Method for preparing 2-aryl-3-difluoromethyl benzothiophene by electrochemical reaction

Abstract

The invention relates to a method for preparing 2-aryl-3-difluoromethyl benzothiophene by utilizing an electrochemical reaction. Specifically, the invention provides an electrochemical anodic oxidation cathode reduction characteristic instead of a traditional chemical oxidation reducing agent, sodium difluoromethanesulfinate is used as a difluoromethyl donor, and a difluoromethyl free radical is excited through electrochemical anodic oxidation, so that the difluoromethyl free radical is synthesized. The preparation of the target molecule 2-aryl-3-difluoromethyl benzothiophene is realized through intramolecular cyclization initiated by addition of free radicals to active alkyne. The method does not need to add an additional transition metal catalyst and a super-stoichiometric redox agent, has the advantages of mild reaction conditions, high product yield, good chemical selectivity and the like, better conforms to the purpose of green and sustainable development of the current society, and has a good industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 2-aryl-3-difluoromethylbenzothiophene by means of an electrochemical reaction. Background Technology

[0002] Benzothiophene and its derivatives are important components of heterocyclic compounds, widely found in natural products, functional materials, pharmaceuticals, and pesticides. They possess excellent pharmacological activity and industrial development value. In the pharmaceutical field, they exhibit antimicrobial, anticancer, anti-inflammatory, antioxidant, anticonvulsant, antituberculosis, and antidiabetic activities, and can be used to prepare drugs such as raloxifene, zileutone, and proxicam. In the industrial field, they can be used to prepare indigo dyes, organic light-emitting semiconductors, and photovoltaic cells. In agriculture, they can be used to produce organophosphorus insecticides such as basil. Therefore, the development of synthetic methods for benzothiophene and its derivatives has significant research and practical value.

[0003] In recent years, the introduction of fluorine atoms has significantly impacted the chemical, physical, and biological properties of organic molecules, making the introduction of fluorine atoms or fluorine-containing groups a common method in drug and pesticide development. Difluoromethyl groups have attracted considerable attention due to two key properties: first, they can serve as lipophilic hydrogen bond donors, enhancing the selectivity of biomolecule-drug binding; second, they can act as a more lipophilic bioisostere for thiols, alcohols, and amide groups. Therefore, developing efficient methods for introducing difluoromethyl groups into benzothiophene is of significant research importance for the development and modification of this type of active pharmaceutical ingredient.

[0004] With the popularization of the concept of green and sustainable development, green synthesis tools in the field of organic synthesis are constantly being developed. Electrochemical reactions, due to their anodic oxidation and cathodic reduction characteristics, have become an ideal alternative to traditional redox conversion methods. In electrochemical systems, substrates or reagents can directly undergo redox processes without the use of exogenous chemical oxidants or reductants. By adjusting the applied current or electromotive force, the reaction progress of the substrate can be precisely controlled. Therefore, exploring green synthesis methods for difluoromethylated benzothiophene using electrochemical reaction systems has significant research value and practical application potential. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing 2-aryl-3-difluoromethylbenzothiophene by means of an electrochemical reaction, which replaces the use of traditional redox agents and transition metal catalysts with an electrochemical reaction system, and develops a production process that is simple to operate, efficient, green and environmentally friendly and easy to scale up.

[0006] To address the aforementioned problems, this invention provides a method for preparing 2-aryl-3-difluoromethylbenzothiophene via an electrochemical reaction, the method comprising the step of reacting a compound of formula I with a compound of formula II under electrolytic conditions to form a compound of formula III.

[0007]

[0008] Among them, R 1 Selected from C 1-6 Alkyl, C6 aryl or C 5-6 Heteroaryl, the C 1-6 Alkyl, C6 aryl or C 5-6 The heteroaryl group is optionally selected from one or more halogens, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkyl groups are substituted;

[0009] R 2 Selected from halogen, cyano, C 1-6 Alkyl, the C 1-6 The alkyl group is substituted by one or more halogens;

[0010] n is a number between 0 and 4.

[0011] In some embodiments, R in the compound shown in Formula I 1 Selected from C6 aryl (phenyl), wherein the C6 aryl group is optionally selected from one or more halogens, cyano, nitro, C... 1-6 Alkyl, C 1-6 Alkyl groups are substituted.

[0012] In some embodiments, R in the compound shown in Formula I 2 Selected from halogen or C 1-6 Alkyl groups, such as bromine, chlorine, methyl, or ethyl.

[0013] In some embodiments, the compound represented by Formula I is selected from:

[0014]

[0015] In some embodiments, the compound represented by Formula III is selected from:

[0016]

[0017] In some embodiments, the electrolyte in the electrolysis conditions is selected from at least one of tetraethylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, tetramethylammonium tetrafluoroborate, tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, or tetrabutylammonium hexafluorophosphate.

[0018] In some embodiments, the electrolyte used in the electrolysis conditions is selected from tetrabutylammonium tetrafluoroborate.

[0019] In some implementations, the electrolysis conditions use a graphite rod electrode as the anode and a platinum sheet electrode as the cathode.

[0020] In some embodiments, the constant current in the electrolysis conditions is selected from 6-15mA, including but not limited to 6, 7, 8, 9, 10, 11, 12, 13, 14, 15mA or any two of these values. In some embodiments, the constant current in the electrolysis conditions is selected from 8-12mA.

[0021] In some embodiments, the aforementioned reaction solvent is selected from a mixture of acetonitrile and water. In some embodiments, the volume ratio of acetonitrile to water is 4:1.

[0022] In some embodiments, the molar ratio of the compound of Formula II to the compound of Formula I is 1.5:1 to 3:1, including but not limited to 1.5:1, 1.7:1, 1.8:1, 2:1, 2.1:1, 2.2:1, 2.6:1, 2.8:1, 3:1, or any value between any two numbers. In some embodiments, the molar ratio of the compound of Formula II to the compound of Formula I is 1.5:1 to 2:1.

[0023] On the other hand, in some embodiments, the molar ratio of the electrolyte to the compound shown in Formula I is 0.25:1 to 1:1, for example 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1, 0.65:1, 0.6:1, 0.65:1, 0.7:1, 0.8:1, 0.9:1 or any value between any two numbers.

[0024] In some embodiments, the molar ratio of the electrolyte to the compound shown in Formula I is 0.5:1 to 1:1.

[0025] To ensure complete reaction, the aforementioned reaction time is 2–4 hours, for example, 2.5 hours, 3 hours, and 3.5 hours. The aforementioned reaction temperature is selected from 25–40°C, for example, 25°C, 30°C, 35°C, and 40°C.

[0026] In some implementations, the aforementioned method includes the following steps:

[0027] 1) Add the compound shown in Formula I, the compound shown in Formula II, the electrolyte and the reaction solvent sequentially to a membraneless electrolytic cell equipped with electrodes. Connect the electrodes to an adjustable DC regulated power supply and stir the reaction under a constant temperature water bath.

[0028] 2) The reaction was monitored to be complete by thin-layer chromatography. The product was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target product.

[0029] In some implementations, the adjustable DC regulated power supply in step (1) of the aforementioned method is rated as 5A / 30V, 10A / 30V, or 5A / 60V.

[0030] The preparation method of the present invention also includes one or more steps such as filtration, extraction, drying, concentration or purification (e.g., column chromatography).

[0031] Beneficial effects:

[0032] (1) Compared with the prior art, the present invention adopts an electrochemical synthesis method, and for the first time achieves the efficient preparation of 2-aryl-3-difluoromethylbenzothiophene without the need for the addition of additional transition metal catalysts and superstoichiometric chemical oxidants. This method has the advantages of simple operation, mild reaction conditions, high product yield, good chemical selectivity and easy scale-up, which is more in line with the concept of green and sustainable development in today's society.

[0033] (2) The present invention achieves a yield of up to 93% of the product 2-phenyl-3-difluoromethylbenzothiophene in a short time through an electrochemical reaction method.

[0034] The term "filtration" in this invention is merely a description of one method of separating solids and liquids, and does not refer to only one specific operation. In actual production, methods such as centrifugation or spin-filtering also fall into this category.

[0035] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0036] The term "cyano" refers to -CN.

[0037] The term "nitro" refers to -NO2.

[0038] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including, but not limited to, halogens.

[0039] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0040] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including but not limited to halogens.

[0041] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

[0042]

[0043] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, such as 7-, 8-, or 9-membered, and more preferably 5- or 6-membered. Examples include, but are not limited to:

[0044] The term “optional” or “optional” means that the event or situation described below may, but does not have to, occur, including the circumstances under which the event or situation may or may not occur.

[0045] The values ​​used in this invention are instrument measurements and are subject to a certain degree of error. Generally, ±20% is within a reasonable error range. Of course, the context in which the value is used needs to be considered, and the values ​​can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. Attached Figure Description

[0046] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0047] Figure 1 , Figure 2 , Figure 3 The 1H NMR spectrum, fluorine spectrum, and carbon spectrum of the product 2-phenyl-3-difluoromethyl-benzothiophene prepared by the method in Example 1 are shown.

[0048] Figure 4 , Figure 5 , Figure 6 The 1H NMR spectrum, fluorine spectrum, and carbon spectrum of 2-p-tolyl-3-difluoromethyl-benzothiophene prepared in Example 21.

[0049] Figure 7 , Figure 8 , Figure 9 The 1H NMR spectrum, fluorine spectrum, and carbon spectrum of 2-p-chlorophenyl-3-difluoromethyl-benzothiophene prepared in Example 22.

[0050] Figure 10 , Figure 11 , Figure 12 The 1H NMR spectrum, fluorine spectrum, and carbon spectrum of 2-p-cyanophenyl-3-difluoromethyl-benzothiophene prepared in Example 23 are shown.

[0051] Figure 13 , Figure 14 , Figure 15 The 1H NMR spectrum, fluorine spectrum, and carbon spectrum of 2-phenyl-3-difluoromethyl-6-methylbenzothiophene prepared in Example 24 are shown. Detailed Implementation

[0052] The present invention can be better understood from the following embodiments.

[0053] In the following examples, the conversion rate was determined by HPLC.

[0054] Example 1

[0055] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode as the cathode, connected to a DC power supply. The reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 93%. The product was characterized by NMR mass spectrometry. 1 HNMR (400MHz, CDCl3) δ8.16 (d, J = 8.1Hz, 1H), 7.85 (d, J = 9.7Hz, 1H), 7.60-7.32 (m, 7H), 6.77 (t, J = 54.0Hz, 1H). 19 F NMR (376MHz, CDCl3) δ-109.21. 13C NMR (101MHz, CDCl3) δ 147.02, 138.94, 136.77, 132.02, 129.80, 129.44, 129.02, 125.14, 125.12, 124.77, 123.83 (t, J = 2.1Hz), 122.08, 112.52 (t, J = 233.8Hz). HRMS (ESI) m / z theoretical value: C 15 H 10 F2S[M+H] + 261.0544, measured value: 261.0539.

[0056] Example 2

[0057] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (1.0 mmol, 137.95 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 91%.

[0058] Example 3

[0059] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.5 mmol, 68.98 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 75%.

[0060] Example 4

[0061] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), tetrabutylammonium chloride (0.25 mmol, 69.48 mg), and acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction flask was connected to a DC power supply and placed in a 30°C water bath with stirring for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 71%.

[0062] Example 5

[0063] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutylammonium hexafluorophosphate (0.25 mmol, 96.86 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 89%.

[0064] Example 6

[0065] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetraethyltetrafluoroborate (0.25 mmol, 54.27 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 87%.

[0066] Example 7

[0067] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetramethyltetrafluoroborate (0.25 mmol, 40.23 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 83%.

[0068] Example 8

[0069] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.5 mmol, 80.46 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 93%.

[0070] Example 9

[0071] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.125 mmol, 20.12 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 65%.

[0072] Example 10

[0073] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 12 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 87%.

[0074] Example 11

[0075] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 4 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 61%.

[0076] Example 12

[0077] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. Graphite rod electrodes were used as the anode and cathode, and the reaction was connected to a DC power supply. The reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 67%.

[0078] Example 13

[0079] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. Platinum sheet electrodes were used as the anode and cathode, and the reaction was connected to a DC power supply. The reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 79%.

[0080] Example 14

[0081] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A platinum sheet electrode was used as the anode, and a graphite rod electrode was used as the cathode. The reaction was connected to a DC power supply and placed in a 30°C water bath with stirring for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 63%.

[0082] Example 15

[0083] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (5 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 73%.

[0084] Example 16

[0085] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent DMF (5 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 66%.

[0086] Example 17

[0087] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent DMSO (5 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 62%.

[0088] Example 18

[0089] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), reaction solvent DMF (4 mL), and water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 30°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 71%.

[0090] Example 19

[0091] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 40°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 92%.

[0092] Example 20

[0093] In a diaphragm-free electrolytic cell equipped with electrodes, 2-phenylethynyl-anisole (0.5 mmol, 112.03 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode was used as the cathode. The reaction was connected to a DC power supply, and the reaction flask was placed in a 25°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-benzothiophene, with a yield of 87%.

[0094] Table 1. Yields of 2-phenyl-3-difluoromethylbenzothiophene compounds

[0095]

[0096]

[0097] Example 21

[0098] In a diaphragm-free electrolytic cell equipped with electrodes, 2-p-methylphenylethynyl-anisole (0.5 mmol, 119.04 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutylammonium tetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode as the cathode, connected to a DC power supply. The reaction flask was placed in a 25°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-p-tolyl-3-difluoromethyl-benzothiophene, with a yield of 95%. The product was characterized by NMR mass spectrometry. 1 H NMR (400MHz, CDCl3) δ8.18(d,J=7.6Hz,1H),7.87(d,J=7.8Hz,1H),7.64-7.12(m,6H),6.81(t,J=54.0Hz,1H),2.46(s,3H). 19 F NMR (376MHz, CDCl3) δ-109.17. 13 C NMR (101MHz, CDCl3) δ 147.25, 139.60, 138.80, 136.80, 129.69, 129.62, 129.04, 125.20, 125.02, 124.98, 123.70, 122.02, 112.59 (t, J = 233.3Hz), 21.29. HRMS (ESI) m / z theoretical value: C 16 H 12 F2S[M+H] + 275.0701, Measured value: 275.0704.

[0099] Example 22

[0100] In a diaphragm-free electrolytic cell equipped with electrodes, 2-p-chlorophenylethynyl-anisole (0.5 mmol, 129.01 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode as the cathode, connected to a DC power supply. The reaction flask was placed in a 25°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-p-chlorophenyl-3-difluoromethyl-benzothiophene, with a yield of 90%. The product was characterized by NMR mass spectrometry. 1H NMR (400MHz, CDCl3) δ8.15 (d, J = 8.0Hz, 1H), 7.85 (d, J = 7.5Hz, 1H), 7.59-7.35 (m, 6H), 6.73 (t, J = 53.9Hz, 1H). 19 F NMR (376MHz, CDCl3) δ-109.09. 13 C NMR (101MHz, CDCl3) δ 145.41 (t, J = 10.2Hz), 138.83, 136.62, 135.75, 130.96, 130.40, 129.26, 125.34, 125.24, 124.82, 123.81 (t, J = 2.1Hz), 122.07, 112.21 (t, J = 234.1Hz). HRMS (ESI) m / z theoretical value: C 15 H9ClF2S[M+H] + :295.0154, Measured value:295.0148.

[0101] Example 23

[0102] In a diaphragm-free electrolytic cell equipped with electrodes, 2-p-cyanophenylethynyl-anisole (0.5 mmol, 124.53 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode as the cathode, connected to a DC power supply. The reaction flask was placed in a 25°C water bath and stirred at a constant current of 8 mA for 3 hours. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-p-cyanophenyl-3-difluoromethyl-benzothiophene, with a yield of 79%. The product was characterized by NMR mass spectrometry. 1 H NMR (400MHz, CDCl3) δ8.16(d,J=8.0Hz,1H),7.88(d,J=7.3Hz,1H),7.80(d,J= 8.4Hz,2H),7.64(d,J=8.4Hz,2H),7.57-7.33(m,2H),6.74(t,J=53.8Hz,1H). 19 F NMR (376MHz, CDCl3) δ -108.91. 13C NMR (101MHz, CDCl3) δ 143.99 (t, J = 9.4Hz), 139.10, 136.71, 136.55, 132.67, 130.43, 125.83, 125.51, 124.00, 122.17, 118.13, 113.14, 112.80 (t, J = 233Hz). HRMS (ESI) m / z theoretical value: C 16 H9F2NS[M+H] + :286.0497, Measured value:286.0491.

[0103] Example 24

[0104] In a diaphragm-free electrolytic cell equipped with electrodes, 5-methyl-2-phenylethynyl anisole (0.5 mmol, 119.04 mg), sodium difluoromethyl sulfinate (0.75 mmol, 103.46 mg), electrolyte tetrabutyltetrafluoroborate (0.25 mmol, 82.32 mg), and reaction solvent acetonitrile (4 mL) / water (1 mL) were added sequentially. A graphite rod electrode was used as the anode, and a platinum sheet electrode as the cathode, connected to a DC power supply. The reaction flask was placed in a 25°C water bath and stirred for 3 hours under a constant current of 8 mA. The reaction mixture was washed with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the target product 2-phenyl-3-difluoromethyl-6-methylbenzothiophene, with a yield of 94%. The product was characterized by NMR mass spectrometry. 1 H NMR (400MHz, CDCl3) δ8.04 (d, J = 8.3Hz, 1H), 7.65 (s, 1H), 7.57-7.35 (m, 5H), 7.29 (d, J = 8.3Hz, 1H), 6.76 (t, J = 54.0Hz, 1H), 2.50 (s, 3H). 19 F NMR (376MHz, CDCl3) δ-109.15. 13 C NMR (101MHz, CDCl3) δ 145.79 (t, J = 10.3Hz), 139.22, 135.23, 134.49, 132.14, 129.74, 129.25, 128.95, 126.82, 124.54 (t, J = 24.8Hz), 123.37 (t, J = 2.0Hz), 121.81, 112.53 (t, J = 233.6Hz), 21.56. HRMS (ESI) m / z theoretical value: C 16 H 12 F2S[M+H] + 275.0701, Measured value: 275.0711.

[0105] This invention provides a method and approach for preparing 2-aryl-3-difluoromethylbenzothiophene compounds using an electrochemical reaction. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for preparing 2-aryl-3-difluoromethylbenzothiophene, characterized in that, The method includes the step of reacting the compound of Formula I with the compound of Formula II under electrolytic conditions to form the compound of Formula III. Among them, R 1 Selected from C 1-6 Alkyl, C6 aryl or C 5-6 heteroaryl, the C 1-6 Alkyl, C6 aryl or C 5-6 The heteroaryl group is optionally selected from one or more halogens, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkyl groups are substituted; R 2 Selected from halogen, cyano, C 1-6 Alkyl, the C 1-6 The alkyl group is substituted by one or more halogens; n is a number between 0 and 4.

2. The method according to claim 1, characterized in that, The electrolyte in the electrolysis conditions is selected from at least one of tetraethylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, tetramethylammonium tetrafluoroborate, tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide or tetrabutylammonium hexafluorophosphate, preferably tetrabutylammonium tetrafluoroborate.

3. The method according to claim 1 or 2, characterized in that, In the electrolysis conditions, a graphite rod electrode is used as the anode and a platinum sheet electrode is used as the cathode; the constant current is selected from 6-15mA, preferably 8-12mA.

4. The method according to any one of claims 1-3, characterized in that, The reaction solvent is selected from a mixed solution of acetonitrile and water, preferably with a volume ratio of acetonitrile to water of 4:

1.

5. The method according to any one of claims 1-4, characterized in that, The molar ratio of the compound shown in Formula II to the compound shown in Formula I is 1.5:1 to 3:1, preferably 1.5:1 to 2:

1.

6. The method according to claim 2, characterized in that, The molar ratio of the electrolyte to the compound shown in Formula I is 0.25:1 to 1:1, preferably 0.5:1 to 1:

1.

7. The method according to any one of claims 1-6, characterized in that, The compound represented by Formula I is selected from:

8. The method according to claim 1, characterized in that, The reaction temperature is selected from 25 to 40℃; the reaction time is 2 to 4 hours.

9. The method according to any one of claims 1-8, characterized in that, The method includes the following steps: 1) Add the compound shown in Formula I, the compound shown in Formula II, the electrolyte and the reaction solvent sequentially to a membraneless electrolytic cell equipped with electrodes. Connect the electrodes to an adjustable DC regulated power supply and stir the reaction under a constant temperature water bath. 2) The reaction was monitored to be complete by thin-layer chromatography. The product was washed with water, extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, concentrated, and then purified by column chromatography to obtain the target product.

10. The method according to claim 9, characterized in that, The adjustable DC regulated power supply mentioned in step (1) has specifications of 5A / 30V, 10A / 30V or 5A / 60V.

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