Synthesis method of benzofuran

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a benzofuran compound. In an inert gas environment, a 2-fluorotoluene compound as shown in a formula 1 and a methyl benzoate compound as shown in a formula 2 are mixed and reacted with an organic solvent methyl tert-butyl ether in the presence of bis (trimethylsilyl) amino cesium and cesium sulfate, and the benzofuran compound as shown in a formula 3 is synthesized under a heating condition. Wherein the methyl benzoate compound as shown in the formula 2 can also be replaced by 2-naphthoic acid methyl ester or 1-naphthoic acid methyl ester. The research develops a benzofuran synthesis strategy without transition metal catalysis. According to the method, on the basis of commercially available raw materials, the construction of a benzofuran skeleton is realized through a simple and efficient path. Due to the mild and green reaction characteristic, a route with practical value is provided for synthesis of active medicine molecules and key intermediates of the active medicine molecules.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a one-pot method for the efficient synthesis of benzofuran, using 2-fluorotoluene and methyl benzoate as starting materials. Background Technology

[0002] Benzofurans and their derivatives are an important class of heterocyclic compounds widely found in natural products and drug molecules, possessing excellent biological activity and potential pharmacological applications. In drug development, these structures often serve as key pharmacophores, exhibiting a variety of biological activities, including antitumor, anti-inflammatory, antiviral, and antioxidant effects. Examples include naturally derived benzofuran compounds such as XH-14 and salvianolic acid C. Traditional benzofuran synthesis methods mainly involve cyclization reactions using salicylaldehyde-based substrates with appropriate reagents (aromatic aldehydes, protected thiazolyls, Wittig reagents, or alkynes). However, current synthetic methods for benzofurans still suffer from limitations such as harsh reaction conditions, expensive catalysts, cumbersome procedures, or low yields. Therefore, this invention provides a novel one-pot method for preparing benzofurans that uses readily available raw materials, involves simple steps, and yields excellent results, potentially providing technical support for the large-scale preparation and related research of these compounds. Summary of the Invention

[0003] This invention provides a one-pot, highly efficient synthetic method for preparing benzofurans from readily available 2-fluorotoluene and methyl benzoate. This method can yield a variety of benzofuran compounds with biological activity and pharmaceutical value. The specific scheme is as follows:

[0004]

[0005] A method for synthesizing benzofuran compounds involves reacting 2-fluorotoluene compounds of Formula 1 and methyl benzoate compounds of Formula 2 with an organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate under an inert gas environment, and synthesizing benzofuran compounds of Formula 3 under heating conditions.

[0006] Where R 1 Selected from any one of hydrogen, 3-fluoro, 5-chloro, 6-bromine, or 5-methoxy, R 2 It is selected from any one of hydrogen, 4-methyl, 4-methoxy, 3-methoxy, 4-dimethylamino, or 4-chloro.

[0007]

[0008] In an inert gas environment, 2-fluorotoluene (Formula 1) and methyl 2-naphthocarboxylate (Formula 4) were reacted with the organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate to synthesize the benzofuran compound (Formula 3) under heating conditions.

[0009]

[0010] In an inert gas environment, 2-fluorotoluene (Formula 1) and methyl 1-naphthocarboxylate (Formula 5) were reacted with the organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate to synthesize the benzofuran compound (Formula 3) under heating conditions.

[0011] This invention employs a one-pot synthesis strategy, using structurally simple, economically available 2-fluorotoluene compounds and methyl benzoate compounds as raw materials to efficiently construct benzofuran compounds. This method effectively reduces reaction steps, contributing to higher product yields; simultaneously, it exhibits good functional group compatibility, and the R in the substrate... 1 R 2 The diverse range of functional groups allows for a wider range of applicability.

[0012] Preferred, R 1 Selected from any one of hydrogen, 3-fluoro, 5-chloro, 6-bromine, or 5-methoxy, R 2 It is selected from any one of 4-methyl, 4-methoxy, 3-methoxy, 4-dimethylamino, or 4-chloro.

[0013] Preferably, the inert gas is nitrogen.

[0014] Preferably, the organic solvent is methyl tert-butyl ether.

[0015] Preferably, the molar ratio of the 2-fluorotoluene compound shown in Formula 1, the methyl benzoate compound shown in Formula 2, the bis(trimethylsilyl)aminocesium and cesium sulfate in the reaction is 9.1–7.6:1:2:1; and the reaction temperature is 110°C.

[0016] Preferably, using the method of the present invention, benzofuran compounds with the following structures can be synthesized:

[0017]

[0018]

[0019] The benzofuran compound shown in Formula 3 was synthesized by reacting a 2-fluorotoluene compound shown in Formula 1 and a methyl benzoate compound shown in Formula 2 with an organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate, under heating conditions.

[0020] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0021] The raw materials used in the synthesis method of this invention are all inexpensive and readily available;

[0022] The synthesis method of this invention does not use transition metal catalysts, making it green and environmentally friendly;

[0023] This invention employs a one-pot synthesis method, which avoids the separation and purification of intermediates and improves the yield of the product.

[0024] The operation steps required by this invention are relatively simple, requiring no extreme heating or cooling, and the reaction can be carried out under normal pressure, making it safe and convenient.

[0025] R in this invention 1 R 2 Since there are multiple options, the method of the present invention has a wider range of applications and can synthesize a variety of benzofuran compounds. Attached Figure Description

[0026] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. Figure A is the proton NMR spectrum, and Figure B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The carbon NMR spectrum of the product obtained in Example 1; Figure 2A The above is the proton NMR spectrum of the product obtained in Example 2. Figure 2B The carbon NMR spectrum of the product obtained in Example 2; Figure 3A The above is the proton NMR spectrum of the product obtained in Example 3. Figure 3B The carbon NMR spectrum of the product obtained in Example 3; Figure 4A The above is the proton NMR spectrum of the product obtained in Example 4. Figure 4B The carbon NMR spectrum of the product obtained in Example 4; Figure 5A The above is the proton NMR spectrum of the product obtained in Example 5. Figure 5B The carbon NMR spectrum of the product obtained in Example 5; Figure 6A The above is the proton NMR spectrum of the product obtained in Example 6. Figure 6B The carbon NMR spectrum of the product obtained in Example 6; Figure 7A The above is the proton NMR spectrum of the product obtained in Example 7. Figure 7BThe carbon NMR spectrum of the product obtained in Example 7; Figure 8A The above is the proton NMR spectrum of the product obtained in Example 8. Figure 8B The carbon NMR spectrum of the product obtained in Example 8; Figure 9A The image shows the proton NMR spectrum of the product obtained in Example 9. Figure 9B The carbon NMR spectrum of the product obtained in Example 9; Figure 10A The above is the proton NMR spectrum of the product obtained in Example 10. Figure 10B The carbon NMR spectrum of the product obtained in Example 10; Figure 11A The above is the proton NMR spectrum of the product obtained in Example 11. Figure 11B The carbon NMR spectrum of the product obtained in Example 11; Figure 12A The above is the proton NMR spectrum of the product obtained in Example 12. Figure 12B The image shows the carbon NMR spectrum of the product obtained in Example 12. Specific Implementation

[0027] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M and a JEOL 400M.

[0028] Example 1

[0029] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl benzoate (12.5 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (15.1 mg, 78% yield). 1H NMR (401MHz, CDCl3) δ: 7.91-7.86 (m, 2H), 7.62-7.53 (m, 2H), 7.50-7.42 (m, 2H), 7.39-7.23 (m, 3H), 7.04 (s, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 156.0, 155.0, 130.6, 129.3, 128.9, 128.7, 125.1, 124.4, 123.1, 121.1, 111.3, 101.4ppm.

[0030] By changing the raw materials in Example 1, the following 10 sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding nuclear magnetic resonance spectrum of the product is as follows. Figure 1A B. The NMR spectra of the remaining 2-10 groups of products correspond to the serial numbers of the respective embodiments.

[0031] The table lists the structural formulas of the products in each of the 1-10 embodiments. The last column lists the yield of the products in each embodiment and indicates the specific implementation conditions of each embodiment. The specific meaning of the implementation conditions of each embodiment is shown below the table.

[0032]

[0033]

[0034] Example 2

[0035] In a nitrogen-filled glove box, 1,2-difluoro-3-methylbenzene (0.1 mL, 0.86 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl benzoate (12.5 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic septum. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (16.1 mg, 79% yield). 1H NMR (400MHz, CDCl3) δ: 7.91-7.86 (m, 2H), 7.46 (t, J=7.6Hz, 2H), 7.40-7.32 (m, 2H), 7.14 (td, J=7.9, 4.4Hz, 1H), 7.06-6.98 (m, 2H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ: 157.1, 148.1 (d, J 1 C-F =249.1Hz), 141.9 (d, J) 3 C-F =11.1Hz), 132.9 (d, J) 4 C-F =3.3Hz), 129.9, 129.1, 129.0, 125.2, 123.6 (d, J 4 C-F =5.9Hz), 116.6 (d, J) 4 C-F =3.8Hz), 110.7 (d, J) 2 C-F =16.2Hz), 101.6 (d, J) 4 C-F =2.1Hz)ppm.

[0036] Example 3

[0037] In a nitrogen-filled glove box, 4-chloro-1-fluoro-2-methylbenzene (0.1 mL, 0.82 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl benzoate (12.5 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic septum. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (19.2 mg, 84% yield). 1 H NMR (400MHz, CDCl3) δ: 7.87-7.80 (m, 2H), 7.53 (d, J=2.1Hz, 1H), 7.47-7.35 (m, 4H), 7.22 (dd, J=8.7, 2.2Hz, 1H), 6.96 (s, 1H)ppm.13 C{ 1 H} NMR (101MHz, CDCl3) δ: 157.5, 153.3, 130.7, 130.0, 129.1, 129.0, 128.6, 125.1, 124.5, 120.5, 112.2, 100.9ppm.

[0038] Example 4

[0039] In a nitrogen-filled glove box, 1-bromo-3-fluoro-2-methylbenzene (0.1 mL, 0.8 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl benzoate (12.5 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic septum. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (22.8 mg, 84% yield). 1 H NMR (401MHz, CDCl3) δ: 7.91-7.83 (m, 2H), 7.49-7.43 (m, 3H), 7.41-7.35 (m, 2H), 7.14 (t, J=8.0Hz, 1H), 7.05 (d, J=0.8Hz, 1H)ppm. 13 C{ 1 ¹H NMR (101MHz, CDCl₃) δ: 156.6, 154.6, 130.9, 130.0, 129.2, 129.0, 126.0, 125.2, 114.0, 110.4, 101.4 ppm. One resonance signal was not observed due to resonance signal overlap.

[0040] Example 5

[0041] In a nitrogen-filled glove box, 1-fluoro-4-methoxy-2-methylbenzene (0.1 mL, 0.76 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl benzoate (12.5 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic septum. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (14.6 mg, 65% yield). 1 H NMR (401MHz, CDCl3) δ: 7.86-7.80 (m, 2H), 7.47-7.38 (m, 3H), 7.37-7.31 (m, 1H), 7.04 (d, J=2.6Hz, 1H), 6.96 (d, J=0.7Hz, 1H), 6.88 (dd, J=8.9, 2.6Hz, 1H), 3.85 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 156.8, 156.2, 150.0, 130.6, 129.9, 128.9, 128.6, 125.0, 113.1, 111.7, 103.4, 101.6, 56.0ppm.

[0042] Example 6

[0043] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 4-methylbenzoate (14.2 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (19.1 mg, 92% yield). 1H NMR (401MHz, CDCl3) δ: 7.80 (dd, J=8.9, 2.0Hz, 2H), 7.57-7.48 (m, 2H), 7.27-7.20 (m, 2H), 6.97 (d, J=8.9Hz, 2H), 6.88 (s, 1H), 3.85 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 158.7, 156.1, 154.8, 129.6, 126.5, 123.9, 123.4, 122.9, 120.7, 114.3, 111.1, 99.7, 55.5ppm.

[0044] Example 7

[0045] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 4-methoxybenzoate (14.2 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (18.8 mg, 84% yield). 1 H NMR (400MHz, CDCl3) δ: 7.79 (d, J=8.6Hz, 2H), 7.59-7.46 (m, 2H), 7.27-7.19 (m, 2H), 6.97 (d, J=8.6Hz, 2H), 6.88 (s, 1H), 3.85 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 160.1, 156.1, 154.8, 129.6, 126.5, 123.8, 123.4, 122.9, 120.7, 114.3, 111.1, 99.8, 55.5ppm.

[0046] Example 8

[0047] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 3-methoxybenzoate (14.2 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (16.4 mg, 73% yield). 1 H NMR (400MHz, CDCl3) δ: 7.60-7.56 (m, 1H), 7.55-7.51 (m, 1H), 7.48-7.40 (m, 2H), 7.36 (t, J=7.9Hz, 1H), 7.31-7.21 (m, 2H), 7.02 (d, J=0.9Hz, 1H), 6.91 (ddd, J=8.2, 2.6, 0.9Hz, 1H), 3.89 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 158.6, 131.9, 130.0, 129.3, 124.5, 123.1, 121.1, 117.6, 114.6, 111.3, 110.2, 101.8, 55.5ppm.

[0048] Example 9

[0049] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 4-dimethylaminobenzoate (16.0 μL, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (14.9 mg, 63% yield).1 H NMR (400MHz, CDCl3) δ: 7.77-7.73 (m, 2H), 7.54-7.47 (m, 2H), 7.25-7.19 (m, 2H), 6.80 (s, 1H), 6.79-6.75 (m, 2H), 3.02 (s, 6H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 157.1, 154.6, 150.7, 130.0, 126.3, 123.2, 122.8, 120.3, 118.7, 112.3, 110.9, 98.2, 40.5ppm.

[0050] Example 10

[0051] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 4-chlorobenzoate (17.1 mg, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (16.3 mg, 41% yield). 1 H NMR (400MHz, CDCl3) δ: 7.81-7.76 (m, 2H), 7.60-7.55 (m, 1H), 7.51 (d, J=8.1Hz, 1H), 7.43-7.38 (m, 2H), 7.32-7.20 (m, 2H)., 7.01 (s, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 155.0, 154.9, 134.4, 129.2, 126.2, 124.7, 123.2, 121.1, 111.3.101.9ppm.

[0052] Example 11

[0053] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 2-naphthoate (18.6 mg, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (16.1 mg, 66% yield). 1 H NMR (400MHz, CDCl3) δ: 8.38 (s, 1H), 7.94-7.83 (m, 4H), 7.63-7.47 (m, 4H), 7.28 (m, 2H), 7.14 (s, 1H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ: 156.1, 155.1, 133.6, 133.4, 129.4, 128.6, 128.6, 127 .94, 127.8, 126.8, 126.6, 124.6, 124.0, 123.1, 122.9, 121.1, 111.3, 102.1ppm.

[0054] Example 12

[0055] In a nitrogen-filled glove box, 2-fluorotoluene (0.1 mL, 0.91 mmol), CsN(SiMe3)2 (58.6 mg, 0.2 mmol), cesium sulfate (36.2 mg, 0.1 mmol), methyl 1-naphthoate (18.6 mg, 0.1 mmol), and anhydrous methyl tert-butyl ether (0.5 mL) were added sequentially to a dry microwave-safe vial containing magnetic induction. The vial was then removed from the glove box and sealed with a cap fitted with a rubber diaphragm. The reaction mixture was placed in an oil bath at 110 °C for 12 hours. The sealed vial was removed from the oil bath and cooled to room temperature, then 3 drops of water were added at room temperature. The reaction mixture was passed through a silica gel septum, washed with an additional 6 mL of ethyl acetate (3 × 2 mL), and the combined solutions were concentrated under reduced pressure. The crude product was loaded onto a silica gel column and purified by rapid chromatography to give the product (21.5 mg, 88% yield). 1H NMR(400MHz,CDCl3)δ:8.62-8.37(m,1H),7.98-7.86(m,3H),7.71-7.65(m,1H),7.64-7.53(m,4H),7.39-7.26(m,2H),7.14-7.07(m,1H)ppm. 13 C{ 1 H}NMR(101MHz,CDCl3)δ:155.7,155.1,134.0,130.8,129.7,129.2,128.8,128.4,127.4,127.0,126.3,125.6,125.4,124.5,123.1,121.1,111.4,106.1ppm.

Claims

1. A method for synthesizing benzofuran compounds, characterized in that: In an inert gas environment, 2-fluorotoluene compounds of Formula 1 and methyl benzoate compounds of Formula 2 were reacted with the organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate to synthesize benzofuran compounds of Formula 3 under heating conditions; wherein R 1 Selected from any one of hydrogen, 3-fluoro, 5-chloro, 6-bromine, or 5-methoxy, R 2 It is selected from any one of hydrogen, 4-methyl, 4-methoxy, 3-methoxy, 4-dimethylamino, or 4-chloro.

2. A method for synthesizing benzofuran compounds, characterized in that: In an inert gas environment, 2-fluorotoluene (Formula 1) and methyl 2-naphthocarboxylate (Formula 4) were reacted with the organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate to synthesize the benzofuran compound (Formula 3) under heating conditions.

3. A method for synthesizing benzofuran compounds, characterized in that: In an inert gas environment, 2-fluorotoluene (Formula 1) and methyl 1-naphthocarboxylate (Formula 5) were reacted with the organic solvent methyl tert-butyl ether in the presence of bis(trimethylsilyl)aminocesium and cesium sulfate to synthesize the benzofuran compound (Formula 3) under heating conditions.

4. The synthesis method according to claims 1, 2 and 3, characterized in that, The inert gas mentioned is nitrogen.

5. The synthesis method according to claim 1, characterized in that, The molar ratio of the 2-fluorotoluene compound shown in Formula 1, the methyl benzoate compound shown in Formula 2, bis(trimethylsilyl)aminocesium and cesium sulfate in the reaction is 9.1–7.6:1:2:1; the reaction temperature is 110 °C.

6. The synthesis method according to claim 2, characterized in that, In the reaction, the molar ratio of 2-fluorotoluene (Formula 1), methyl 2-naphthoic acid (Formula 4), bis(trimethylsilyl)aminocesium, and cesium sulfate is 9.1:1:2:1; the reaction temperature is 110℃.

7. The synthesis method according to claim 3, characterized in that, The molar ratio of 2-fluorotoluene (Formula 1), methyl 1-naphthoic acid (Formula 5), ​​bis(trimethylsilyl)aminocesium, and cesium sulfate in the reaction is 9.1:1:2:1; the reaction temperature is 110℃.

8. The synthesis method according to claim 1, characterized in that, The 2-fluorotoluene compounds, methyl benzoate compounds, and the product benzofuran compounds mentioned are one of the following:

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