=8.4,1.7Hz,1H),7.49–7.43(m,2H),7.32–7.27(m,2H),7.26–7.21(m,2H),7.20–7.11(m,4H),4.25(s,2H).

[0127] Example 26

[0128] Preparation and characterization of compound III-7:

[0129]

[0130] Under nitrogen protection, I-7 (39.8 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was then separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-7 in 71% yield. ¹H NMR (500MHz, CDCl₃): δ 7.93–7.79 (m, 4H), 7.54–7.50 (m, 2H), 7.48–7.43 (m, 1H), 7.37–7.32 (m, 1H), 7.25–7.08 (m, 8H), 7.02–6.98 (m, 1H), 4.02–3.94 (m, 2H).

[0131] Example 27

[0132] Preparation and characterization of compound III-8:

[0133]

[0134] Under nitrogen protection, I-8 (34.8 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 5:1) to give product III-8 in 78% yield. 1 H NMR (500MHz, DMSO–d6): δ11.36(s,1H),8.62(d,J=1.6Hz,1H),8.46(dd,J=4.7,1.3Hz,1H),7.85–7.77(m,1H),7.49(d,J =7.9Hz,1H),7.44(m,1H),7.37(d,J=8.0Hz,1H),7.28–7.22(m,2H),7.19–7.07(m,4H),7.04–6.99(m,1H),4.16(s,2H).

[0135] Example 28

[0136] Preparation and characterization of compound III-9:

[0137]

[0138] Under nitrogen protection, I-9 (35.4 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L in THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-9 in 47% yield. 1H NMR (500MHz, CDCl3): δ7.92–7.78(m,2H),7.39–7.32(m,3H),7.32–7.23(m,4H),7.22–7.17(m,4H),4.35(s,2H).

[0139] Example 29

[0140] Preparation and characterization of compound III-10:

[0141]

[0142] Under nitrogen protection, I-10 (36.5 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was then separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-10 in 83% yield. ¹H NMR (500MHz, CDCl₃): δ 7.79 (s, 1H), 7.59–7.53 (m, 2H), 7.52–7.48 (m, 2H), 7.41–7.33 (m, 4H), 7.33–7.27 (m, 1H), 7.25–7.20 (m, 2H), 7.17 (dd, J = 8.8, 4.3Hz, 1H), 6.93 (td, J = 9.0, 2.5Hz, 1H), 4.25 (s, 2H).

[0143] Example 30

[0144] Preparation and characterization of compound III-11:

[0145]

[0146] Under nitrogen protection, I-11 (36.2 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-11 in 88% yield. 1 H NMR (500MHz, CDCl3): δ7.73(s,1H),7.64–7.58(m,2H),7.56–7.49(m,3H),7.41–7.33(m,3H),7.32–7.28(m ,1H),7.24(d,J=7.0Hz,2H),7.19(d,J=8.2Hz,1H),7.05(dd,J=8.2,1.5Hz,1H),4.26(s,2H),2.49(s,3H).

[0147] Example 31

[0148] Preparation and characterization of compound III-12:

[0149]

[0150] Under nitrogen protection, I-12 (42.4 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-12 in 85% yield. 1 H NMR (500MHz, CDCl3): δ7.97(d,J=1.4Hz,1H),7.83(s,1H),7.70–7.64(m,4H),7.57– 7.52(m,2H),7.50–7.45(m,3H),7.43–7.30(m,6H),7.28–7.24(m,2H),4.29(s,2H).

[0151] Example 32

[0152] Preparation and characterization of compound III-13:

[0153]

[0154] Under nitrogen protection, I-13 (37.8 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was then separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-13 in 66% yield. ¹H NMR (500MHz, CDCl₃): δ 7.74 (s, 1H), 7.60–7.57 (m, 2H), 7.53–7.49 (m, 2H), 7.39–7.31 (m, 3H), 7.30–7.26 (m, 1H), 7.24–7.15 (m, 4H), 6.86 (dd, J = 8.7, 2.5Hz, 1H), 4.23 (s, 2H), 3.84 (s, 3H).

[0155] Example 33

[0156] Preparation and characterization of compound III-14:

[0157]

[0158] Under nitrogen protection, I-14 (41.2 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-14 in 74% yield; ¹H NMR (500MHz, CDCl₃): δ 8.03 (d, J = 0.7Hz, 1H), 7.98 (d, J = 8.5Hz, 1H), 7.94–7.89 (m, 2H), 7.86 (s, 1H), 7.82–7.79 (m, 1H), 7.78 (dd, J = 8.4, 1.7Hz, 1H), 7.56–7.50 (m, 2H), 7.33–7.29 (m, 1H), 7.25–7.22 (m, 1H), 7.21–7.14 (m, 5H), 4.29 (s, 2H), 2.39 (s, 3H).

[0159] Example 34

[0160] Preparation and characterization of compound III-15:

[0161]

[0162] Under nitrogen protection, I-15 (47.4 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-15 in 71% yield; ¹H NMR (500MHz, CDCl₃): δ 8.04 (d, J = 0.7Hz, 1H), 7.98 (d, J = 8.5Hz, 1H), 7.96–7.87 (m, 3H), 7.83–7.77 (m, 2H), 7.64–7.57 (m, 4H), 7.56–7.50 (m, 2H), 7.49–7.45 (m, 2H), 7.40–7.36 (m, 1H), 7.35–7.30 (m, 3H), 7.26–7.18 (m, 2H), 4.36 (s, 2H).

[0163] Example 35

[0164] Preparation and characterization of compound III-16:

[0165]

[0166] Under nitrogen protection, I-16 (42.8 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered after adding a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product Ⅲ-16 in 71% yield; ¹H NMR (500MHz, CDCl₃): δ 8.00 (d, J = 0.6Hz, 1H), 7.96 (d, J = 8.5Hz, 1H), 7.92–7.86 (m, 3H), 7.77 (d, J = 7.8Hz, 1H), 7.75 (dd, J = 8.4, 1.7Hz, 1H), 7.54–7.48 (m, 2H), 7.33–7.30 (m, 1H), 7.23–7.19 (m, 1H), 7.19–7.15 (m, 3H), 6.90–6.86 (m, 2H), 4.26 (s, 2H), 3.81 (s, 3H).

[0167] Example 36

[0168] Preparation and characterization of compound III-17:

[0169]

[0170] Under nitrogen protection, I-17 (41.6 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 30:1) to give product III-17 in 56% yield. 1H NMR (500MHz, CDCl3): δ7.99–7.95(m,2H),7.93–7.82(m,3H),7.78(d,J=7.8Hz,1H),7.73(dd,J=8.4,1.7Hz,1H ),7.55–7.49(m,2H),7.35–7.32(m,1H),7.26–7.22(m,1H),7.21–7.16(m,3H),7.05–7.00(m,2H),4.28(s,2H).

[0171] Example 37

[0172] Preparation and characterization of compound III-18:

[0173]

[0174] Under nitrogen protection, I-18 (45.8 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 20:1) to give product III-18 in 80% yield. 1 H NMR (500MHz, CDCl3): δ8.02(s,1H),8.01–7.89(m,4H),7.81–7.76(m,2H),7.56–7.50(m,2 H),7.33(d,J=7.9Hz,1H),7.25–7.17(m,2H),6.47–6.37(m,3H),4.25(s,2H),3.76(s,6H).

[0175] Example 38

[0176] Preparation and characterization of compound III-19:

[0177]

[0178] Under nitrogen protection, I-19 (41.6 mg, 0.1 mmol, 1.0 equiv) and N,N-diethylethylenediamine (139 mg, 1.2 mmol, 12.0 equiv) were dissolved in 2 mL of dry cyclopentyl methyl ether. Hexamethyldisilamide potassium (1.0 mol / L THF, 0.4 mL, 0.4 mmol, 4.0 equiv) was added with stirring, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, four drops of saturated ammonium chloride solution were added to quench the reaction. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 20:1) to give product III-19 in 60% yield. 1 H NMR (500MHz, CDCl3): δ8.27–8.18(m,2H),8.11–8.07(m,1H),8.03–7.92(m,3H),7.57–7.54(m,1H), 7.50–7.43(m,2H),7.39–7.36(m,1H),7.34–7.28(m,2H),7.24–7.16(m,3H),3.77(q,J=14.0Hz,2H).

[0179] Besides tetrahydrofuran and cyclopentyl methyl ether, aprotic solvents such as dioxane and ethylene glycol dimethyl ether can be used as alternative solvents, but their yields are slightly lower than those of tetrahydrofuran and cyclopentyl methyl ether.

[0180] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method of producing an indole-based compound based on N - an indole compound of the formula (I) ###0001### characterized in that The compound shown in formula (I), a base and an additive are mixed and reacted in aprotic solvent under inert gas protection, saturated ammonium chloride solution is added after the reaction is completed, filtered, washed and dried under reduced pressure, and column chromatography is used for separation to obtain an indole compound; When the additive is 18-crown-6, the mixing ratio of the compound shown in formula (I), the base and the additive is 1:3:6, and the obtained indole compound is product (II); When the additive is N,N When the additive is diethyl ethylenediamine, the mixing ratio of the compound of formula (I), the base and the additive is 1:4:12, and the obtained indole compound is product (III). ； wherein Ar 1 and Ar 2 are each independently any one of phenyl, substituted phenyl, naphthyl, arylheterocyclic group, and R is selected from any one of methyl, aryl, methoxy, halogen. The base is potassium hexamethyldisilazide.

2. The method for preparing an N-arylsulfonyl ortho-alkynylaniline-based indole derivative according to claim 1, characterized by, The aprotic solvent is selected from any one of ethylene glycol dimethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane.

3. The method for preparing an N-arylsulfonyl ortho-alkynylaniline-based indole derivative according to Claim 1, characterized by, Silica gel powder is added after quenching for filtration.

4. The method for preparing an N-arylsulfonyl ortho-alkynylaniline-based indole derivative according to Claim 1, characterized by, Washing is performed with ethyl acetate.

5. The method for preparing an N-arylsulfonyl ortho-alkynylaniline-based indole derivative according to Claim 1, characterized by, In column chromatography separation, PE:EA = 20:1 to 5:

1.

6. The method for preparing an N-arylsulfonyl ortho-alkynylaniline-based indole derivative according to Claim 1, characterized by, The additive for the preparation of product (II) was 6 equivalents of 18-crown-6 and the additive for the preparation of product (III) was 12 equivalents of N,N diethylethylenediamine.

7. The method of producing an N-arylsulfonyl ortho-alkynylaniline-based indole derivative according to Claim 1, characterized by, The reaction temperature for preparing product (II) is room temperature, and the reaction time is 12 to 18 hours; the reaction temperature for preparing product (III) is 80 to 100 DEG C, and the reaction time is 12 to 18 hours.

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