One-pot synthesis method of benzothiophene-3-ketone and 3-oxygen substituted benzothiophene

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a one-pot synthesis method of benzothiophene-3-ketone and 3-oxygen substituted benzothiophene. 2-methyl fluorobenzoate as shown in a formula 1 and phenylmethyl mercaptan as shown in a formula 2 are mixed with an organic solvent tetrahydrofuran for reaction under the condition of bis (trimethylsilyl) lithium amide, and then an electrophilic reagent alkyl halide is added for reaction to synthesize the benzothiophene-3-ketone compound as shown in a formula 3. 2-methyl fluorobenzoate as shown in a formula 1 and phenylmethyl mercaptan as shown in a formula 2 are mixed with an organic solvent tetrahydrofuran for reaction under the condition of bis (trimethylsilyl) lithium amide, and then an electrophilic reagent alkyl halide is added for reaction to synthesize 3-alkoxy benzothiophene as shown in a formula 4; wherein the electrophilic reagent alkyl halide can be replaced by TBSCl, and 3-siloxy benzothiophene as shown in a formula 5 is synthesized; wherein the electrophilic reagent alkyl halide can be replaced by Tf2O, and 3-sulfonyloxy benzothiophene shown as a formula 6 is synthesized. No transition metal participates in the method, separation and purification of the intermediate are avoided, and the synthesis efficiency is greatly improved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a synthetic method for efficiently preparing benzothiophene-3-one and 3-oxosubstituted benzothiophene from methyl 2-fluorobenzoate and benzyl thiol via an electrophilic trapping reaction. Background Technology

[0002] Benzothiophene compounds are an important class of heterocyclic compounds whose unique molecular structures give them great potential for application in medicinal chemistry and materials science. In the pharmaceutical field, the benzothiophene core structure is considered the core framework, and its derivatives typically exhibit broad and significant biological activities. Existing technologies have disclosed various benzothiophene-based compounds with antibacterial and antifungal pharmacological properties (Figure 1), such as raloxifene, azoxifene, zileuton, and sertaconazole. Furthermore, benzothiophene derivatives also have important applications in non-pharmaceutical fields such as optoelectronic materials. Despite the significant pharmaceutical potential of benzothiophene derivatives, developing new synthetic methods remains a serious challenge. Therefore, there is an urgent need to develop synthetic routes with milder reaction conditions and greater cost-effectiveness.

[0003] Summary of the Invention

[0004] This invention provides a method for the efficient synthesis of benzothiophene-3-one and 3-oxo-substituted benzothiophene from readily available methyl 2-fluorobenzoate and benzyl mercaptan via an electrophilic trapping reaction. Specifically, benzothiophene-3-one derivatives and 3-alkoxy-substituted benzothiophene can be synthesized by directly adding an electrophilic alkyl halide and performing a one-pot, two-step tandem reaction; 3-oxo-substituted benzothiophene can be synthesized by directly adding an electrophilic TBSCl or Tf₂O and performing a one-pot, two-step tandem reaction. The specific scheme is as follows:

[0005]

[0006] A method for synthesizing benzothiophene-3-one compounds involves reacting methyl 2-fluorobenzoate (Formula 1) and benzyl thiol (Formula 2) in an inert gas environment with an organic solvent tetrahydrofuran in the presence of lithium bis(trimethylsilyl)amino. An electrophilic alkyl halide is then added to synthesize the benzothiophene-3-one compound shown in Formula 3. Wherein R... 1 Selected from any one of methyl, ethyl, isopropyl, or tert-butyl, R 2 It is selected from either allyl or benzyl.

[0007] A method for synthesizing 3-oxy-substituted benzothiophene compounds involves reacting methyl 2-fluorobenzoate (Formula 1) and benzyl thiol (Formula 2) in an inert gas environment with a tetrahydrofuran organic solvent in the presence of lithium bis(trimethylsilyl)amino. An electrophilic alkyl halide is then added to synthesize 3-alkoxybenzothiophene (Formula 4). The electrophilic alkyl halide can be replaced with TBSCl to synthesize 3-siloxybenzothiophene (Formula 5). The electrophilic alkyl halide can be replaced with Tf₂O to synthesize 3-sulfonyloxybenzothiophene (Formula 6). R… 1 It is selected from any one of methyl, ethyl, isopropyl or tert-butyl.

[0008] The method of this invention employs an electrophilic capture strategy in a one-pot process to achieve the capture of intermediates in the reaction of methyl 2-fluorobenzoate and benzyl mercaptan by an electrophilic reagent, resulting in the efficient synthesis of benzothiophene-3-one compounds and 3-oxosubstituted benzothiophene compounds. This reduces the number of reaction steps, thereby increasing product yield. The raw materials used in the synthesis method are simple and economical. The R in this invention... 1 R 2 It offers a variety of options and has wider applicability.

[0009] Preferred, R 1 Selected from any one of methyl, ethyl, isopropyl, or tert-butyl, R 2 It is selected from either allyl or benzyl.

[0010] Preferably, the inert gas is nitrogen.

[0011] Preferably, the organic solvent is tetrahydrofuran.

[0012] Preferably, the molar ratio of methyl 2-fluorobenzoate (Formula 1), benzyl mercaptan (Formula 2), lithium bis(trimethylsilyl)amino and alkyl halide in the reaction is 1:1.1:2.2:3; and the reaction temperature is 30°C and 110°C.

[0013] Preferably, the molar ratio of methyl 2-fluorobenzoate (Formula 1), benzyl mercaptan (Formula 2), lithium bis(trimethylsilyl)amino and TBSCl in the reaction is 1:1.1:2.2:3; and the reaction temperature is 30°C and 110°C.

[0014] Preferably, the molar ratio of methyl 2-fluorobenzoate (Formula 1), benzyl mercaptan (Formula 2), lithium bis(trimethylsilyl)amino and Tf2O in the reaction is 1:1.1:2.2:3; and the reaction temperature is 30℃ and 110℃.

[0015] Preferably, using the method of the present invention, benzothiophene-3-one compounds with the following structures can be synthesized:

[0016]

[0017] Preferably, the method of the present invention can synthesize 3-oxygen-substituted benzothiophene compounds with the following structures:

[0018]

[0019]

[0020] 3-O-substituted benzothiophene (Formula 3) was synthesized by reacting methyl 2-fluorobenzoate and benzyl mercaptan with a tetrahydrofuran organic solvent under bis(trimethylsilyl)aminolithium conditions, followed by the addition of an electrophilic alkyl halide. 3-Alkoxybenzothiophene (Formula 4) was synthesized by reacting methyl 2-fluorobenzoate and benzyl mercaptan with a tetrahydrofuran organic solvent under bis(trimethylsilyl)aminolithium conditions, followed by the addition of an electrophilic alkyl halide. The electrophilic alkyl halide could be replaced with TBSCl to synthesize 3-siloxybenzothiophene (Formula 5); the electrophilic alkyl halide could be replaced with Tf2o to synthesize 3-sulfonyloxybenzothiophene (Formula 6).

[0021] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0022] The raw materials used in the synthesis method of this invention are all inexpensive and readily available;

[0023] The synthesis method of this invention does not use transition metal catalysts, making it green and environmentally friendly;

[0024] This invention employs a one-pot, two-step synthesis method, which avoids the separation and purification of intermediates and improves the yield of the product.

[0025] 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.

[0026] R in this invention 1 R 2 With a variety of options available, the method of this invention has a wider range of applications and can synthesize a variety of benzothiophene-3-one compounds and 3-oxosubstituted benzothiophene compounds. Attached Figure Description

[0027] 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 image shows 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 7B The 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

[0028] To facilitate understanding by those skilled in the art, the concept of the present invention will be further described 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.

[0029] Example 1

[0030] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Iodomethane (42.6 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (40% yield). 1 H NMR (400MHz, CDCl3) δ: 7.89-7.85 (m, 2H), 7.81-7.75 (m, 2H), 7.48-7.43 (m, 2H), 7.42-7.38 (m, 1H), 7.37-7.31 (m, 2H), 3.88 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 147.5, 135.8, 134.9, 133.0, 128.9, 128.0, 127.9, 126.9, 125.1, 124.4, 122.9, 121.1, 61.0ppm.

[0031] By changing the raw materials in Example 1, the following 12 sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding NMR spectrum of the product is shown in Figure 1. The NMR spectra of the products in the remaining sets 2-12 correspond to the sequence numbers of the respective examples.

[0032] The table lists the structural formulas of the products in each of the 1-12 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.

[0033]

[0034]

[0035] Example 2

[0036] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C and reacted for 10 hours. Iodoethane (46.8 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C and reacted for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (44% yield). 1 H NMR (400MHz, DMSO-d6) δ: 7.92-7.87 (m, 2H), 7.80-7.75 (m, 2H), 7.48-7.38 (m, 3H), 7.37-7.32 (m, 2H), 4.10-4.05 (m, 2H), 1.39 (t, J = 7.0Hz, 3H) ppm. 13 C{ 1 H} NMR (101MHz, DMSO-d6) δ: 146.5, 135.8, 135.4, 133.3, 128.9, 128.0, 127.8, 127.1, 125.1, 124.4, 122.8, 121.2, 69.4, 16.0ppm.

[0037] Example 3

[0038] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (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 30 °C for 10 hours. Next, 1-iodopropane (51.0 mg, 0.3 mmol) was added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 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 with Na2SO4, 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 obtain the product (56% yield). 1 H NMR (400MHz, CDCl3) δ: 7.92-7.88 (m, 2H), 7.82-7.76 (m, 2H), 7.49-7.44 (m, 2H), 7.4 3-7.31(m,3H), 3.96(t,J=6.6Hz,2H), 1.89-1.76(m,2H), 1.06(t,J=7.4Hz,3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 146.7, 135.9, 135.3, 133.3, 128.8, 128.1, 127.8, 127.0, 125.1, 124.4, 122.9, 121.2, 23.7, 10.7ppm.

[0039] Example 4

[0040] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Next, 1-iodobutane (55.2 mg, 0.3 mmol) was added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 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 with Na2SO4, 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 obtain the product (52% yield). 1 H NMR (400MHz, CDCl3) δ: 7.92-7.86 (m, 2H), 7.81-7.75 (m, 2H), 7.48-7.43 (m, 2H), 7.39-7.32 (m , 3H), 3.99 (t, J = 6.5Hz, 2H), 1.84-1.72 (m, 2H), 1.58-1.50 (m, 2H), 0.96 (t, J = 7.4Hz, 3H) ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 146.8, 135.9, 135.3, 133.3, 128.8, 128.1, 127.8, 127.0, 125.1, 124.4, 122.9, 121.2, 73.5, 32.5, 19.4, 14.1ppm.

[0041] Example 5

[0042] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Allyl bromide (36.3 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (81% yield). 1 H NMR (400MHz, CDCl3) δ: 7.78-7.73 (m, 1H), 7.62-7.58 (m, 2H), 7.57-7.52 (m, 1H), 7.43-7.38 (m, 1H), 7.35-7.30 (m, 2H), 7.29-7.2 5 (m, 1H), 7.21-7.17 (m, 1H), 5.77-5.64 (m, 1H), 5.23-5.16 (m, 1H), 5.09-5.04 (m, 1H), 3.27-3.20 (m, 1H), 3.07-3.00 (m, 1H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 202.1, 151.9, 138.8, 136.2, 132.6, 130.0, 128.8, 128.0, 127.6, 127.4, 125.08, 123.9, 120.0, 68.9, 43.4ppm.

[0043] Example 6

[0044] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Next, benzyl bromide (51.3 mg, 0.3 mmol) was added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 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 with Na2SO4, 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 obtain the product (70% yield). 1 H NMR (400MHz, CDCl3) δ: 7.75-7.63 (m, 3H), 7.48-7.42 (m, 1H), 7.36-7.27 (m, 4H), 7.16-7.07 (m, 6H), 3.75-3.58 (m, 2H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 202.3, 151.5, 138.9, 136.0, 135.9, 130.8, 130.2, 128.6, 128.1, 127.8, 127.7, 127.4, 127.1, 124.9, 123.7, 70.5, 45.5ppm.

[0045] Example 7

[0046] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Iodomethane (42.6 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (54% yield). 11 H NMR (400MHz, CDCl3) δ: 7.83-7.78 (m, 1H), 7.62-7.56 (m, 1H), 7.48-7.38 (m, 3H), 7.35-7.21 (m, 4H), 2.01 (s, 3H) ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 203.4, 152.0, 140.3, 136.3, 130.7, 128.8, 128.0, 127.9, 126.8, 125.1, 124.0, 63.8, 25.7ppm.

[0047] Example 8

[0048] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C and reacted for 10 hours. Iodoethane (46.8 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C and reacted for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (48% yield). 1H NMR (400MHz, CDCl3) δ: 7.78-7.72 (m, 1H), 7.59-7.53 (m, 3H), 7.42 (d, J=8.0Hz, 1H), 7.34-7.2 9 (m, 2H), 7.27-7.24 (m, 1H), 7.22-7.17 (m, 1H), 2.47-2.32 (m, 2H), 0.97 (t, J=7.2Hz, 3H)ppm. 13 C{ 1 H} NMR (101MHz, DMSO-d6) δ: 202.9, 152.1, 139.2, 136.1, 130.3, 128.7, 127.9, 127.5, 127.3, 125.0, 124.0, 70.7, 32.5, 10.0ppm.

[0049] Example 9

[0050] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Next, 1-iodopropane (51.01 mg, 0.3 mmol) was added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 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 with Na2SO4, 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 obtain the product (40% yield). 1 H NMR (400MHz, CDCl3) δ: 7.77-7.72 (m, 1H), 7.59-7.53 (m, 3H), 7.43-7.39 (m, 1H), 7.33-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7 .21-7.17(m,1H),2.41-2.33(m,1H),2.30-2.22(m,1H),1.52-1.42(m,1H),1.31-1.23(m,1H),0.92(t,J=7.3Hz,3H)ppm. 13 C{ 1H} NMR (101MHz, CDCl3) δ: 202.9, 152.1, 139.4, 136.1, 130.1, 128.7, 127.9, 127.5, 127.2, 125.0, 123.9, 70.0, 41.6, 19.0, 14.3ppm.

[0051] Example 10

[0052] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. Next, 1-iodobutane (55.2 mg, 0.3 mmol) was added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 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 with Na2SO4, 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 obtain the product (43% yield). 1 H NMR (400MHz, CDCl3) δ: 7.78-7.72 (m, 1H), 7.59-7.55 (m, 2H), 7.41 (d, J=8.0Hz, 1H), 7.35-7.23 (m, 4H), 7.22-7.16 (mn, 1H), 2.45-2.34 (m, 1H), 2.32-2.20 (m, 1H), 1.46-1.17 (m, 4H), 0.85 (t, J = 7.2Hz, 3H) ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 202.9, 152.1, 139.4, 136.1, 130.1, 128.7, 127.9, 127.5, 127.2, 125.0, 123.9, 70.0, 39.2, 27.7, 22.9, 14.0ppm.

[0053] Example 11

[0054] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C for 10 hours. TBS-Cl (45.0 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (88% yield). 1 H NMR (400MHz, CDCl3) δ: 7.83-7.72 (m, 4H), 7.48-7.43 (m, 2H), 7.41-7.33 (m, 3H), 1.11 (s, 9H), -0.09 (s, 6H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 141.8, 136.0, 135.7, 133.9, 129.2, 128.6, 127.6, 124.8, 124.0, 123.4, 122.7, 121.7, 26.0, 18.4, -4.0ppm.

[0055] Example 12

[0056] In a nitrogen-filled glove box, methyl 2-fluorobenzoate (15.4 mg, 0.1 mmol), LiN(SiMe3)2 (36.8 mg, 0.22 mmol), benzyl mercaptan (13.7 mg, 0.11 mmol), and anhydrous THF (0.5 mL) were added sequentially to a dry microwave-safe vial containing a magnetic inlet. 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 30 °C and reacted for 10 hours. Tf2O (84.6 mg, 0.3 mmol) was then added to the vial using a microsyringe, and the reaction mixture was placed in an oil bath at 110 °C and reacted for 5 hours. The sealed vial was removed from the oil bath and cooled to room temperature. Three drops of water were then added at room temperature. The reaction mixture was passed through a silica gel septum with Na2SO4, 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 obtain the product (76% yield).1 H NMR(400MHz,CDCl3)δ:7.87(d,J=8.1Hz,1H),7.84-7.77(m,1H),7.73-7.66(m,2H),7.54-7.42(m,5H)ppm. 13 C{ 1 H}NMR(101MHz,CDCl3)δ:135.4,134.2,132.8,132.4,130.3,129.6,129.2,129.1,126.0,125.7,122.8,120.9,118.5(q,J=320.9Hz)ppm。

Claims

1. A method for synthesizing a benzothiophene-3-ketone compound, characterized in that: In an inert gas environment, methyl 2-fluorobenzoate shown in formula 1 and benzyl mercaptan shown in formula 2 are mixed and reacted in the presence of lithium bis(trimethylsilyl)amide and an organic solvent tetrahydrofuran, and then reacted with an electrophilic reagent alkyl halide to synthesize benzothiophene-3-ketone compounds shown in formula 3; wherein R 1 is any one selected from methyl, ethyl, isopropyl or tert-butyl, R 2 is any one selected from allyl or benzyl.

2. A method for synthesizing a 3-oxygen-substituted benzothiophene compound, characterized in that: In an inert gas environment, 2-fluorobenzoic acid methyl ester shown in formula 1 and benzyl mercaptan shown in formula 2 are mixed and reacted in the presence of lithium bis(trimethylsilyl)amide and an organic solvent tetrahydrofuran, and then an electrophilic reagent alkyl halide is added to synthesize 3-alkoxybenzothiophene compounds shown in formula 4; wherein R 1 is any one selected from methyl, ethyl, isopropyl or tert-butyl.

3. A method for synthesizing a 3-oxygen-substituted benzothiophene compound, characterized in that: In an inert gas environment, methyl 2-fluorobenzoate shown in formula 1 and benzyl mercaptan shown in formula 2 are mixed with lithium bis(trimethylsilyl)amide in an organic solvent tetrahydrofuran, and then an electrophilic reagent TBSCl is added to synthesize 3-siloxylbenzothiophene shown in formula 5.

4. A method for synthesizing a 3-oxygen-substituted benzothiophene compound, characterized in that: In an inert gas environment, methyl 2-fluorobenzoate shown in formula 1 and benzyl mercaptan shown in formula 2 are mixed with lithium bis(trimethylsilyl)amide in an organic solvent tetrahydrofuran, and then an electrophilic reagent Tf2O is added to synthesize 3-sulfonyloxybenzothiophene shown in formula 6.

5. The method of synthesis according to claim 1, claim 2, claim 3 and claim 4, wherein The inert gas is nitrogen.

6. The method of synthesis of claim 1 and claim 2, wherein, In the reaction, the molar ratio of methyl 2-fluorobenzoate shown in formula 1, benzyl mercaptan shown in formula 2, lithium bis(trimethylsilyl)amide, and alkyl halide is 1:1.1:2.2:3, and the reaction temperature is 30°C and 110°C.

7. The method of synthesis of claim 3, wherein, In the reaction, the molar ratio of methyl 2-fluorobenzoate shown in formula 1, benzyl mercaptan shown in formula 2, lithium bis(trimethylsilyl)amide, and TBSCl is 1:1.1:2.2:3, and the reaction temperature is 30°C and 110°C.

8. The method of synthesis of claim 4, wherein, In the reaction, the molar ratio of methyl 2-fluorobenzoate shown in formula 1, benzyl mercaptan shown in formula 2, lithium bis(trimethylsilyl)amide, and Tf2O is 1:1.1:2.2:3, and the reaction temperature is 30°C and 110°C.

9. The method of synthesis of claim 1, wherein, The methyl 2-fluorobenzoate, the mercaptan, the alkyl halide, and the product benzothiophene-3-ketone are as follows:

10. The method of synthesis according to claim 2, claim 3 and claim 4, wherein, The methyl 2-fluorobenzoate, the mercaptan, the alkyl halide, and the product 3-oxygen-substituted benzothiophene are as follows, wherein the alkyl halide can be replaced by TBSCl or Tf2O:

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