Preparation method of six-membered azaspiro dihydrobenzofuran compound

Abstract

The invention discloses a preparation method of a six-membered azaspiro dihydrobenzofuran compound. According to the method, a C2-alkyne benzofuran derivative is taken as a raw material, metal palladium is taken as a catalyst, and a corresponding product is generated through reaction in an organic solvent at the temperature of 40-120 DEG C under the combined action of a ligand and acetic anhydride. Under the action of palladium, a ligand, a solvent and acetic anhydride, alkyne triple bonds and indole double bonds are subjected to triple addition and bicyclic addition, and rapid construction of a six-membered azaspiro structure dihydrobenzofuran product is achieved. The reaction conditions are mild, the operation is simple and convenient, and the method has the advantages of easily available reaction raw materials, wide substrate applicability, excellent yield and enantioselectivity, easily separated target products and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of catalytic synthesis, and relates to a preparation method of a six-membered nitrogen heterospiro-structured dihydrobenzofuran derivative. More specifically, it relates to a method for synthesizing a six-membered nitrogen heterospiro-structured dihydrobenzofuran product through an intramolecular 1,6-enyne cycloisomerization reaction of a C2-alkynyl benzofuran derivative catalyzed by palladium. Background Art

[0002] The six-membered spirodihydrobenzofuran structure has been confirmed to exist in pharmaceuticals, pesticides, and biomolecular structures. For example, Griseofulvin containing a similar six-membered spirodihydrobenzofuran is an antifungal drug approved for the treatment of dermatophytosis caused by Microsporum and Trichophyton, and was initially isolated from Penicillium griseofulvum by Oxford and its partners (J. Org. Chem., 1981, 46, 22-27); or Filifolinol, which has been shown to have antiviral activity and has been successfully isolated in large quantities from Helioproteus filifolium Miers (Boraginaceae) (Phytochemistry, 1994, 36, 249-250). In addition, Spirodesertol A and Spirodesertol B also have a similar spiro structure and exhibit good antitumor properties against A-549, SMMC-7721, and MCF-7 cancer cell lines. Both of these compounds were isolated from the root extract of Salvia miltiorrhiza by the research group of Zheng, G. (Org. Chem. Front. 2020, 7, 3137-3145).

[0003]

[0004] Nitrogen heterocycles are very important compounds and are ubiquitous in bioactive molecules, natural products, and pharmaceutical preparations. The research group of Timothy J. Donohoe (Chem. Commun., 2020, 56, 3563-3566) reported a reaction in which iridium and a base act together to form a final nitrogen heterocyclic product through borrowing hydrogen from a primary amine to a diol intermolecularly. Although the above reaction can generate a nitrogen heterocyclic structure, since the diol is easily oxidized and unstable, and the intermolecular reaction is not easy to control the reaction site, the preparation method for synthesizing the nitrogen heterocyclic structure still needs to be improved.

[0005]

[0006] However, this patent can achieve a stable intramolecular cycloaddition reaction of raw materials to generate a nitrogen heterocycle, and does not require a base to participate in the reaction. In summary, the method for synthesizing the nitrogen heterocyclic structure in this patent has milder and more stable conditions. Summary of the Invention

[0007] In view of the above problems existing in the prior art, the object of the present invention is to provide a hexahydroazaspirocyclic structure-containing dihydrobenzofuran product and a preparation method thereof. Through the palladium-catalyzed intramolecular cyclization reaction of C2-alkynyl benzofuran derivatives, the hexahydroazaspirocyclic structure-containing dihydrobenzofuran derivatives are efficiently synthesized in one step.

[0008] To achieve the above object, the following technical solutions are proposed:

[0009] A preparation method of a hexahydroazaspirocyclic dihydrobenzofuran compound, using a C2-alkynyl benzofuran derivative as a raw material, reacting in acetic anhydride and an organic solvent at a temperature of 40-120 °C under the action of a palladium catalyst and a ligand. After the reaction is completed, a hexahydroazaspirocyclic structure-containing dihydrobenzofuran product is obtained through treatment. The reaction general formula is as follows:

[0010]

[0011] In the formula: R1 is selected from one of H, alkyl, alkoxy, trifluoromethyl or halogen; R2 is alkyl, benzyl or substituted phenyl; Ar' is substituted phenyl, naphthalene or thiophene.

[0012] Further, the alkyl in R1 and R2 is selected from C1-C10 straight-chain or branched-chain alkanes; the alkoxy in R1 is independently selected from C1-C10 straight-chain or branched-chain alkoxys; the halogen in R1 is selected from one of fluorine, chlorine or bromine; Ar' is a benzene ring mono-substituted or multi-substituted with alkyl, or is naphthalene or thiophene. The substituents on the benzene ring in Ar' are phenyl, trifluoromethyl, C1-C4 alkyl or H, and the substituents on the substituted phenyl in R2 are H, C1-C4 alkyl or C1-C4 alkoxy.

[0013] Further, R1 is selected from one of H, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl or halogen, and R2 is C1-C4 alkyl, benzyl or phenyl substituted with C1-C4 alkoxy.

[0014] Further, the solvent is selected from one or more of propionic acid, acetic acid, tetrahydrofuran, trifluoromethanesulfonic acid, acetic acid and tetrahydrofuran. The volume usage of the solvent and the molar ratio of the C2-alkynyl benzofuran derivative are 5-100:1, with the volume unit being milliliters and the molar unit being millimoles.

[0015] Further, the palladium catalyst is selected from any one of palladium acetate, palladium trifluoroacetate, tetrakis(acetonitrile)palladium tetrafluoroborate, palladium acetylacetonate, dichlorobis(triphenylphosphine)palladium, palladium dibromide. The molar amount of the palladium catalyst is 1-10% of the molar amount of the C2-alkynyl benzofuran derivative, preferably 4-6%.

[0016] Further, the ligand is selected from any one of triphenylphosphine, (rac)-BINAP, (6,6'-dimethoxybiphenyl-2,2'-yl) bis(diphenylphosphine), bipyridine, DPPF, and DPPA. The molar amount of the ligand is 1-10% of the molar amount of the C2-alkynyl benzofuran derivative, preferably 4-6%.

[0017] Further, the feeding ratio of acetic anhydride to the C2-alkynyl benzofuran derivative is 300-1000 μL: 1 mmol, preferably 500-600 μL: 1 mmol.

[0018] Further, the reaction temperature is 80-100 °C, and the reaction time is 4-24 h, preferably 15-18 h.

[0019] Further, the post-treatment step is as follows: after the reaction is completed, the reaction solution is quenched with saturated sodium bicarbonate aqueous solution at 0-5 °C, and then extracted and layered with ethyl acetate. The organic layer is concentrated by rotary evaporation to remove the solvent and then separated by column chromatography to obtain the target product; the mobile phase of the column chromatography is a mixture of petroleum ether and ethyl acetate with a volume ratio of 5-100:1.

[0020] Further, the general reaction formula for the synthesis of the raw material C2-alkynyl benzofuran derivative is as follows:

[0021]

[0022] Step 1: Using THF as the reaction solvent, compound S1 and LiAIH4 are stirred and reacted overnight at room temperature under N2, and then the reaction solution is post-treated to obtain compound S2;

[0023] Step 2: Compound S2 and MnO2 are added to anhydrous CH2Cl2 solvent according to a molar ratio of 1:5-8, and stirred and reacted at room temperature for 40-50 h under an air atmosphere. After the reaction is completed, the solid is removed by filtration and recovered, the filtrate is concentrated under reduced pressure, and purified by column chromatography. The elution solvent is ethyl acetate / petroleum ether with a volume ratio of 1:1-10 to obtain compound S3;

[0024] Step 3: Compound S3 and anhydrous MgSO4 are added to anhydrous CH2Cl2 solvent according to a molar ratio of 1:3-6, and under an N2 atmosphere, the substituted amino compound R 2 NH2, R 2The molar ratio of NH2 to compound S3 is 0.8 - 1.2:1. The resulting mixture is stirred and reacted at 40 - 60 °C for 10 - 15 h. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The obtained crude product is directly put into the next reaction. The crude product is added to anhydrous MeOH, and NaBH4 is added in batches. The resulting mixture is then stirred at room temperature for 1.5 - 3 h. After the reaction ends, MeOH is removed under reduced pressure and then extracted with ethyl acetate. The ethyl acetate phase is concentrated under reduced pressure, and the residue is separated and purified by column chromatography. The elution solvent is ethyl acetate / petroleum ether with a volume ratio of 1:1 - 5 to obtain compound S4;

[0025] Step 4: Using CH2Cl2 as the reaction solvent, compound S4 is stirred and reacted with DMAP, DCC, and substituted phenylpropiolic acid at room temperature. After the reaction is completed, the solid is removed by filtration and recovered. The filtrate is concentrated under reduced pressure and separated and purified by column chromatography. The elution solvent is ethyl acetate / petroleum ether with a volume ratio of 1:5 - 20 to obtain the C2-alkynyl benzofuran derivative shown in Formula I. Among them, the substituent R1 in the structures of compounds S1 - S4 and the substituent Ar' in the substituted propiolic acid are the same as those in Formula I and Formula II.

[0026] By adopting the above technology, compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] The present invention uses C2-alkynyl benzofuran as a raw material, and under the action of palladium catalysis and ligands, a cycloaddition reaction is carried out to efficiently synthesize a six-membered nitrogen heterospiro-structured dihydrobenzofuran derivative in one step. The present invention realizes the rapid construction of a six-membered nitrogen heterospiro-structured dihydrobenzofuran derivative through a three-plus-two cycloaddition of an alkyne and an alkene under the action of palladium, a ligand, acetic anhydride, and a solvent. This method is convenient to operate and has the advantages of easily available reaction raw materials, wide substrate applicability, and easy separation of the target product, and is suitable for popularization and application. Specific Embodiments

[0028] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0029] In the embodiments of the present invention, the synthesis of the raw material C2-alkynyl benzofuran derivative is as follows:

[0030]

[0031] Step 1:

[0032] Add LiAIH4 (60.0 mmol, 2.0 eq.) and THF (50 mL) to a dry flask. Under N2, slowly add a THF solution (10 mL) of compound S1 (30.0 mmol, 1.0 eq.) to the mixture and stir at 0 °C. Then stir the reaction mixture at room temperature overnight. Subsequently, quench the reaction system with 10% aqueous NaOH solution (15 ml), extract with ethyl acetate, and dry over Na2SO4. Concentrate the organic phase under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:5 v / v) to obtain compound S2.

[0033] Step 2:

[0034] In a dry flask, add compound S2 (18.0 mmol, 1.0 eq.), MnO2 (120 mmol) and anhydrous CH2Cl2 (30 mL) under an air atmosphere. Stir the resulting mixture at room temperature for 48 h. When the reaction is complete, remove the solid by filtration. Concentrate the filtrate under reduced pressure and purify by column chromatography, eluting with ethyl acetate / petroleum ether (1:15 v / v) to obtain compound S3.

[0035] Step 3:

[0036] In a dry flask, add compound S3 (10.0 mmol, 1.0 eq.), anhydrous MgSO4 (50.0 mmol) and anhydrous CH2Cl2 (25 mL) under a nitrogen atmosphere. Then add R 2 NH2 (9.0 mmol) via syringe. Stir the resulting mixture at 50 °C (oil bath) for 12 h. When the reaction is complete, concentrate the solution under reduced pressure. Then use the crude product directly without further purification.

[0037] Dissolve the above crude product in anhydrous MeOH (25 mL), then add NaBH4 (15.0 mmol) portionwise at 0 °C. Stir the resulting mixture at room temperature for 2 h. After the reaction is complete, remove MeOH under reduced pressure, extract with ethyl acetate, concentrate the ethyl acetate phase under reduced pressure, and purify the residue by column chromatography, eluting with ethyl acetate / petroleum ether (1:3 v / v) to obtain compound S4.

[0038] Step 4:

[0039] At 0 °C, 4-DMAP (0.6 mmol) and DCC (6.6 mmol) were added to a stirred solution of compound S4 (6.0 mmol, 1.0 eq.) in CH2Cl2 (15 ml). The mixture was stirred at 0 °C for 5 min, and then a solution of substituted phenylpropiolic acid (6.6 mmol) in CH2Cl2 (10 mL) was slowly added. The resulting mixture was stirred at room temperature for 10 h. After completion of the reaction, the solid was removed by filtration. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (volume ratio 1:10) to give C2-alkynyl benzofuran derivatives 1a - 14a.

[0040] The structural formulas of C2-alkynyl benzofuran derivatives 1a - 14a are shown in Table 1. The substituents R1 in the structures of the above compounds S1 - S4 and the substituent Ar' in the substituted phenylpropiolic acid are the same as those in the structures of derivatives 1a - 14a.

[0041] According to the above synthetic method of C2-alkynyl benzofuran derivatives, the reaction yields of derivatives 1a - 14a were as follows: the yield of 1a was 65%, the yield of 2a was 51%, the yield of 3a was 53%, the yield of 4a was 43%, the yield of 5a was 37%, the yield of 6a was 38%, the yield of 7a was 40%, the yield of 8a was 39%, the yield of 9a was 38%, the yield of 10a was 52%, the yield of 11a was 49%, the yield of 12a was 70%, the yield of 13a was 69%, and the yield of 14a was 75%. The NMR data of derivatives 1a - 14a are listed below.

[0042] Example 1

[0043] In a reaction tube, C2-alkynyl benzofuran derivative 1a (75.8 mg, 0.2 mmol), palladium(II) tetra(acetonitrile) tetrafluoroborate (0.36 mg, 5 mol%), and (rac)-BINAP (7.5 mg, 6 mol%) were added in sequence. Then acetic acid (1.6 mL) and tetrahydrofuran (0.4 mL) were added via syringe. The reaction mixture was reacted at 110 °C for 10 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 1 was separated by column chromatography (petroleum ether:ethyl acetate = 5:1, volume ratio) with a yield of 20%.

[0044] 1H NMR of compound 1:

[0045] 11H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.6 Hz, 1H), 7.31 - 7.27 (m, 5H), 7.25 - 7.19 (m, 4H), 7.17 - 7.14 (m, 2H), 6.99 - 6.95 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 5.46 (d, J = 1.2 Hz, 1H), 4.94 (d, J = 1.2 Hz, 1H), 4.85 (d, J = 14.8 Hz, 1H), 4.50 (d, J = 14.8 Hz, 1H), 3.72 (d, J = 13.2 Hz, 1H), 3.34 (d, J = 13.2 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): δ 163.6, 160.3, 151.1, 145.6, 136.2, 135.2, 131.2, 129.2, 128.6, 128.38, 128.35, 127.6, 127.0, 124.6, 124.5, 121.8, 121.7, 111.3, 104.3, 86.8, 55.9, 49.9. HRMS m / z (ESI+): Calculated for C 26 H 22 NO2 + ([M + H] + ): 380.1645, found 380.1647.

[0046] 1H NMR of C2-alkynyl benzofuran derivative 1a:

[0047] 1 1H NMR (500 MHz, CDCl3): δ 7.60 - 7.58 (m, 0.75H), 7.49 - 7.42 (m, 3.25H), 7.40 - 7.32 (m, 5.00H), 7.31 - 7.20 (m, 5.00H), 4.90 (s, 1.20H), 4.87 (s, 0.80H), 4.68 (s, 1.20H), 4.67 (s, 0.80H), 2.16 (s, 1.80H), 2.14 (s, 1.20H). 1313C NMR (125 MHz, CDCl3): δ 154.9, 154.8, 154.4, 154.3, 147.8, 147.2, 136.2, 136.1, 132.50, 132.45, 130.2, 129.6, 129.5, 128.9, 128.7, 128.62, 128.56, 128.4, 128.0, 127.74, 127.72, 124.7, 124.5, 122.5, 122.4, 120.5, 120.3, 119.50, 119.45, 114.5, 114.2, 111.2, 111.1, 91.5, 90.9, 81.7, 81.6, 52.2, 46.9, 43.2, 37.9, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 26 H 22 NO2 + ([M+H] + ): 380.1645, found 380.1650.

[0048] Example 2

[0049] In a reaction tube, C2-alkynyl benzofuran derivative 1a (75.8 mg, 0.2 mmol), palladium(II) tetra(acetonitrile) tetrafluoroborate (0.36 mg, 5 mol%), and (rac)-BINAP (7.5 mg, 6 mol%) were added successively. Then, acetic anhydride (100 μL), acetic acid (1.6 mL), and tetrahydrofuran (0.4 mL) were added via syringe. The reaction mixture was reacted at 110 °C for 10 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 1 was separated by column chromatography (petroleum ether:ethyl acetate = 5:1, v / v). The yield increased to 70% under the condition of adding a small amount of acetic anhydride, which was much higher than the yield of 20% without adding acetic anhydride.

[0050] 1H NMR of compound 1:

[0051] 11H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.6 Hz, 1H), 7.31 - 7.27 (m, 5H), 7.25 - 7.19 (m, 4H), 7.17 - 7.14 (m, 2H), 6.99 - 6.95 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 5.46 (d, J = 1.2 Hz, 1H), 4.94 (d, J = 1.2 Hz, 1H), 4.85 (d, J = 14.8 Hz, 1H), 4.50 (d, J = 14.8 Hz, 1H), 3.72 (d, J = 13.2 Hz, 1H), 3.34 (d, J = 13.2 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): δ 163.6, 160.3, 151.1, 145.6, 136.2, 135.2, 131.2, 129.2, 128.6, 128.38, 128.35, 127.6, 127.0, 124.6, 124.5, 121.8, 121.7, 111.3, 104.3, 86.8, 55.9, 49.9. HRMS m / z (ESI+): Calculated for C 26 H 22 NO2 + ([M + H] + ): 380.1645, found 380.1647.

[0052] 1H NMR of C2-alkynyl benzofuran derivative 1a:

[0053] 1 1H NMR (500 MHz, CDCl3): δ 7.60 - 7.58 (m, 0.75H), 7.49 - 7.42 (m, 3.25H), 7.40 - 7.32 (m, 5.00H), 7.31 - 7.20 (m, 5.00H), 4.90 (s, 1.20H), 4.87 (s, 0.80H), 4.68 (s, 1.20H), 4.67 (s, 0.80H), 2.16 (s, 1.80H), 2.14 (s, 1.20H). 1313C NMR(125 MHz, CDCl3): δ 154.9, 154.8, 154.4, 154.3, 147.8, 147.2, 136.2, 136.1, 132.50, 132.45, 130.2, 129.6, 129.5, 128.9, 128.7, 128.62, 128.56, 128.4, 128.0, 127.74, 127.72, 124.7, 124.5, 122.5, 122.4, 120.5, 120.3, 119.50, 119.45, 114.5, 114.2, 111.2, 111.1, 91.5, 90.9, 81.7, 81.6, 52.2, 46.9, 43.2, 37.9, 8.0, 7.9. HRMS m / z(ESI+): Calculated for C 26 H 22 NO2 + ([M + H] + ): 380.1645, found 380.1650.

[0054] Example 3

[0055] In a reaction tube, C2-alkynyl benzofuran derivative 2a (78.6 mg, 0.2 mmol), palladium acetate (2.2 mg, 5 mol%), (rac)-BINAP (7.5 mg, 6 mol%) were added in sequence. Then acetic anhydride (100 μL) and acetic acid (2.0 mL) were added via a syringe. The reaction mixture was reacted at 40 °C for 8 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 2 was separated by column chromatography (petroleum ether: ethyl acetate = 20:1, volume ratio) with a yield of 65%.

[0056] 1H NMR of compound 2:

[0057] 11H NMR (500 MHz, CDCl3): δ 7.39 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.30 - 7.28 (m, 4H), 7.26 - 7.22 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 7.00 - 6.95 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.37 (s, 1H), 5.45 (d, J = 1.0 Hz, 1H), 4.94 (d, J = 1.0 Hz, 1H), 4.84 (d, J = 14.5 Hz, 1H), 4.48 (d, J = 14.5 Hz, 1H), 3.71 (d, J = 13.0 Hz, 1H), 3.31 (d, J = 13.0 Hz, 1H), 2.26 (s, 3H). 13 13C NMR (125 MHz, CDCl3): δ 163.8, 160.3, 151.1, 145.7, 139.3, 136.3, 132.3, 131.1, 129.1, 128.6, 128.4, 127.6, 126.9, 124.6, 123.8, 121.8, 121.7, 111.3, 104.3, 86.9, 55.9, 49.9, 21.2. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1809.

[0058] 1H NMR of C2-alkynyl benzofuran derivative 2a:

[0059] 1 1H NMR (500 MHz, CDCl3): δ 7.49 - 7.42 (m, 2.80H), 7.39 - 7.35 (m, 2.80H), 7.34 - 7.24 (m, 4.30H), 7.23 - 7.20 (m, 1.10H), 7.15 (d, J = 8.0 Hz, 0.80H), 7.11 (d, J = 8.0 Hz, 1.20H), 4.89 (s, 1.20H), 4.87 (s, 0.80H), 4.68 (s, 1.20H), 4.67 (s, 0.80H), 2.35 (s, 1.20H), 2.32 (s, 1.80H), 2.16 (s, 1.80H), 2.15 (s, 1.20H). 1313C NMR (125 MHz, CDCl3): δ 155.1, 154.9, 154.4, 154.3, 147.9, 147.3, 140.8, 136.3, 136.2, 132.5, 132.4, 129.7, 129.5, 129.4, 129.3, 128.9, 128.8, 128.7, 128.4, 128.0, 127.8, 127.7, 124.7, 124.4, 122.5, 122.4, 119.49, 119.45, 117.4, 117.2, 114.5, 114.1, 111.2, 111.1, 91.9, 91.4, 81.4, 81.2, 52.2, 46.9, 43.2, 37.9, 21.71, 21.69, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1806.

[0060] Example 4:

[0061] Add C2-alkynyl benzofuran derivative 3a (87.0 mg, 0.2 mmol), palladium acetate (2.2 mg, 5 mol%), (rac)-BINAP (7.5 mg, 6 mol%) into the reaction tube in sequence. Then add acetic anhydride (100 μL) and tetrahydrofuran (2.0 mL) through a syringe. The reaction mixture is reacted at 120 °C for 24 h. The mixture is quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by a rotary evaporator, the target product compound 3 is separated by column chromatography (petroleum ether: ethyl acetate = 100:1, v / v) with a yield of 50%.

[0062] 13C NMR of compound 3:

[0063] 11H NMR (500 MHz, CDCl3): δ 7.43 - 7.41 (m, 1H), 7.30 - 7.27 (m, 4H), 7.26 - 7.22 (m, 4H), 7.12 - 7.10 (m, 2H), 7.00 - 6.97 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 5.47 (d, J = 1.0 Hz, 1H), 4.98 (d, J = 1.0 Hz, 1H), 4.85 (d, J = 15.0 Hz, 1H), 4.47 (d, J = 15.0 Hz, 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.29 (d, J = 13.0 Hz, 1H), 1.24 (s, 9H). 13 13C NMR (125 MHz, CDCl3): δ 163.8, 160.4, 152.5, 151.0, 145.5, 136.3, 131.9, 131.1, 128.6, 128.4, 127.6, 126.7, 125.4, 124.5, 123.5, 121.9, 121.8, 111.4, 104.3, 86.9, 55.7, 50.0, 34.7, 31.2. HRMS m / z (ESI+): Calculated for C 30 H 30 NO2 + ([M + H] + ): 436.2271, found 436.2274.

[0064] 1H NMR of C2-alkynyl benzofuran derivative 3a:

[0065] 1 1H NMR (500 MHz, CDCl3): δ 7.55 - 7.53 (m, 0.75H), 7.47 - 7.42 (m, 3.15H), 7.40 - 7.36 (m, 3.10H), 7.34 - 7.21 (m, 6.00H), 4.90 (s, 1.20H), 4.88 (s, 0.80H), 4.69 (s, 1.20H), 4.67 (s, 0.80H), 2.17 (s, 1.80H), 2.16 (s, 1.20H), 1.31 (s, 3.50H), 1.29 (s, 5.50H). 1313C NMR (125 MHz, CDCl3): δ 155.0, 154.9, 154.32, 154.25, 153.8, 147.9, 147.3, 136.3, 136.1, 132.34, 132.29, 129.6, 129.5, 128.8, 128.7, 128.4, 128.0, 127.8, 127.7, 125.63, 125.57, 124.6, 124.4, 122.5, 122.4, 119.5, 119.4, 117.4, 117.2, 114.4, 114.1, 111.2, 111.1, 91.9, 91.3, 81.3, 81.1, 52.1, 46.8, 43.2, 37.9, 35.01, 34.99, 31.09, 31.06, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 30 H 30 NO2 + ([M+H] + ): 436.2271, found 436.2276.

[0066] Example 5

[0067] In a reaction tube, C2-alkynyl benzofuran derivative 4a (81.8 mg, 0.2 mmol), palladium chloride (1.7 mg, 5 mol%), and DPPF (6.6 mg, 6 mol%) were added in sequence. Then, acetic anhydride (100 μL), acetic acid (1.6 mL), and tetrahydrofuran (0.4 mL) were added via syringe. The reaction mixture was reacted at 80 °C for 5 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 4 was separated by column chromatography (petroleum ether:ethyl acetate = 5:1, v / v) with a yield of 79%.

[0068] 13C NMR of compound 4:

[0069] 11H NMR (500 MHz, CDCl3): δ 7.41 - 7.39 (m, 1H), 7.31 - 7.27 (m, 4H), 7.25 - 7.22 (m, 2H), 7.12 - 7.09 (m, 2H), 6.97 (t, J = 7.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.74 - 6.71 (m, 2H), 6.35 (s, 1H), 5.46 (d, J = 1.0 Hz, 1H), 4.95 (d, J = 1.0 Hz, 1H), 4.84 (d, J = 15.0 Hz, 1H), 4.47 (d, J = 15.0 Hz, 1H), 3.72 - 3.70 (m, 4H), 3.30 (d, J = 13.0 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): δ 163.9, 160.5, 160.3, 150.7, 145.6, 136.3, 131.2, 128.6, 128.5, 128.4, 127.6, 127.3, 124.5, 122.9, 121.84, 121.77, 113.9, 111.3, 104.3, 86.9, 55.8, 55.2, 49.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO3 + ([M + H] + ): 410.1751, found 410.1755.

[0070] 1H NMR of C2-alkynyl benzofuran derivative 4a:

[0071] 1 1H NMR (500 MHz, CDCl3): δ 7.55 - 7.53 (m, 0.75H), 7.48 - 7.42 (m, 3.15H), 7.39 - 7.25 (m, 6.20H), 7.24 - 7.21 (m, 0.90H), 6.90 - 6.87 (m, 0.79H), 6.85 - 6.82 (m, 1.21H), 4.89 (s, 1.24H), 4.88 (s, 0.76H), 4.69 (s, 1.24H), 4.67 (s, 0.76H), 3.82 (s, 1.20H), 3.80 (s, 1.80H), 2.161 (s, 1.79H), 2.156 (s, 1.21H). 1313C NMR (125 MHz, CDCl3): δ 161.1, 155.2, 155.1, 154.3, 154.2, 147.9, 147.3, 136.3, 136.2, 134.30, 134.25, 129.6, 129.5, 128.8, 128.6, 128.4, 127.9, 127.7, 127.6, 124.6, 124.4, 122.5, 122.3, 119.43, 119.38, 114.4, 114.3, 114.2, 114.1, 112.3, 112.2, 111.2, 111.1, 92.0, 91.5, 81.0, 80.8, 55.39, 55.37, 52.1, 46.8, 43.2, 37.8, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO3 + ([M + H] + ): 410.1751, found 410.1752.

[0072] Example 6

[0073] In a reaction tube, C2-alkynyl benzofuran derivative 5a (91.0 mg, 0.2 mmol), palladium bromide (2.7 mg, 5 mol%), and DPPA (3.3 mg, 6 mol%) were added in sequence. Then, acetic anhydride (100 μL), acetic acid (1.6 mL), and tetrahydrofuran (0.4 mL) were added via a syringe. The reaction mixture was reacted at 40 °C for 14 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by a rotary evaporator, the target product compound 5 was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v / v), with a yield of 71%.

[0074] NMR of compound 5:

[0075] 11H NMR (500 MHz, CDCl3): δ 7.50 - 7.49 (m, 2H), 7.44 - 7.40 (m, 3H), 7.38 - 7.35 (m, 2H), 7.32 - 7.26 (m, 6H), 7.24 - 7.22 (m, 3H), 6.98 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 5.48 (d, J = 1.0 Hz, 1H), 4.98 (d, J = 1.0 Hz, 1H), 4.85 (d, J = 14.5 Hz, 1H), 4.49 (d, J = 14.5 Hz, 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.33 (d, J = 13.0 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): δ 163.6, 160.4, 150.7, 145.6, 141.9, 140.1, 136.3, 134.0, 131.3, 128.8, 128.7, 128.4, 127.67, 127.65, 127.5, 127.1, 127.0, 124.5, 124.3, 121.89, 121.85, 111.4, 104.5, 86.9, 55.9, 50.0. HRMS m / z (ESI+): Calculated for C 32 H 26 NO2 + ([M + H] + ): 456.1958, found 456.1961.

[0076] 1H NMR of C2-alkynyl benzofuran derivative 5a:

[0077] 1 1H NMR (500 MHz, CDCl3): δ 7.67 - 7.66 (m, 0.75H), 7.60 - 7.54 (m, 5.20H), 7.47 - 7.41 (m, 4.00H), 7.38 - 7.35 (m, 3.10H), 7.34 - 7.26 (m, 3.80H), 7.24 - 7.21 (m, 1.15H), 4.92 (s, 1.20H), 4.89 (s, 0.80H), 4.70 (s, 1.20H), 4.68 (s, 0.80H), 2.171 (s, 1.74H), 2.168 (s, 1.26H). 1313C NMR (125 MHz, CDCl3): δ 154.9, 154.8, 154.4, 154.3, 147.9, 147.2, 143.0, 139.88, 139.87, 136.2, 136.1, 133.0, 132.9, 129.6, 129.5, 128.97, 128.95, 128.9, 128.7, 128.4, 128.1, 128.0, 127.8, 127.7, 127.3, 127.2, 127.11, 127.10, 124.7, 124.4, 122.5, 122.4, 119.5, 119.4, 119.2, 119.1, 114.5, 114.1, 111.2, 111.1, 91.4, 90.9, 82.3, 82.1, 52.2, 46.9, 43.2, 37.9, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 32 H 26 NO2 + ([M + H] + ): 456.1958, found 456.1961.

[0078] Example 7

[0079] In a reaction tube, C2-alkynyl benzofuran derivative 6a (89.4 mg, 0.2 mmol), palladium acetate (2.2 mg, 5 mol%), and triphenylphosphine (3.1 mg, 6 mol%) were added successively. Then, acetic anhydride (100 μL), acetic acid (1.6 mL), and tetrahydrofuran (0.4 mL) were added via syringe. The reaction mixture was reacted at 100 °C for 24 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 6 was separated by column chromatography (petroleum ether:ethyl acetate = 30:1, v / v) with a yield of 30%.

[0080] 1H NMR of compound 6:

[0081] 11H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.34 - 7.26 (m, 8H), 6.99 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 5.47 (s, 1H), 4.93 (s, 1H), 4.85 (d, J = 15.0 Hz, 1H), 4.52 (d, J = 15.0 Hz, 1H), 3.73 (d, J = 13.5 Hz, 1H), 3.37 (d, J = 13.5 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): δ 163.1, 160.1, 149.6, 145.4, 138.9, 136.0, 131.4, 130.9 (q, J = 32.5 Hz), 128.6, 128.4, 127.7, 127.4, 126.0, 125.3 (q, J = 3.8 Hz), 124.3, 123.8 (q, J = 271.3 Hz), 122.0, 121.8, 111.3, 104.6, 86.6, 55.9, 50.0. 19 19F NMR (375 MHz, CDCl3) δ -62.8. HRMS m / z (ESI+): Calculated for C 27 H 21 F3NO2 + ([M + H] + ): 448.1519, found 448.1528.

[0082] 1H NMR of C2-alkynyl benzofuran derivative 6a:

[0083] 1 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 8.0 Hz, 0.75H), 7.64 (d, J = 8.0 Hz, 0.75H), 7.60 - 7.59 (s, 2.20H), 7.48 - 7.43 (m, 2.00H), 7.40 - 7.37 (m, 1.20H), 7.35 - 7.27 (m, 5.00H), 7.25 - 7.22 (m, 1.10H), 4.90 (s, 1.20H), 4.86 (s, 0.80), 4.70 (s, 1.20H), 4.67 (s, 0.80H), 2.17 (s, 1.80H), 2.15 (s, 1,20H). 1313C NMR (125 MHz, CDCl3): δ 154.34, 154.26, 154.2, 147.6, 146.8, 136.0, 135.8, 132.7, 132.6, 131.8 (q, J = 32.5 Hz), 129.6, 129.4, 128.9, 128.7, 128.4, 128.1, 127.8, 127.6, 125.54 (q, J = 3.8 Hz), 125.48 (q, J = 3.8 Hz), 124.8, 124.7, 124.5, 124.3, 124.1, 122.6, 122.5, 122.4, 119.50, 119.45, 114.6, 114.3, 111.2, 111.1, 89.4, 88.9, 83.4, 83.2, 52.2, 47.0, 43.2, 38.0, 8.0, 7.9. 19 19F NMR (375 MHz, CDCl3) δ -63.04, -63.07. HRMS m / z (ESI+): Calculated for C 27 H 21 F3NO2 + ([M + H] + ): 448.1519, found 448.1521.

[0084] Example 8

[0085] In a reaction tube, C2-alkynylbenzofuran derivative 7a (78.7 mg, 0.2 mmol), palladium acetate (2.2 mg, 5 mol%), (6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine) (7.0 mg, 6 mol%) were added successively. Then acetic anhydride (100 μL), acetic acid (1.6 mL) and tetrahydrofuran (0.4 mL) were added via syringe. The reaction mixture was reacted at 120 °C for 6 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 7 was separated by column chromatography (petroleum ether:ethyl acetate = 50:1) with a yield of 72%.

[0086] NMR of compound 7:

[0087] 11H NMR (500 MHz, CDCl3): δ 7.39 - 7.37 (m, 1H), 7.32 - 7.28 (m, 4H), 7.25 - 7.22 (m, 2H), 7.07 - 7.05 (m, 2H), 7.01 (s, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.92 - 6.89 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.37 (s, 1H), 5.45 (d, J = 1.0 Hz, 1H), 4.94 (d, J = 1.0 Hz, 1H), 4.84 (d, J = 14.5 Hz, 1H), 4.50 (d, J = 14.5 Hz, 1H), 3.72 (d, J = 13.0 Hz, 1H), 3.33 (d, J = 13.0 Hz, 1H), 2.20 (s, 3H). 13 13C NMR (125 MHz, CDCl3): δ 163.7, 160.3, 151.3, 145.7, 137.9, 136.2, 135.1, 131.1, 129.9, 128.6, 128.4, 128.1, 127.8, 127.6, 124.6, 124.2, 124.0, 121.67, 121.65, 111.2, 104.2, 86.8, 55.9, 49.9, 21.3. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1808.

[0088] 1H NMR of C2-alkynyl benzofuran derivative 7a:

[0089] 1 1H NMR (500 MHz, CDCl3): δ 7.46 - 7.34 (m, 5.30H), 7.32 - 7.29 (m, 3.20H), 7.28 - 7.19 (m, 4.50H), 4.90 (s, 1.20H), 4.87 (s, 0.80H), 4.68 (s, 1.20H), 4.67 (s, 0.80H), 2.32 (s, 1.20H), 2.29 (s, 1.80H), 2.16 (s, 1.80H), 2.15 (s, 1.20H). 1313C NMR (125 MHz, CDCl3): δ 155.0, 154.8, 154.4, 154.3, 147.9, 147.2, 138.40, 138.35, 136.2, 136.1, 132.98, 132.96, 131.2, 129.64, 129.58, 129.5, 128.9, 128.8, 128.7, 128.51, 128.46, 128.4, 128.3, 128.0, 127.8, 127.7, 124.7, 124.4, 122.5, 122.4, 120.3, 120.1, 119.49, 119.45, 114.5, 114.2, 111.2, 111.1, 91.8, 91.3, 81.4, 81.3, 52.2, 46.9, 43.2, 37.9, 21.24, 21.19, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M+H] + ): 394.1802, found 394.1806.

[0090] Example 9

[0091] In a reaction tube, C2-alkynyl benzofuran derivative 8a (78.7 mg, 0.2 mmol), palladium trifluoroacetate (3.3 mg, 5 mol%), (rac)-BINAP (7.5 mg, 6 mol%) were added in sequence. Then acetic anhydride (100 μL) and acetic acid (2.0 mL) were added via a syringe. The reaction mixture was reacted at 120 °C for 18 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by a rotary evaporator, the target product compound 8 was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, volume ratio) with a yield of 25%.

[0092] NMR of compound 8:

[0093] 11H NMR (500 MHz, CDCl3): δ 7.33 - 7.32 (m, 4H), 7.27 - 7.23 (m, 2H), 7.14 - 7.11 (m, 2H), 7.10 - 7.06 (m, 1H), 6.94 - 6.89 (m, 2H), 6.83 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 5.43 (d, J = 0.5 Hz, 1H), 5.01 (d, J = 0.5 Hz, 1H), 4.84 (d, J = 14.5 Hz, 1H), 4.57 (d, J = 14.5 Hz, 1H), 3.77 (d, J = 13.0 Hz, 1H), 3.46 (d, J = 13.0 Hz, 1H), 2.34 (s, 3H). 13 13C NMR (125 MHz, CDCl3): δ 163.5, 160.4, 150.9, 145.8, 136.2, 135.5, 135.1, 130.9, 130.3, 128.6, 128.5, 128.1, 127.9, 127.6, 126.4, 125.1, 124.7, 121.4, 121.3, 110.7, 103.7, 87.2, 55.8, 50.1, 20.7. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1806.

[0094] 1H NMR of C2-alkynyl benzofuran derivative 8a:

[0095] 1 1H NMR (500 MHz, CDCl3): δ 7.58 - 7.56 (m, 0.35H), 7.48 - 7.45 (m, 1.50H), 7.44 - 7.41 (m, 1.00H), 7.38 - 7.34 (m, 2.60H), 7.32 - 7.27 (m, 3.95H), 7.25 - 7.21 (m, 1.90H), 7.19 - 7.12 (m, 1.70H), 4.93 (s, 1.20H), 4.90 (s, 0.80H), 4.69 (s, 1.20H), 4.65 (s, 0.80H), 2.50 (s, 1.14H), 2.36 (s, 1.86H), 2.18 (s, 1.86H), 2.14 (s, 1.14H). 1313C NMR (125 MHz, CDCl3): δ 155.1, 154.9, 154.4, 154.3, 147.9, 147.0, 141.54, 141.51, 136.3, 136.0, 133.1, 133.0, 130.21, 130.18, 129.8, 129.7, 129.6, 129.5, 128.9, 128.7, 128.4, 128.0, 127.7, 127.6, 125.83, 125.80, 124.7, 124.4, 122.5, 122.4, 120.4, 120.2, 119.5, 119.4, 114.5, 114.2, 111.2, 111.1, 90.6, 90.0, 85.4, 85.3, 52.1, 46.8, 43.2, 38.0, 20.8, 20.7, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1805.

[0096] Example 10

[0097] In a reaction tube, C2-alkynyl benzofuran derivative 9a (85.8 mg, 0.2 mmol), palladium acetylacetonate (3.0 mg, 5 mol%), (rac)-BINAP (7.5 mg, 6 mol%) were added successively. Then acetic anhydride (100 μL) and trifluorobenzenesulfonic acid (2.0 mL) were added via syringe. The reaction mixture was reacted at 80 °C for 18 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 9 was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v / v) with a yield of 38%.

[0098] 13C NMR of compound 9:

[0099] 11H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 7.5 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.44 - 7.38 (m, 3H), 7.32 - 7.31 (m, 4H), 7.27 - 7.21 (m, 3H), 7.00 - 6.96 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 5.45 (d, J = 1.0 Hz, 1H), 4.96 (d, J = 1.0 Hz, 1H), 4.87 (d, J = 15.0 Hz, 1H), 4.53 (d, J = 15.0 Hz, 1H), 3.76 (d, J = 13.5 Hz, 1H), 3.38 (d, J = 13.5 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): δ 163.6, 160.4, 151.1, 145.7, 136.3, 133.4, 132.9, 132.8, 131.3, 128.6, 128.5, 128.4, 128.0, 127.63, 127.56, 126.9, 126.8, 126.4, 124.9, 124.7, 124.4, 121.81, 121.77, 111.3, 104.5, 86.9, 56.1, 50.0. HRMS m / z (ESI+): Calculated for C 30 H 24 NO2 + ([M + H] + ): 430.1802, found 430.1804.

[0100] 1H NMR of C2-alkynyl benzofuran derivative 9a:

[0101] 1 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 0.40H), 8.03 (s, 0.60H), 7.83 - 7.76 (m, 3.00H), 7.60 (d, J = 1.5 Hz, 0.20H), 7.58 (d, J = 1.5 Hz, 0.20H), 7.54 - 7.48 (m, 3.10H), 7.46 - 7.43 (m, 1.60H), 7.39 - 7.38 (m, 2.30H), 7.34 - 7.31 (m, 2.00H), 7.30 - 7.28 (m, 1.30H), 7.27 - 7.24 (m, 0.80H), 7.23 - 7.21 (s, 0.50H), 4.95 (s, 1.20H), 4.92 (s, 0.80H), 4.71 (s, 1.20H), 4.70 (s, 0.80H), 2.18 (s, 1.80H), 2.17 (s, 1.20H).13 C NMR (125 MHz, CDCl3): δ 154.9, 154.8, 154.4, 154.3, 147.9, 147.2, 136.2, 136.1, 133.64, 133.62, 133.43, 133.36, 132.71, 132.65, 129.7, 129.5, 128.9, 128.7, 128.4, 128.3, 128.10, 128.07, 128.0, 127.89, 127.85, 127.8, 127.7, 127.0, 126.9, 124.7, 124.4, 122.5, 122.4, 119.5, 119.4, 117.7, 117.5, 114.5, 114.2, 111.3, 111.1, 91.9, 91.4, 81.9, 81.7, 52.2, 46.9, 43.2, 38.0, 8.1, 7.9. HRMS m / z (ESI+): Calculated for C 30 H 24 NO2 + ([M + H] + ): 430.1802, found 430.1805.

[0102] Example 11

[0103] In a reaction tube, 10a of C2-alkynyl benzofuran derivative (77.1 mg, 0.2 mmol), palladium acetate (2.2 mg, 5 mol%), 1,1'-bis(diphenylphosphino)ferrocene (DPPF) (6.6 mg, 6 mol%) were added in sequence. Then acetic anhydride (100 μL) and propionic acid (2.0 mL) were added via a syringe. The reaction mixture was reacted at 90 °C for 20 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by a rotary evaporator, the target product compound 10 was separated by column chromatography (petroleum ether:ethyl acetate = 5:1, volume ratio) with a yield of 68%.

[0104] 1H NMR of compound 10:

[0105] 11H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.6 Hz, 1H), 7.31 - 7.25 (m, 7H), 7.05 - 7.03 (m, 1H), 7.00 - 6.97 (m, 1H), 6.92 - 6.88 (m, 2H), 6.53 (s, 1H), 5.48 (d, J = 1.2 Hz, 1H), 5.04 (d, J = 1.2 Hz, 1H), 4.84 (d, J = 14.8 Hz, 1H), 4.46 (d, J = 14.4 Hz, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.31 (d, J = 12.8 Hz, 1H). 13 13C NMR (125 MHz, CDCl3): 163.9, 160.3, 145.1, 144.5, 136.5, 136.2, 131.1, 128.6, 128.40, 128.38, 128.1, 127.7, 127.6, 124.3, 122.0, 121.9, 120.9, 111.3, 104.6, 86.9, 55.1, 50.0. HRMS m / z (ESI+): Calculated for C 24 H 20 NO2S + ([M + H] + ): 386.1209, found 386.1212.

[0106] 1H NMR of C2-alkynyl benzofuran derivative 10a:

[0107] 1 1H NMR (500 MHz, CDCl3): δ 7.48 - 7.41 (m, 2.70H), 7.39 - 7.25 (m, 7.30H), 7.24 - 7.21 (m, 1.10H), 7.05 - 7.03 (m, 0.35H), 7.01 - 6.99 (m, 0.55H), 4.85 (s, 1.15H), 4.83 (s, 0.85H), 4.684 (s, 1.15H), 4.679 (s, 0.85H), 2.17 (s, 1.18H), 2.16 (s, 1.82H). 1313C NMR (125 MHz, CDCl3): δ 154.7, 154.6, 154.33, 154.26, 147.7, 147.2, 136.1, 136.0, 135.4, 135.3, 130.31, 130.25, 129.6, 129.4, 128.9, 128.7, 128.4, 128.0, 127.8, 127.7, 127.5, 127.4, 124.7, 124.4, 122.5, 122.4, 120.2, 120.0, 119.5, 119.4, 114.5, 114.2, 111.2, 111.1, 85.7, 85.6, 85.2, 84.8, 52.1, 46.9, 43.1, 37.9, 8.1, 7.9. HRMS m / z (ESI+): Calculated for C 24 H 20 NO2S + ([M+H] + ): 386.1209, found 386.1208.

[0108] Example 12

[0109] In a reaction tube, C2-alkynyl benzofuran derivative 11a (78.7 mg, 0.2 mmol), palladium (II) chloride triphenylphosphine complex (7.0 mg, 5 mol%), (rac)-BINAP (7.5 mg, 6 mol%) were added in sequence. Then acetic anhydride (100 μL) and propionic acid (2.0 mL) were added via a syringe. The reaction mixture was reacted at 110 °C for 10 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 11 was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v / v) with a yield of 71%.

[0110] 1H NMR of compound 11:

[0111] 11H NMR (500 MHz, CDCl3) δ 7.31 - 7.28 (m, 4H), 7.26 - 7.24 (m, 2H), 7.21 - 7.18 (m, 3H), 7.16 - 7.14 (m, 2H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.38 (s, 1H), 5.41 (d, J = 1.0 Hz, 1H), 4.90 (d, J = 1.0 Hz, 1H), 4.84 (d, J = 15.0 Hz, 1H), 4.48 (d, J = 15.0 Hz, 1H), 3.70 (d, J = 13.0 Hz, 1H), 3.32 (d, J = 13.0 Hz, 1H), 2.30 (s, 3H). 13 13C NMR (125 MHz, CDCl3): δ 163.7, 158.4, 151.2, 145.9, 136.3, 135.3, 132.0, 131.2, 129.2, 128.6, 128.37, 128.36, 127.6, 127.0, 124.5, 124.4, 122.0, 110.9, 103.9, 86.9, 56.0, 50.0, 20.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1806.

[0112] 1H NMR of C2-alkynyl benzofuran derivative 11a:

[0113] 1 1H NMR (500 MHz, CDCl3): δ 7.60 - 7.58 (m, 1.00H), 7.50 - 7.48 (m, 1.21H), 7.43 - 7.27 (m, 9.00H), 7.24 (s, 1.00H), 7.09 (td, J = 8.5, 1.5 Hz, 1.00H), 4.88 (s, 1.18H), 4.85 (s, 0.82H), 4.67 (s, 1.13H), 4.66 (s, 0.87H), 2.45 (s, 1.23H), 2.44 (s, 1.77H), 2.13 (s, 1.76H), 2.12 (s, 1.24H). 1313C NMR (125 MHz, CDCl3): δ 154.9, 154.8, 152.8, 152.7, 147.9, 147.3, 136.2, 136.1, 132.5, 132.4, 132.0, 131.8, 130.2, 129.7, 129.5, 128.9, 128.7, 128.6, 128.5, 128.4, 128.0, 127.8, 127.7, 125.9, 125.7, 120.5, 120.4, 119.34, 119.28, 114.2, 113.9, 110.7, 110.6, 91.4, 90.9, 81.7, 81.6, 52.1, 46.8, 43.2, 37.9, 21.4, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1805.

[0114] Example 13

[0115] In a reaction tube, C2-alkynyl benzofuran derivative 12a (78.6 mg, 0.2 mmol), palladium bromide (2.7 mg, 5 mol%), diphenylphosphoryl azide (DPPA) (3.3 mg, 6 mol%) were added successively. Then acetic anhydride (100 μL), acetic acid (1.6 mL) and tetrahydrofuran (0.4 mL) were added via syringe. The reaction mixture was reacted at 100 °C for 10 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 12 was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v / v) with a yield of 68%.

[0116] NMR of compound 12:

[0117] 11H NMR (500 MHz, CDCl3): δ 7.31 - 7.27 (m, 5H), 7.25 - 7.23 (m, 2H), 7.21 - 7.18 (m, 2H), 7.17 - 7.14 (m, 2H), 6.77 (d, J = 3.0 Hz, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 5.37 (d, J = 1.0 Hz, 1H), 4.86 (d, J = 1.0 Hz, 1H), 4.82 (d, J = 15.0 Hz, 1H), 4.50 (d, J = 15.0 Hz, 1H), 3.70 (d, J = 13.0 Hz, 1H), 3.32 (d, J = 13.0 Hz, 1H), 2.32 (s, 3H). 13 13C NMR (125 MHz, CDCl3): δ 163.7, 160.6, 151.2, 145.6, 142.0, 136.2, 135.3, 129.1, 128.6, 128.38, 128.35, 127.6, 127.0, 124.4, 122.8, 121.9, 121.4, 111.7, 103.2, 87.0, 56.0, 50.0, 21.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1804.

[0118] 1H NMR of C2-alkynyl benzofuran derivative 12a:

[0119] 1 1H NMR (500 MHz, CDCl3): δ 7.61 - 7.58 (m, 0.75H), 7.50 - 7.48 (m, 1.15H), 7.44 - 7.28 (m, 8.80H), 7.25 - 7.24 (m, 1.30H), 7.06 (t, J = 8.0 Hz, 1.00H), 4.88 (s, 1.17H), 4.85 (s, 0.83H), 4.67 (s, 1.16H), 4.66 (s, 0.84H), 2.47 (s, 3.00H), 2.131 (s, 1.71H), 2.128 (s, 1.29H). 1313C NMR (125 MHz, CDCl3): δ 154.9, 154.8, 154.73, 154.69, 147.2, 146.5, 136.2, 136.1, 135.0, 134.7, 132.5, 132.4, 130.2, 128.8, 128.7, 128.6, 128.5, 128.4, 128.0, 127.74, 127.67, 127.2, 127.0, 123.9, 123.8, 120.5, 120.4, 119.0, 118.9, 114.4, 114.0, 111.5, 111.4, 91.4, 90.8, 81.7, 81.6, 52.0, 46.8, 43.2, 37.9, 21.7, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO2 + ([M + H] + ): 394.1802, found 394.1804.

[0120] Example 14

[0121] In a reaction tube, C2-alkynyl benzofuran derivative 13a (81.8 mg, 0.2 mmol), palladium bromide (2.7 mg, 5 mol%), and bipyridine (1.9 mg, 6 mol%) were added in sequence. Then, acetic anhydride (100 μL) and tetrahydrofuran (2.0 mL) were added via syringe. The reaction mixture was reacted at 110 °C for 15 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 13 was separated by column chromatography (petroleum ether:ethyl acetate = 5:1, v / v) with a yield of 59%.

[0122] NMR of compound 13:

[0123] 1 1H NMR (500 MHz, CDCl3): δ 7.40 - 7.38 (m, 1H), 7.27 - 7.23 (m, 3H), 7.21 - 7.18 (m, 3H), 7.15 - 7.14 (m, 2H), 6.97 (td, J = 7.5, 1.0 Hz, 1H), 6.84 - 6.82 (m, 3H), 6.37 (s, 1H), 5.45 (d, J = 1.5 Hz, 1H), 4.93 (d, J = 1.5 Hz, 1H), 4.75 (d, J = 14.5 Hz, 1H), 4.46 (d, J = 14.5 Hz, 1H), 3.77 (s, 3H), 3.70 (d, J = 13.0 Hz, 1H), 3.31 (d, J = 13.0 Hz, 1H).13 C NMR (125 MHz, CDCl3): δ 163.5, 160.4, 159.1, 151.0, 145.7, 135.3, 131.2, 129.8, 129.1, 128.3, 127.0, 124.62, 124.56, 121.8, 121.7, 114.0, 111.2, 104.3, 86.9, 55.8, 55.3, 49.4. HRMS m / z (ESI+): Calculated for C 27 H 24 NO3 + ([M + H] + ): 410.1751, found 410.1754.

[0124] 13C NMR of C2-alkynyl benzofuran derivative 13a:

[0125] 1 H NMR (500 MHz, CDCl3): δ 7.59 - 7.57 (m, 0.78H), 7.52 - 7.50 (m, 1.22H), 7.47 - 7.31 (m, 5.00H), 7.30 - 7.25 (m, 2.30H), 7.24 - 7.21 (m, 1.70H), 6.91 - 6.88 (m, 1.20H), 6.86 - 6.83 (m, 0.80H), 4.86 (s, 0.80H), 4.84 (s, 1.20H), 4.67 (s, 1.20H), 4.61 (s, 0.80H), 3.79 (s, 1.80H), 3.78 (s, 1.20H), 2.182 (s, 1.80H), 2.175 (s, 1.20H). 13 C NMR (125 MHz, CDCl3): δ 159.4, 159.2, 154.8, 154.6, 154.32, 154.25, 148.0, 147.3, 132.5, 132.4, 130.17, 130.16, 129.8, 129.7, 129.5, 129.1, 128.58, 128.55, 128.3, 128.0, 124.6, 124.4, 122.5, 122.4, 120.5, 120.4, 119.5, 119.4, 114.4, 114.2, 114.04, 114.02, 111.2, 111.1, 91.3, 90.8, 81.8, 81.6, 55.34, 55.29, 51.6, 46.3, 43.0, 37.6, 8.1, 7.9. HRMS m / z (ESI+): Calculated for C 27 H 24 NO3+ ([M+H] + ): 410.1751, found 410.1754.

[0126] Example 15

[0127] In a reaction tube, C2-alkynyl benzofuran derivative 14a (66.2 mg, 0.2 mmol), palladium acetate (2.2 mg, 5 mol%), (rac)-BINAP (7.5 mg, 6 mol%) were added in sequence. Then acetic anhydride (100 μL), acetic acid (1.6 mL) and tetrahydrofuran (0.4 mL) were added via a syringe. The reaction mixture was reacted at 100 °C for 18 h. The mixture was quenched with saturated sodium bicarbonate solution at 0 °C and then extracted with ethyl acetate. After removing the solvent by rotary evaporator, the target product compound 14 was separated by column chromatography (petroleum ether: ethyl acetate = 5:1, v / v) with a yield of 84%.

[0128] 1H NMR of compound 14:

[0129] 1 H NMR (500 MHz, CDCl3): δ 7.48 - 7.46 (m, 1H), 7.30 - 7.25 (m, 2H), 7.23 - 7.15 (m, 4H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.32 (s, 1H), 5.55 (d, J = 1.0 Hz, 1H), 5.01 (d, J = 1.0 Hz, 1H), 3.86 (d, J = 13.0 Hz, 1H), 3.42 - 3.36 (m, 3H), 1.56 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl3): δ 163.5, 160.5, 150.8, 145.6, 135.2, 131.2, 129.1, 128.3, 127.0, 124.6, 124.5, 121.9, 121.8, 111.3, 104.2, 87.0, 56.3, 48.1, 20.6, 11.3. HRMS m / z (ESI+): Calculated for C 22 H 22 NO2 + ([M+H] + ): 332.1645, found 332.1650.

[0130] 1H NMR of C2-alkynyl benzofuran derivative 14a:

[0131] 11H NMR (500 MHz, CDCl3): δ 7.58 - 7.57 (m, 0.70H), 7.52 - 7.50 (m, 1.25H), 7.48 - 7.47 (m, 1.00H), 7.42 - 7.32 (m, 3.95H), 7.30 - 7.20 (m, 2.10H), 4.97 (s, 0.70H), 4.78 (s, 1.30H), 3.65 (t, J = 7.5 Hz, 1.28H), 3.41 (t, J = 7.5 Hz, 0.72H), 2.30 (s, 1.88H), 2.28 (s, 1.12H), 1.76 - 1.68 (m, 1.27H), 1.62 - 1.55 (m, 0.73H), 0.97 (t, J = 7.3 Hz, 1.88H), 0.90 (t, J = 7.5 Hz, 1.12H). 13 13C NMR (125 MHz, CDCl3): δ 154.7, 154.5, 154.23, 154.16, 148.2, 147.7, 132.4, 130.1, 129.7, 129.5, 128.6, 124.7, 124.4, 122.5, 122.4, 120.60, 120.58, 119.5, 119.4, 114.1, 113.7, 111.2, 111.1, 90.7, 90.2, 82.0, 81.7, 50.4, 46.2, 44.3, 38.8, 21.8, 20.3, 11.4, 11.3, 8.0, 7.9. HRMS m / z (ESI+): Calculated for C 22 H 22 NO2 + ([M + H] + ): 332.1645, found 332.1650.

[0132] Examples 1 - 14 relate to the experimental results corresponding to the synthesis methods of specific indolinone compounds, which are listed in Table 1:

[0133] Table 1 Results of the Copper-Catalyzed Synthesis of Indolinone [a]

[0134]

[0135]

[0136]

[0137]

[0138] [a] The reaction conditions are shown in the examples; [b] Isolated yield.

[0139] The above are only several specific embodiments of the present invention, and the description thereof is relatively specific and detailed. However, the protection scope of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed by the present invention should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the appended claims.

Claims

1. A method for preparing a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound, characterized in that Using a C2-alkyne-based benzofuran derivative as a raw material, under the action of a palladium catalyst and a ligand, the reaction is carried out in acetic anhydride and an organic solvent at a temperature of 40 - 120 °C. After the reaction is completed, a dihydrobenzofuran product containing a six-membered azaspiro ring structure is obtained through treatment. The general reaction formula is as follows: In the formula: R1 is selected from one of H, alkyl, alkoxy, trifluoromethyl or halogen; R2 is alkyl, benzyl or substituted phenyl; Ar’ is substituted phenyl, naphthalene or thiophene; The alkyl in R1 and R2 is selected from C1 - C10 straight-chain or branched-chain alkanes; the alkoxy in R1 is independently selected from C1 - C10 straight-chain or branched-chain alkoxides; the halogen in R1 is selected from one of fluorine, chlorine or bromine; Ar’ is a benzene ring mono-substituted or multi-substituted with alkyl, or is naphthalene or thiophene. The substituents of the benzene ring in Ar’ are phenyl, trifluoromethyl, C1 - C4 alkyl or H, and the substituents of the substituted phenyl in R2 are H, C1 - C4 alkyl or C1 - C4 alkoxide.

2. The preparation method of a six-membered nitrogen heterocyclic spirodihydrobenzofuran compound according to claim 1, characterized in that, R1 is selected from one of H, C1 - C4 alkyl, C1 - C4 alkoxy, trifluoromethyl or halogen, and R2 is C1 - C4 alkyl, benzyl or phenyl substituted with C1 - C4 alkoxy.

3. The preparation method of a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound according to claim 1, characterized in that, The solvent is selected from one or more of propionic acid, acetic acid, tetrahydrofuran, trifluoromethanesulfonic acid, acetic acid and tetrahydrofuran. The volume ratio of the solvent used to the amount of substance of the C2-alkyne-based benzofuran derivative is 5 - 100:1, with the volume unit in milliliters and the amount of substance unit in millimoles.

4. The preparation method of a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound according to claim 1, characterized in that, The palladium catalyst is selected from any one of palladium acetate, palladium trifluoroacetate, tetrakis(acetonitrile)palladium tetrafluoroborate, palladium acetylacetonate, dichlorobis(triphenylphosphine)palladium, palladium dibromide. The molar amount of the palladium catalyst is 1 - 10% of the molar amount of the C2-alkyne-based benzofuran derivative, preferably 4 - 6%.

5. The preparation method of a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound according to claim 1, characterized in that, The ligand is selected from any one of triphenylphosphine, (rac)-BINAP, (6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine), bipyridine, DPPF, DPPA. The molar amount of the ligand is 1 - 10% of the molar amount of the C2-alkyne-based benzofuran derivative, preferably 4 - 6%; The feeding ratio of acetic anhydride to the C2-alkyne-based benzofuran derivative is 300 - 1000 μL:1 mmol, preferably 500 - 600 μL:1 mmol.

6. The preparation method of a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound according to claim 1, characterized in that, The reaction temperature is 80 - 100 °C, the reaction time is 4 - 24 h, preferably 15 - 18 h.

7. A method for preparing a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound according to any one of claims 1-6, characterized in that, The post-treatment steps are as follows: after the reaction is completed, the reaction solution is quenched with saturated sodium bicarbonate aqueous solution at a temperature of 0 - 5 °C, then extracted and layered with ethyl acetate. After the organic layer is evaporated to remove the solvent by rotary evaporation, the target product is obtained by column chromatography separation; the mobile phase of column chromatography is a mixture of petroleum ether and ethyl acetate with a volume ratio of 5 - 100:

1.

8. The preparation method of a six-membered nitrogen heterocyclic spirodihydrobenzofuran compound according to claim 1, characterized in that, The general reaction formula for the synthesis of the raw material C2-alkyne-based benzofuran derivative is as follows: Step 1: Using THF as the reaction solvent, compound S1 and LiAIH4 are stirred and reacted overnight under N2 at room temperature, and then the reaction solution is post-treated to obtain compound S2; Step 2: Compound S2 and MnO2 are added into anhydrous CH2Cl2 solvent in a molar ratio of 1:5 - 8. Under an air atmosphere, the mixture is stirred at room temperature for 40 - 50 h. After the reaction is completed, the solid is removed by filtration and recovered. The filtrate is concentrated under reduced pressure and purified by column chromatography. The eluting solvent is ethyl acetate / petroleum ether with a volume ratio of 1:1 - 10 to obtain compound S3; Step 3: Add compound S3 and anhydrous MgSO4 into anhydrous CH2Cl2 solvent at a molar ratio of 1:3 - 6. Under a nitrogen atmosphere, add substituted amino compound R 2 NH2, R 2 The molar ratio of NH2 to compound S3 is 0.8 - 1.2:

1. The resulting mixture is stirred and reacted at 40 - 60 °C for 10 - 15 h. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The obtained crude product is directly put into the next step of the reaction. The crude product is added to anhydrous MeOH, and NaBH4 is added in batches. The resulting mixture is then stirred at room temperature for 1.5 - 3 h. After the reaction is over, MeOH is removed under reduced pressure and then extracted with ethyl acetate. The ethyl acetate phase is concentrated under reduced pressure, and the residue is separated and purified by column chromatography. The elution solvent is ethyl acetate / petroleum ether with a volume ratio of 1:1 - 5 to obtain compound S4; Step 4: Using CH2Cl2 as the reaction solvent, compound S4 is stirred and reacted with DMAP, DCC and substituted phenylpropiolic acid at room temperature. After the reaction is completed, the solid is removed by filtration and recovered. The filtrate is concentrated under reduced pressure and purified by column chromatography. The eluting solvent is ethyl acetate / petroleum ether with a volume ratio of 1:5 - 20 to obtain the C2-alkyne series benzofuran derivative shown in Formula I; Among them, the substituent R1 in the structures of compounds S1 - S4 and the substituent Ar' in the substituted phenylpropiolic acid are the same as those in Formula I and Formula II.

9. The preparation method of a six-membered nitrogen-containing spirocyclic dihydrobenzofuran compound according to claim 8, characterized in that, In Step 1, the molar ratio of compound S1 to LiAIH4 is 1.5 - 3:

1. The post-treatment step after the reaction is completed is: quenching the reaction system with 5 - 15% aqueous NaOH solution, extracting with ethyl acetate and drying over Na2SO4. The organic phase is concentrated under reduced pressure, and the residue is purified by column chromatography. The eluting solvent is ethyl acetate / petroleum ether with a volume ratio of 1:1 - 10 to obtain compound S2.

10. The preparation method of a six-membered nitrogen heterocyclic spirodihydrobenzofuran compound according to claim 8, characterized in that, In Step 3, the molar ratio of NaBH4 to compound S3 is 1.2 - 1.6:1; in Step 4, the molar ratios of compound S4 to DMAP, DCC and substituted propiolic acid are 1:0.05 - 0.2:1 - 1.2:1 - 1.2.

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