A method for synthesizing a benzofuran derivative
By using electrophilic substitution reactions of diaryl iodides and ketone derivatives in the presence of a base, the synthesis process of benzofuran derivatives has been simplified, solving the problem of high reaction complexity in existing technologies and enabling efficient and inexpensive industrial production.
Patent Information
- Application Number
- CN202411861806.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-17
- Publication Date
- 2025-12-19
- Estimated Expiration
- 2044-12-17
AI Technical Summary
Existing technologies for synthesizing benzofuran derivatives suffer from problems such as high reaction complexity, the need for transition metal catalysts, and harsh conditions, making industrial-scale production difficult.
Using diaryl iodide salts and ketone derivatives as raw materials, the synthesis process is simplified by carrying out two consecutive electrophilic substitution reactions in the presence of a base.
A simple, inexpensive, and efficient synthesis method is provided, with high product selectivity and a yield of up to 82%, which is suitable for industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a method for synthesizing a benzofuran derivative, and belongs to the field of organic synthesis in organic chemistry. BACKGROUND
[0002] Benzofuran derivatives are a class of very important aromatic oxygen-containing heterocyclic organic compounds, which are widely present in natural products and drug molecules with potential biological activity. For example, Ailanthoidol with anti-inflammatory, anti-tumor, anti-fungal and other activities is extracted from the stems and leaves of Zanthoxylum bungeanum Maxim, Stemofuran with strong anti-fungal effect is extracted from the roots of the herb Stemona, Amiodarone with a clinical application rate of more than 60% for anti-arrhythmia, Methoxsalen for treating psoriasis, eczema, vitiligo and skin lymphoma, etc. In view of the important role of such compounds in the field of medicine, etc., it is of great significance to develop a new and efficient method for constructing diverse benzofuran compounds, especially polysubstituted benzofuran derivatives.
[0003] The traditional synthesis method of benzofuran mainly uses benzene derivatives with various substituents as substrates, and constructs the furan ring by Lewis acid catalysis and transition metal catalytic oxidation to realize the synthesis of polysubstituted benzofuran derivatives. This strategy as a classical method for synthesizing benzofuran has been widely used. However, the use of metal catalysts, ligands and various additives in the reaction increases the complexity of the reaction; and the strategy without using transition metal catalysts usually requires highly functionalized substrates or harsh conditions, which are not conducive to the industrialized synthesis of benzofuran. Therefore, it is still very necessary to develop a simple and efficient method for synthesizing benzofuran and its derivatives. SUMMARY
[0004] In order to overcome the above-mentioned defects, the present application uses commercially available or simply prepared diaryl iodonium salt and ketone derivative as raw materials, and obtains benzofuran derivative through two consecutive electrophilic substitution reactions under the action of base. The method provides a simple, inexpensive and efficient way for the synthesis of benzofuran derivatives.
[0005] A method for synthesizing a benzofuran derivative, comprising the following operations: using diaryl iodonium salt 1 and ketone derivative 2 as raw materials, adding a solvent, reacting in the presence of a base, and then obtaining benzofuran derivative 3.
[0006]
[0007] Wherein: LG = -F, -Cl, -Br, -I in the structure of substrate 1; EWG = -CN, -NO2, -CF3, -CCl3, -CBr3, -COH, -COMe, -COOMe, -COOH, -COMe, -CONH2, -CONHMe, -SO3H, -SO2Me, -SO2CF3, and other electron-withdrawing groups; R1= single or multiple organic functional groups; X= -OTf, -OTs, -BF4, and other anion ligands.
[0008] The ketone derivatives used in substrate 2 include chain ketones and cyclic ketones; R2= alkyl or aryl in the structure of chain ketones; R3= various electron-withdrawing groups; cyclic ketones include various size ketone derivatives.
[0009] In some embodiments, the R 1 is any one of 2-fluoro, 3-fluoro, 2,3-difluoro, 2-nitro, 3-nitro, 2-trifluoromethyl, 3-trifluoromethyl functional groups; R 2 is selected from alkyl or aryl; R 3 is selected from any one of nitro, ester, carbonyl, trifluoromethyl, sulfone, cyano.
[0010] Further, the alkyl in R 2 is selected from any one of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl; the aryl is selected from any one of phenyl, p-methylbenzene, m-methylbenzene, o-methylbenzene, p-fluorobenzene, p-chlorobenzene, p-bromobenzene, 2-naphthyl.
[0011] Further, in the above technical solution, the base is selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, silver carbonate, sodium hydride, potassium tert-butoxide, sodium hydroxide, N,N-diisopropyl ethylamine, 4-dimethylamino pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and other various reaction-able bases.
[0012] Further, in the above technical solution, the reaction solvent is selected from dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethyl acetamide, acetone, tetrahydrofuran, carbon tetrachloride, acetonitrile, dichloroethane, toluene, dichloromethane, and other various reaction-able solvents.
[0013] Further, in the above technical solution for synthesizing benzofuran derivatives, the molar ratio of the base to diaryl iodonium salt is 1-6:1.
[0014] Further, in the above technical solution for synthesizing benzofuran derivatives, the molar ratio of the diaryl iodonium salt to the ketone derivative is 1:1-6.
[0015] Furthermore, in the above technical solution, benzofuran derivatives are synthesized at a reaction temperature selected from 0℃ to 110℃.
[0016] Beneficial effects of the invention:
[0017] This invention provides a simple, inexpensive, and efficient synthetic method for synthesizing benzofuran derivatives. The raw materials used in the reaction are simple and readily available, 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 and also lays a good foundation for the development of benzofuran drugs. Detailed Implementation
[0018] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.
[0019] Example 1
[0020] The preparation method of benzofuran derivatives includes the following steps:
[0021]
[0022] 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 dimethyl sulfoxide (1 mL) solvent 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, a benzofuran derivative, in 82% yield (20.5 mg).
[0023] 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).
[0024] 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.
[0025] HRMS: exact mass calcd for C 12 H 11 NO5(M+H) + : requires m / z 250.0637,found m / z 250.0633.
[0026] Example 2
[0027]
[0028] In a 10 ml Schlenk 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, thin layer chromatography (TLC) was used to monitor the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 80%, 17.6 mg.
[0029] 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).
[0030] 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.
[0031] HRMS: exact mass calcd for C 11 H9NO4(M+H) +: requires m / z 220.0532, foundm / z 220.0528.
[0032] Example 3
[0033]
[0034] In a 10 ml Schlenk 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, thin layer chromatography (TLC) was used to monitor the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 50%, 11.6 mg.
[0035] 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).
[0036] 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.
[0037] HRMS: exact mass calcd for C 12 H9NO4 (M+H) + : requires m / z 231.0532, foundm / z 231.0527.
[0038] Example 4
[0039]
[0040] In a 10 ml Schlenk tube, diaryliodonium 1a (49.3 mg, 0.10 mmol, 1.0 equiv), potassium bicarbonate (30 mg, 0.3 mmol), benzoyl ethyl 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, thin layer chromatography (TLC) was used to monitor the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 72%, 22.4 mg.
[0041] 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).
[0042] 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.
[0043] HRMS: exact mass calcd for C 17 H 13 NO5(M+H) + : requires m / z 311.0794, found m / z 311.0788.
[0044] Example 5
[0045]
[0046] In a 10 ml Schlenk 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, thin layer chromatography (TLC) was used to monitor the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 45%, 12.2 mg.
[0047] 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).
[0048] 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.
[0049] 19 F NMR (376 MHz, Chloroform- d ) δ -61.01 (s, 3F).
[0050] HRMS: exact mass calcd for C 13 H 11 F3O3 (M+H) + : requires m / z 272.0660, found m / z 272.0555.
[0051] Example 6
[0052]
[0053] In a 10 ml Schlenk 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 dimethylsulfoxide (1 mL) were added. The mixture was stirred at room temperature for 12 h, thin layer chromatography (TLC) was used to monitor the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 66%, 20.9 mg.
[0054] 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).
[0055] 13 C 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.
[0056] 19 F NMR (376 MHz, Chloroform-d) δ -58.58 (s, 3F).
[0057] HRMS: exact mass calcd for C 13 H 10 F3NO5 (M+H) + : requires m / z 317.0511, found m / z 317.0507.
[0058] Example 7
[0059]
[0060] In a 10 ml Schlenk 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, thin layer chromatography (TLC) was used to monitor the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 60%, 14.9 mg.
[0061] 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).
[0062] 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.
[0063] HRMS: exact mass calcd for C 12 H 11 NO5(M+H) + : requires m / z 249.0637, found m / z 249.0633.
[0064] Example 8
[0065]
[0066] In a 10 ml Schlenk 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 stirred at 100 oC stirred for 12 h, thin layer chromatography (TLC) monitored the reaction, after the reaction was completed, the reaction was separated by column chromatography with petroleum ether / ethyl acetate as eluent to obtain the target product benzofuran derivative, yield 45%, 9.8 mg.
[0067] 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).
[0068] 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.
[0069] HRMS: exact mass calcd for C 11 H9NO4 (M+H) + : requires m / z 219.0532, found m / z 219.0527.
Claims
1. A method for synthesizing a benzofuran derivative, characterized by, The benzofuran derivative is selected from any one of , , , , , , , . The synthesis method of the benzofuran derivative comprises the following operation steps: taking diaryliodonium salt 1 and ketone derivative 2 as raw materials, adding a solvent, reacting in the presence of a base, and then obtaining benzofuran derivative 3 or 4. Wherein: LG in the structure of substrate 1 =-F, -Cl, -Br, -I; X = -OTf, -OTs, or -BF4 counter anion.
2. The method of synthesis of benzofuran derivatives according to claim 1, characterized by: 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-diisopropyl ethylamine, 4-dimethylamino pyridine, 1,8-diazabicycloundec-7-ene, and triethylamine.
3. The method of synthesis of benzofuran derivatives according to claim 1, characterized in that: The solvent is selected from any one of dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethyl acetamide, acetone, tetrahydrofuran, carbon tetrachloride, acetonitrile, dichloroethane, toluene, and dichloromethane.
4. The method of synthesis of benzofuran derivatives according to claim 1, characterized in that: The reaction temperature is 0 ℃ to 110 ℃.