Synthesis method of benzofuran derivative

Abstract

The invention relates to a method for synthesizing benzofuran derivatives, and belongs to the field of organic synthesis in organic chemistry. The benzofuran derivative is synthesized by taking iodonium salt and ketone derivatives as raw materials through continuous two-step nucleophilic substitution reaction. The route and reaction conditions adopted in the method are simple and mild, the raw materials are easy to obtain, the product selectivity is high, the variety is rich, and the method is expected to be further applied to industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing benzofuran derivatives, and belongs to the field of organic synthesis in organic chemistry. Background Art

[0002] Benzofuran derivatives are a very important class of aromatic oxygen-containing heterocyclic organic compounds, which are widely present in natural products and drug molecules with potential biological activity. For example, Ailanthoidol, which is isolated and extracted from the stems and leaves of Zanthoxylum bungeanum, has anti-inflammatory, anti-tumor, and anti-fungal activities; Stemofuran, which is isolated and extracted from the roots of the herb Stemona odorata and has strong anti-fungal effects; Amiodarone, an antiarrhythmic drug with a clinical application rate of over 60%; and Methoxsalen, a drug used to treat psoriasis, eczema, vitiligo, and skin lymphoma. Given the important role of such compounds in the fields of medicine and the like, it is of great research significance to develop a new and efficient method for constructing diverse benzofuran compounds, especially a synthetic method for polysubstituted benzofuran derivatives.

[0003] The traditional synthesis method of benzofuran mainly uses benzene derivatives with various substituents as substrates, and constructs furan rings through Lewis acid catalysis and transition metal catalytic oxidative cyclization to achieve the synthesis of multi-substituted benzofuran derivatives. This strategy has been widely used as a classic method for synthesizing benzofuran. However, the use of metal catalysts, ligands, and multiple additives in the reaction increases the complexity of the reaction; strategies that do not use transition metal catalysis usually require highly functionalized substrates or harsh conditions, which are not conducive to the industrial synthesis of benzofuran. Therefore, it is still very necessary to develop a simple and efficient method for synthesizing benzofuran and its derivatives. Summary of the invention

[0004] In order to overcome the above defects, the present invention uses commercially available or simple diaryliodonium salts and ketone derivatives as raw materials, and obtains benzofuran derivatives through two consecutive electrophilic substitution reactions under the action of a base. The method provides a simple, cheap and efficient way to synthesize benzofuran derivatives.

[0005] A method for synthesizing a benzofuran derivative comprises the following steps: using a diaryl iodonium salt 1 and a ketone derivative 2 as raw materials, adding a solvent, reacting in the presence of a base, and then obtaining a benzofuran derivative 3.

[0006]

[0007] Wherein: LG in the structure of substrate 1 = -F, -Cl, -Br, -I; EWG = electron-withdrawing groups such as -CN, -NO2, -CF3, -CCl3, -CBr3, -COH, -COMe, -COOMe, -COOH, -COMe, -CONH2, -CONHMe, -SO3H, -SO2Me, -SO2CF3; R1 = single or multiple organic functional groups; X = coordinated anions such as -OTf, -OTs, -BF4.

[0008] The ketone derivatives used in substrate 2 include chain ketones and cyclic ketones; in the chain ketone structure, R2 = alkyl or aryl; R3 = various electron-withdrawing groups; and the cyclic ketone includes ketone derivatives of various sizes.

[0009] In some embodiments, the R 1 is any one of 2-fluoro, 3-fluoro, 2,3-difluoro, 2-nitro, 3-nitro, 2-trifluoromethyl, and 3-trifluoromethyl functional groups; R 2 is selected from alkyl or aryl; R 3 Any one selected from nitro, ester, carbonyl, trifluoromethyl, sulfone and cyano.

[0010] Furthermore, R 2 The alkyl group is selected from any one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl and tert-butyl; the aryl group is selected from any one of phenyl, p-methylbenzene, m-methylbenzene, o-methylbenzene, p-fluorobenzene, p-chlorobenzene, p-bromobenzene and 2-naphthyl.

[0011] Furthermore, in the above technical scheme, the base is selected from various bases that can react, such as cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, silver carbonate, sodium hydride, potassium tert-butoxide, sodium hydroxide, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, triethylamine, etc.

[0012] Furthermore, in the above technical solution, the reaction solvent is selected from various solvents that can react, such as dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, carbon tetrachloride, acetonitrile, dichloroethane, toluene, and dichloromethane.

[0013] Furthermore, in the above technical scheme, when synthesizing the benzofuran derivative, the molar ratio of the base to the diaryliodonium salt is 1-6:1.

[0014] Furthermore, in the above technical scheme, when synthesizing benzofuran derivatives, the molar ratio of the diaryliodonium salt to the ketone derivative is 1:1-6.

[0015] Furthermore, in the above technical solution, the reaction temperature for synthesizing the benzofuran derivative is selected from 0°C to 110°C.

[0016] Beneficial effects of the invention: The present invention provides a simple, cheap and efficient synthesis method for synthesizing benzofuran derivatives. The raw materials used in the reaction are simple and easy to obtain, and the product selectivity is high. The yield of the target product can reach up to 82%, which is expected to be applied to industrial production. At the same time, it also lays a good foundation for the development of benzofuran drugs. DETAILED DESCRIPTION

[0017] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0018] Example 1 The preparation method of benzofuran derivatives comprises the following steps:

[0019] In a 10 ml Shrek tube, diaryliodonium salt 1a (49.3 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), ethyl acetoacetate 2a (19.5 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 82% and 20.5 mg.

[0020] 1 H NMR (400 MHz, Chloroform- d ) δ 8.32 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H),8.06 (d, J = 8.8 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.84 (s, 3H), 1.46 (t, J = 7.2Hz, 3H). 13 C NMR (100 MHz, Chloroform- d) δ 168.6, 163.4, 152.2, 145.0, 132.3,121.8, 119.5, 109.7, 107.3, 60.9, 14.9, 14.4. HRMS: exact mass calculation for C 12 H 11 NO5(M+H) + : requires m / z 250.0637, found m / z 250.0633. Example 2

[0021] In a 10 ml Shrek tube, diaryliodonium salt 1a (49.3 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), acetylacetone 2b (15 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 80%, 17.6 mg.

[0022] 1 H NMR (400 MHz, Chloroform- d ) δ 8.34 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H),8.07 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 2.85 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.7, 163.8, 152.3, 145.1, 132.2, 121.8,119.6, 10.9.5, 107.3, 51.8, 14.9. HRMS: exact mass calculation for C 11 H9NO4(M+H) + : requires m / z 220.0532, foundm / z 220.0528. Example 3

[0023] In a 10 ml Shrek tube, diaryliodonium salt 1a (49.3 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), 1,3-cyclohexanedione 2c (16.8 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 50%, 11.6 mg.

[0024] 1 H NMR(400 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.27 (d, J = 8.8 Hz,1H), 8.16 (d, J = 8.8 Hz, 1H), 3.13 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.4 Hz,2H), 2.34 (t, J = 6.4 Hz, 2H). 13 C NMR(100 MHz, Chloroform-d) δ 194.0, 175.0, 153.3, 145.5, 129.6,121.7, 120.3, 116.4, 107.7, 37.7, 24.1, 22.2. HRMS: exact mass calculation for C 12 H9NO4(M+H) + : requires m / z 231.0532, foundm / z 231.0527. Example 4

[0025] In a 10 ml Shrek tube, diaryliodonium 1a (49.3 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), ethyl benzoyl acetate 2d (28.8 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 72%, 22.4 mg.

[0026] 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.56-7.53 (m, 3H), 4.44 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). 13 C NMR(100 MHz, Chloroform-d) δ 165.2, 163.0, 152.3, 145.5, 133.2,131.4, 129.8, 128.5, 128.3, 122.8, 119.6, 109.2, 107.6, 61.2, 14.2. HRMS: exact mass calculation for C 17 H 13 NO5(M+H) + : requires m / z 311.0794, found m / z 311.0788. Example 5

[0027] In a 10 ml Shrek tube, diaryliodonium salt 1b (51.6 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), ethyl acetoacetate 2a (19.3 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 45%, 12.2 mg.

[0028] 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 7.57 – 7.48 (m, 2H), 4.44 (q, J = 7.2 Hz, 2H), 2.80 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). 13 C NMR(100 MHz, Chloroform-d) δ 165.3, 163.8, 154.9,126.6 126.5,125.9, 123.2, 120.6(dm, J = 199 Hz), 111.2, 109.4, 60.7, 14.5, 14.4. 19 F NMR (376 MHz, Chloroform- d ) δ -61.01 (s, 3F). HRMS: exact mass calculation for C 13 H 11 F3O3(M+H) + : requires m / z 272.0660, found m / z 272.0555. Example 6

[0029] In a 10 ml Shrek tube, diaryliodonium salt 1c (56.1 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), ethyl acetoacetate 2a (19.3 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 66% and 20.9 mg.

[0030] 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.04 (s, 1H), 4.46 (q,J = 7.2 Hz, 2H), 2.87 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, Chloroform-d) δ 169.0, 162.7, 153.0, 145.0, 129.8,122.5 (d, J = 267 Hz), 121.7 (q, J = 6.0 Hz.), 120.3 (d, J = 40 Hz), 109.9,109.1, 61.2, 14.8, 14.3. 19 F NMR (376 MHz, Chloroform-d) δ -58.58 (s, 3F). HRMS: exact mass calculation for C 13 H 10 F3NO5(M+H) + : requires m / z 317.0511, found m / z 317.0507. Example 7

[0031] In a 10 ml Shrek tube, diaryliodonium salt 1d (55.3 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), ethyl acetoacetate 2a (19.3 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative with a yield of 60%, 14.9 mg.

[0032] 1 H NMR(400 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.22 (d, J = 8.8 Hz,1H), 7.52 (d, J = 8.8 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 2.83 (s, 3H), 1.48(t, J = 7.2 Hz, 3H). 13 C NMR(100 MHz, Chloroform-d) δ 166.6, 163.3, 156.2, 145.0, 126.9,120.3, 118.4, 111.2, 110.0, 60.9, 14.5, 14.4. HRMS: exact mass calculation for C 12 H 11 NO5(M+H) + : requires m / z 249.0637, found m / z 249.0633. Example 8

[0033] In a 10 ml Shrek tube, diaryliodonium salt 1d (55.3 mg, 0.10 mmol, 1.0 equiv), NaH (12 mg, 0.3 mmol), acetylacetone 2b (15 mg, 0.15 mmol, 1.5 equiv) and solvent dimethyl sulfoxide (1 mL) were added. The mixture was heated at 100 °C. o The mixture was stirred at 40 °C for 12 h and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reactants were separated by column chromatography using petroleum ether / ethyl acetate as eluent to obtain the target product, benzofuran derivative, with a yield of 45%, 9.8 mg.

[0034] 1 H NMR(400 MHz, Chloroform-d)δ 8.84 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 4.00 (s, 3H), 2.83 (s, 3H). 13 C NMR(100 MHz, Chloroform-d) δ 166.8, 163.8, 156.2, 145.0, 126.8,120.4, 118.4, 111.3, 109.9 51.9, 14.5. HRMS: exact mass calculation for C 11 H9NO4(M+H) + : requires m / z 219.0532, foundm / z 219.0527.

Claims

1. A benzofuran derivative, characterized in that: The structural formula is or , the R 1 is any one of 2-fluoro, 3-fluoro, 2,3-difluoro, 2-nitro, 3-nitro, 2-trifluoromethyl, and 3-trifluoromethyl functional groups; R 2 is selected from alkyl or aryl; R 3 Any one selected from nitro, ester, carbonyl, trifluoromethyl, sulfone and cyano.

2. The benzofuran derivative according to claim 1, characterized in that R 2 The alkyl group is selected from any one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl and tert-butyl; the aryl group is selected from any one of phenyl, p-methylbenzene, m-methylbenzene, o-methylbenzene, p-fluorobenzene, p-chlorobenzene, p-bromobenzene and 2-naphthyl.

3. A method for synthesizing a benzofuran derivative, characterized in that: The method comprises the following steps: using a diaryl iodonium salt 1 and a ketone derivative 2 as raw materials, adding a solvent, reacting in the presence of a base, and then obtaining a benzofuran derivative 3 or 4; Wherein: LG in the structure of substrate 1 = -F, -Cl, -Br, -I; EWG = any electron-withdrawing group among -CN, -NO2, -CF3, -CCl3, -CBr3, -COH, -COMe, -COOMe, -COOH, -COMe, -CONH2, -CONHMe, -SO3H, -SO2Me, -SO2CF3; X = -OTf, -OTs, or -BF4 coordinated anion.

4. The method for synthesizing a benzofuran derivative according to claim 3, characterized in that: The base is selected from any one of cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, silver carbonate, sodium hydride, potassium tert-butoxide, sodium hydroxide, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, and triethylamine.

5. The method for synthesizing a benzofuran derivative according to claim 3, characterized in that: The solvent is selected from any one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, tetrahydrofuran, carbon tetrachloride, acetonitrile, dichloroethane, toluene and dichloromethane.

6. The method for synthesizing a benzofuran derivative according to claim 3, characterized in that: The reaction temperature is 0°C to 110°C.

7. The method for synthesizing a benzofuran derivative according to any one of claims 3 to 6, characterized in that: The benzofuran derivatives include , , , , , , , Any one of .

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