A method for synthesizing 3-trifluoromethylpyridine or 3-difluoromethylpyridine compounds

Abstract

The present application relates to a kind of synthesis method of organic compound, specifically to a kind of synthesis method of 3-trifluoromethyl pyridine or 3-difluoromethyl pyridine compound. By the pyridine compound shown in formula I, methyl propionic acid ester, dimethyl acetylene dicarboxylate is reacted to prepare the oxazolone-pyridine complex of formula II; With fluoroalkylating agent in the presence of base and solvent, under the condition of photosensitizer, visible light irradiation, at 15~35oC reaction preparation obtains formula III compound, after reaction with acid, preparation obtains the 3-fluoroalkyl substituted pyridine compound shown in formula IV, wherein, R is hydrogen, methyl, methoxy, methylthio, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, nitrile group one or more, or or

Description

(I) Technical Field

[0001] This invention relates to a method for synthesizing organic compounds, and more specifically to a method for synthesizing 3-trifluoromethylpyridine and 3-difluoromethylpyridine compounds. (II) Background Technology

[0002] In medicinal chemistry, trifluoromethyl groups are a very important functional group (see Chem. Rev., 2011, 111, 4475-4521; Chem. Soc. Rev., 2008, 37, 320-330). Introducing trifluoromethyl groups into drug molecules can significantly improve their lipophilicity, metabolic stability, electronegativity, and bioavailability. As of 2019, 79 marketed drug molecules contain trifluoromethyl groups (such as Celecoxib, Letemtovir, Doravirine, and Telotristat Etiprate), and are used in various fields including oncology, infectious diseases, cardiovascular diseases, and neurological diseases. On the other hand, difluoromethyl groups, as bioisosteres of alcoholic and thiohydroxy groups, are increasingly important in drug molecule design (see Nature Chem., 2017, 9, 918-923). Therefore, how to introduce trifluoromethyl and difluoromethyl groups into organic molecules in an efficient, green, and economical manner has always been the direction of continuous efforts for synthetic chemists and medicinal chemists.

[0003] 3-Trifluoromethylpyridine and 3-difluoromethylpyridine skeletons are widely found in pharmaceuticals, pesticides, and functional materials (such as the marketed drugs Tipranavir and Apalutamide). Furthermore, they are common synthetic intermediates and metal ligands (such as the commonly used photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6). The most common method for synthesizing 3-trifluoromethylpyridine and 3-difluoromethylpyridine compounds is the cross-coupling reaction between 3-halogen (or pseudohalogen) substituted pyridine compounds and trifluoromethyl or difluoromethyl sources under the action of a metal catalyst (see Angew. Chem. Int. Ed., 2011, 50, 3793-3798. Org. Lett., 2014, 16, 4268-4271.). However, this method requires prior synthesis of 3-halogen (or pseudohalogen)-substituted pyridine compounds as precursors via meta-selective halogenation of pyridine, and also necessitates high temperatures, limiting its application. In comparison, direct fluoroalkylation of the CH bond at the 3-position of pyridine to synthesize 3-fluoroalkyl-substituted pyridine compounds is undoubtedly a more economical and concise option. However, due to the electron-deficient nature of pyridine itself, it is very difficult to introduce an electron-deficient fluoroalkylating group by CH bond activation on the pyridine ring. Furthermore, the selectivity of CH activation is a challenge. Against this backdrop, Armido Studer et al. creatively utilized a redox neutral dearomatization-aromatization strategy to convert pyridine into electron-rich oxazolidinone-pyridine complexes, thereby achieving meta-selective CH bond functionalization of pyridine and preparing a series of meta-trifluoromethyl and fluoroalkyl-substituted compounds (see Science, 2022, 378, 779-785). However, it should be noted that this method uses gaseous trifluoroiodomethane as the trifluoromethyl source, which is inconvenient and has a low yield. Therefore, given the above background, it is essential to develop a more efficient method for synthesizing 3-trifluoromethylpyridine or 3-difluoromethylpyridine compounds using a solid trifluoromethylating agent as the trifluoromethyl source. (III) Summary of the Invention

[0004] In view of the shortcomings of the existing technology, it is necessary to develop a more efficient method for synthesizing 3-trifluoromethylpyridine or 3-difluoromethylpyridine compounds, which uses solid trifluoromethylating agents as the source of trifluoromethyl groups.

[0005] This invention provides a visible light-promoted method for synthesizing 3-trifluoromethylpyridine or 3-difluoromethylpyridine compounds. The method includes the following steps:

[0006] The pyridine compound shown in Formula I is reacted with methyl pyruvate and dimethyl butynedioate to prepare the oxazolidinone-pyridine complex of Formula II.

[0007] Compound III was prepared by reacting with a fluoroalkylating agent in the presence of a base and solvent, followed by photosensitizer and visible light irradiation at 15–35 °C. Upon reaction with an acid, 3-fluoroalkyl-substituted pyridine compounds of Formula IV were prepared.

[0008]

[0009] Wherein, R is one or more of the following: hydrogen, methyl, methoxy, methylthio, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, and nitrile.

[0010] The molar ratio of the photosensitizer, the oxazolidinone-pyridine complex shown in Formula II, the fluoroalkylating agent, and the base substance is 0.01-0.05:1:1.0-2.0:1.0-3.0.

[0011] The photosensitizer is one of the following: Ru(bpy)3Cl2·6H2O, Ru(Phen3)Cl2, Ru(bpy)3(PF6)2, fac-Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, 4CzIPN, with the following structural formula:

[0012]

[0013] The fluoroalkylating agent includes a trifluoromethylating agent or a difluoromethylating agent, specifically one of CF3SO2Cl, Umemoto reagent, Togni'reagent, and 2-BTSO2F2H, with the following structural formula:

[0014]

[0015] The photosensitizer is preferably Ru(bpy)3Cl2·6H2O.

[0016] The trifluoromethylating agent is preferably Umemoto reagent I, and the difluoromethylating agent is 2-BTSO2F2H.

[0017] The organic solvent may be one of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, dimethyl sulfoxide, dichloromethane, cyclopentylmethyl ether, trifluorotoluene, and ethyl acetate.

[0018] Preferably, the organic solvent is acetonitrile or N-methylpyrrolidone.

[0019] The alkali may be sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, potassium phosphate, DBU, or triethylamine.

[0020] Preferably, the alkali is potassium carbonate.

[0021] The method for synthesizing the above-mentioned 3-trifluoromethylpyridine or 3-difluoromethylpyridine compound of the present invention is carried out according to the following steps:

[0022] Under inert gas protection, pyridine compound (1.0 eq.), methyl pyruvate (2.0 eq.), and acetonitrile (4.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 eq.) was added dropwise while stirring, and the mixture was stirred at room temperature for 2–48 h. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II.

[0023] Under inert gas protection, a photosensitizer, the oxazolidinone-pyridine complex (1.0 eq.) of Formula II, a fluoroalkylating agent, a base, and a solvent were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 15–35 °C for 6–14 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the reaction solution was post-treated to obtain a 3-fluoroalkyl-substituted pyridine compound of Formula IV; the molar ratio of the photosensitizer, the oxazolidinone-pyridine complex of Formula I, the fluoroalkylating agent, and the base was 0.01–0.05:1:1.0–2.0:1.0–3.0.

[0024]

[0025] Wherein, R is one or more of hydrogen, methyl, methoxy, methylthio, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, and nitrile, or is...

[0026] The photosensitizer is one of the following: Ru(bpy)3Cl2·6H2O, Ru(Phen3)Cl2, Ru(bpy)3(PF6)2, fac-Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, 4CzIPN. The structural formula is:

[0027]

[0028] Furthermore, the fluoroalkylating reagents of the present invention include trifluoromethylating reagents and difluoromethylating reagents, including one of CF3SO2Cl, Umemoto reagent, Togni'reagent, and 2-BTSO2F2H.

[0029] The structure is as follows:

[0030]

[0031] Furthermore, the trifluoromethylating agent of the present invention is preferably Umemoto reagent I, and the difluoromethylating agent is preferably 2-BTSO2F2H.

[0032] Furthermore, the photosensitizer is most preferably Ru(bpy)3Cl2·6H2O.

[0033] Furthermore, the organic solvent described in this invention is one of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, dimethyl sulfoxide, dichloromethane, cyclopentyl methyl ether, trifluorotoluene, and ethyl acetate.

[0034] Furthermore, the organic solvent used in this invention is preferably acetonitrile or N-methylpyrrolidone.

[0035] Furthermore, the alkali described in this invention is sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, potassium phosphate, DBU, triethylamine, etc.

[0036] Furthermore, the alkali used in this invention is preferably potassium carbonate.

[0037] Furthermore, the inert protective gas is either nitrogen or argon.

[0038] Furthermore, the post-treatment method of the reaction solution of the present invention is as follows: after the reaction is completed, the pH is adjusted with sodium carbonate aqueous solution, followed by extraction with dichloromethane, the combined organic phases are washed with saturated sodium chloride aqueous solution, 200-300 mesh silica gel for column chromatography is added to the obtained organic phase and the solvent is removed by vacuum distillation, the obtained crude product is separated by silica gel column chromatography, and petroleum ether / ethyl acetate is used as the eluent for elution, the elution process is tracked by TLC, the eluent containing the target product is collected, the eluents are combined, and the solvent is removed by evaporation to obtain the 3-fluoroalkyl substituted pyridine compound represented by Formula III.

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0040] The method described in this invention can synthesize 3-fluoroalkyl-substituted pyridine compounds that are difficult to prepare using existing methods. Compared with widely reported methods such as the cross-coupling of 3-halopyridines with fluoroalkylating agents catalyzed by transition metals to synthesize 3-fluoroalkyl-substituted pyridines, this method does not require 3-halopyridines as a starting material, making the starting material cheaper and more readily available. The reaction is carried out at room temperature, under milder conditions, and exhibits superior functional group tolerance. Compared with the use of trifluoromethylating agents such as trifluoroiodomethane, the fluoroalkylating agent used in this method is a solid, making it more convenient to use and resulting in higher yields. (iv) Specific Implementation Methods

[0041] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0042] Example 1

[0043]

[0044] Under inert gas protection, 1.0 mmol (1.0 eq.) of 4-phenylpyridine, 2.0 mmol (2.0 eq.) of methyl pyruvate, and 2.0 mL of acetonitrile (Formula I) were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol (2.0 eq.) was added dropwise while stirring, and the mixture was stirred at room temperature for 2 hours. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 90%.

[0045] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), oxazolidinone-pyridine complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction, the pH was adjusted to 8-9 with sodium carbonate aqueous solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with saturated sodium chloride aqueous solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1-10 / 1) to give the corresponding 4-phenyl-3-trifluoromethylpyridine. This substance is a colorless liquid with a yield of 68%.

[0046] Characterization data: 1 H NMR(400M, CDCl3): δ9.07(s,1H),8.90(s,1H),7.50-7.45(m,3H),7.40-7.33(m,3H).HRMS(ESI):Calcd.for C 12 H9NF3[M+H] + :224.0682,found:224.0680. The characterization data is consistent with the data reported in the literature.

[0047] Example 2

[0048]

[0049] Under inert gas protection, 1.0 mmol (1.0 eq.) of 4-phenoxypyridine (2.0 mmol (2.0 eq.)), methyl pyruvate (2.0 mmol (2.0 eq.)), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol (2.0 eq.) was added dropwise while stirring at room temperature. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 92%.

[0050] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), oxazolidinone-pyridine complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction, the pH was adjusted to 8-9 with sodium carbonate aqueous solution, and the mixture was extracted three times with dichloromethane to synthesize the organic phase. The organic phase was washed with saturated sodium chloride aqueous solution, and the solvent was removed under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1-10 / 1) to give the corresponding 4-phenoxy-3-trifluoromethylpyridine. This substance is a colorless liquid with a yield of 59%.

[0051] Characterization data: 1 H NMR (400M, CDCl3): δ8.90 (s, 1H), 8.63 (s, 1H), 7.55-7.49 (m, 2H), 7.40-7.32 (m, 1H), 7.23-7.15 (m, 2H), 6.75 (d, J = 6.0Hz, 1H). HRMS (ESI): Calcd.forC 12 H9NOF3[M+H] + :240.0631,found:240.0640. The characterization data is consistent with the data reported in the literature.

[0052] Example 3

[0053]

[0054] Under an inert gas atmosphere, 1.0 mmol (1.0 eq.) of 2-phenylpyridine (2.0 mmol (2.0 eq.)), methyl pyruvate (2.0 mmol (2.0 eq.)), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol (2.0 eq.) was added dropwise while stirring, and the mixture was stirred at room temperature for 2 hours. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 85%.

[0055] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), oxazolidinone-pyridine complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction, the pH was adjusted to 8-9 with sodium carbonate aqueous solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with saturated sodium chloride aqueous solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1-10 / 1) to give the corresponding 2-phenyl-5-trifluoromethylpyridine. This substance is a colorless liquid with a yield of 69%.

[0056] Characterization data: 1 H NMR (400M, CDCl3): δ8.92 (s, 1H), 8.03-7.95 (m, 3H), 7.82 (d, J = 8.5Hz, 1H), 7.50-7.45 (m, 3H), HRMS (ESI): Calcd.for C 12 H9NF3[M+H] + :224.0682,found:224.0688. The characterization data is consistent with the data reported in the literature.

[0057] Example 4

[0058]

[0059] Under an inert gas atmosphere, 2-(4-methoxyphenyl)pyridine (1.0 mmol, 1.0 eq.), methyl pyruvate (2.0 mmol, 2.0 eq.), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol, 2.0 eq.) was added dropwise while stirring, and the mixture was stirred at room temperature for 2 hours. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 86%.

[0060] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), oxazolidinone-pyridine complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the pH was adjusted to 8–9 with an aqueous sodium carbonate solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with a saturated aqueous sodium chloride solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1–10 / 1) to give the corresponding 2-(4-methoxyphenyl)-5-trifluoromethylpyridine. This substance was a white solid with a yield of 72%.

[0061] Characterization data: 1 H NMR (400M, CDCl3): δ8.94 (s, 1H), 8.07 (d, J = 9.0Hz, 2H), 7.96-7.92 (m, 1H), 7.83-7.76 (m, 1H), 7.06-7.01 (m, 2H), 3.92 (s, 3H). HRMS (ESI): Calcd.forC 13 H 11 NOF3[M+H] + :254.0788,found:254.0783. The characterization data is consistent with the data reported in the literature.

[0062] Example 5

[0063]

[0064] Under an inert gas atmosphere, 2-(4-chlorophenyl)pyridine (1.0 mmol, 1.0 eq.), methyl pyruvate (2.0 mmol, 2.0 eq.), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol, 2.0 eq.) was added dropwise while stirring, and the mixture was stirred at room temperature for 2 hours. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 86%.

[0065] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), oxazolidinone-pyridine complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the pH was adjusted to 8–9 with an aqueous sodium carbonate solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with a saturated aqueous sodium chloride solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1–10 / 1) to give the corresponding 2-(4-chlorophenyl)-5-trifluoromethylpyridine. This substance was a white solid with a yield of 63%.

[0066] Characterization data: 1 H NMR (400M, CDCl3): δ8.93 (s, 1H), 8.05-8.01 (m, 3H), 7.88 (d, J = 9.0Hz, 1H), 7.53-7.47 (m, 2H). HRMS (ESI): Calcd.for C 12 H8NClF3[M+H] + :258.0292,found:258.0295. The characterization data are consistent with the data reported in the literature.

[0067] Example 6

[0068]

[0069] Under inert gas protection, 2-(2-thienyl)pyridine (1.0 mmol, 1.0 eq.), methyl pyruvate (2.0 mmol, 2.0 eq.), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol, 2.0 eq.) was added dropwise while stirring, and the mixture was stirred at room temperature for 2 hours. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 80%.

[0070] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), oxazolidinone-pyridine complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction was complete, the pH was adjusted to 8–9 with an aqueous sodium carbonate solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with a saturated aqueous sodium chloride solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1–10 / 1) to give the corresponding 2-(2-thienyl)-5-trifluoromethylpyridine. This substance was a white solid with a yield of 70%.

[0071] Characterization data: 1 H NMR (400M, CDCl3): δ8.80 (s, 1H), 7.92-7.88 (m, 1H), 7.76 (d, J = 9.0Hz, 1H), 7.70-7. 64(m,1H),7.45-7.42(m,1H),7.15(dd,J=4.0Hz,1.0Hz,1H).HRMS(ESI):Calcd.for C 10 H7NSF3[M+H] + :230.0246,found:230.0249. The characterization data is consistent with the data reported in the literature.

[0072] Example 7

[0073]

[0074] Under an inert gas atmosphere, isoquinoline (1.0 mmol, 1.0 eq.), methyl pyruvate (2.0 mmol, 2.0 eq.), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol, 2.0 eq.) was added dropwise while stirring at room temperature. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 90%.

[0075] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), the above-mentioned oxazolidinone-isoquinoline complex (0.5 mmol, 1.0 eq.), Umemoto reagent I (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 2.0 eq.), and acetonitrile (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 h. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 h. After the reaction was completed, the pH was adjusted to 8-9 with sodium carbonate aqueous solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with saturated sodium chloride aqueous solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1-10 / 1) to obtain the corresponding 4-trifluoromethylisoquinoline. The substance is a colorless liquid with a yield of 75%.

[0076] Characterization data: 1 H NMR(400M, CDCl3): δ9.38(s,1H),8.85(s,1H),8.15-8.12(m,1H),8.09-8.06(m,1H),7.86-7.83(m,1H),7.73-7.70(m,1H).HRMS(ESI):Calcd.for C 10 H7NF3[M+H] + :198.0525,found:198.0525. The characterization data is consistent with the data reported in the literature.

[0077] Example 8

[0078]

[0079] Under an inert gas atmosphere, quinoline (1.0 mmol, 1.0 eq.), methyl pyruvate (2.0 mmol, 2.0 eq.), and acetonitrile (2.0 mL) of Formula I were added to a dry Schlenk reaction tube. Dimethyl butynedioate (2.0 mmol, 2.0 eq.) was added dropwise while stirring at room temperature. TLC showed complete conversion of the starting material. The solvent was removed under vacuum, and the crude product was separated by silica gel column chromatography using petroleum ether / ethyl acetate as eluent. The elution process was monitored by TLC, and the eluent containing the target product was collected. The eluents were combined, and the solvent was evaporated to obtain the oxazolidinone-pyridine complex of Formula II, with a yield of 86%.

[0080] Under nitrogen protection, photosensitizer Ru(bpy)Cl2·6H2O (0.01 mmol, 2 mol%), the above-mentioned oxazolidinone-quinoline complex (0.5 mmol, 1.0 eq.), 2-BTSO2F2H (0.75 mmol, 2.0 eq.), Na2CO3 (1.0 mmol, 1.0 eq.), and NMP (5.0 mL) were added to a dry Schlenk reaction tube. The reaction solution was placed 3 cm away from a 15W blue LED light source and reacted at 25 °C for 10 hours. TLC showed complete conversion of the starting material. 6N hydrochloric acid (5.0 mL) was added, and the mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the pH was adjusted to 8-9 with sodium carbonate aqueous solution, and the mixture was extracted three times with dichloromethane. The synthesized organic phase was washed with saturated sodium chloride aqueous solution, and the solvent was removed from the organic phase under vacuum. The crude product was further purified by column chromatography (eluent PE / EA = 30 / 1-10 / 1) to obtain the corresponding 3-trifluoromethylquinoline. The substance is a yellow liquid with a yield of 75%.

[0081] Characterization data: 1 H NMR (400M, CDCl3): δ8.99(d,J=4.0Hz,1H),8.23(s,1H),8.10(d,J=8.0Hz,1H),7.75(d,J=8.0Hz, 1H),7.75(t,J=7.5Hz,1H),7.55(t,J=7.5Hz,1H),6.84(t,J=53.5Hz,1H).HRMS(ESI):Calcd.for C 10 H8NF2[M+H] + :179.0547,found:179.0545. The characterization data is consistent with the data reported in the literature.

Claims

1. A method for synthesizing visible light-promoted 3-trifluoromethylpyridine or 3-difluoromethylpyridine compounds, characterized in that, Includes the following steps: The pyridine compound shown in Formula I was reacted with methyl pyruvate and dimethyl butynedioate to prepare the oxazolidinone-pyridine complex shown in Formula II. Compound III was prepared by reacting with a fluoroalkylating agent in the presence of a base and solvent, followed by photosensitizer and visible light irradiation at 15–35 °C. Upon reaction with an acid, 3-fluoroalkyl-substituted pyridine compounds of Formula IV were prepared. ， Wherein, R is one or more of hydrogen, methyl, methoxy, methylthio, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, and nitrile, or or ; The fluoroalkylating agent is selected from Umemoto reagent, 2-BTSO2F2H, with the following structural formula: ； The photosensitizer is one of the following: Ru(bpy)3Cl2·6H2O, Ru(Phen3)Cl2, Ru(bpy)3(PF6)2, fac-Ir(ppy)3, Ir(ppy)2(dtbbpy)PF6, 4CzIPN, with the following structural formula: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of the photosensitizer, the oxazolidinone-pyridine complex shown in Formula II, the fluoroalkylating agent, and the base substance is 0.01-0.05:1:1.0-2.0:1.0-3.

0.

3. The preparation method according to claim 1, characterized in that, The photosensitizer is Ru(bpy)3Cl2·6H2O.

4. The preparation method according to claim 1, characterized in that, The organic solvent is one of acetonitrile, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, dimethyl sulfoxide, dichloromethane, cyclopentylmethyl ether, trifluorotoluene, and ethyl acetate.

5. The preparation method according to claim 4, characterized in that, The organic solvent is acetonitrile or N-methylpyrrolidone.

6. The preparation method according to claim 1, characterized in that, The alkali is sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, potassium phosphate, DBU, or triethylamine.

7. The preparation method according to claim 6, characterized in that, The alkali is potassium carbonate.

Images