A process for the synthesis of a sulfonyl fluoride compound

Abstract

The application discloses a kind of synthesis process of sulfonyl fluoride compound;Under the protection of nitrogen, containing sulfhydryl compound and dimethyl sulfonium bromide are reacted under the action of base, oxidizing reagent, fluorinating reagent, and sulfuryl fluoride compound is generated by oxidation fluorination reaction;Among them, the base is 2,4,6-trimethylpyridine, the oxidizing agent is sodium chlorite, the fluorinating reagent is potassium hydrogen fluoride, and the sulfhydryl compound is aliphatic mercaptan or contains aromatic ring or heterocyclic thiol;The method of the application has mild conditions, simple and readily available raw materials, simple operation, and has high application value.

Description

Technical Field

[0001] This invention relates to the field of organic intermediate synthesis, and more particularly to a synthesis process for sulfonyl fluoride compounds. Background Technology

[0002] Sulfonyl fluorides are crucial components in various fields, including synthetic chemistry, medicinal chemistry, fine chemicals, and industrial applications. They are also used in chemical biology as covalent protein regulators, strong protease inhibitors, and active probes. Due to the unique structure and properties of the SF bond in sulfonyl fluorides, they not only serve as important functional groups in the synthesis of natural products but are also common intermediates in the industrial production of fluorinated pesticides, dyes, and other fine chemical products. Specific synthetic methods have been reported as follows:

[0003] Method 1: Synthesize sulfonyl fluoride using methanol and water as solvents at 0℃.

[0004]

[0005] The drawback of this reaction is that it requires the use of chlorine gas, a highly toxic gas with a strong, pungent odor, and the experimental waste is highly toxic, posing an extremely high risk factor. It also places stringent requirements on experimental conditions and equipment.

[0006] Method 2: A one-pot synthesis of aromatic sulfonyl fluoride from aryl bromides using palladium as a catalyst.

[0007]

[0008] The drawbacks of this reaction are that it requires the use of the precious metal palladium as a catalyst, produces a large number of byproducts, which significantly affects the post-processing of the experiment, has low atom economy, and results in high reaction costs.

[0009] Method 3: Using DMF as solvent and SOF2 as fluorine source, react at 130℃ for 1 hour to generate the corresponding sulfonyl fluoride compounds.

[0010]

[0011] The drawback of this reaction is that it requires the use of boron trifluoride ether, which is sensitive to moisture and reacts violently with water to release toxic fluorine-containing gas, posing a great danger to human health. Anhydrous reagents must be used, and the reaction also requires high-temperature conditions, which places high demands on the reaction conditions and equipment, greatly increasing the reaction cost.

[0012] Method 4: Using CH3CN and H2O as solvents and KF as a fluorine source, under electrochemical conditions, thiols or thiophenols are converted into sulfonyl fluorides.

[0013]

[0014] The drawbacks of this reaction are that it produces flammable and explosive hydrogen gas, which poses a high risk when scaled up, requires sophisticated experimental equipment, and takes a long time. Summary of the Invention

[0015] To address the aforementioned problems, the present invention aims to provide a low-cost, simple-to-operate, heavy metal-free, mild-condition, and easily applicable synthetic process for sulfonyl fluoride compounds in industrial production.

[0016] To achieve the above objectives, the present invention adopts the following technical solution: a synthesis process for sulfonyl fluoride compounds, characterized in that the process method is as follows:

[0017]

[0018] Wherein, R is a substituent, and the substituent is selected from C6 to C6. 15 aliphatic, C6-C 15 The aromatic group or a 5-10 membered heteroaryl group containing 1-5 O, N, S heteroatoms; the organosulfonate reagent is dimethylsulfonium bromide; the oxidizing agent is one of sodium chlorite, NBS, DDQ or H2O2; the base is one of a tertiary amine, pyridine, cyclohexylmethylamine, or 2,4,6-trimethylpyridine.

[0019] In the process method of this invention, the substituent R is preferably C6-C6. 15 aliphatic or C6-C 15 Aromatic compounds.

[0020] The reaction mechanism of this invention is as follows:

[0021]

[0022] In the process of this invention, the molar ratio of dimethyl sulfonium bromide to R-SH is 1:2 to 3, and the preferred molar ratio is 1:3, which results in the highest yield of the final product.

[0023] In the process of this invention, the molar ratio of dimethylsulfonium bromide to alkali is 1:1 to 2, and the preferred molar ratio is 1:1.5, which results in the highest yield of the final product; the alkali is 2,4,6-trimethylpyridine.

[0024] In the process of this invention, the molar ratio of dimethylsulfonium bromide to KHF2 is 1:2 to 3, and the preferred molar ratio is 1:3, which results in the highest yield of the final product.

[0025] In the synthesis method of the present invention, the molar ratio of dimethyl sulfonium bromide to oxidant is 1:3 to 4, and the preferred molar ratio is 1:4, which results in the highest yield of the final product; the oxidant is sodium chlorite.

[0026] In the process of this invention, the reaction solvent is acetonitrile; from the perspective of reaction yield and simplicity of operation, no other organic solvent is added, that is, a single organic solvent is used as the reaction solvent; the molar concentration of R-SH in the reaction solvent is 0.2 mmol / mL; the molar concentration of KHF2 in the reaction solvent is 0.3 mmol / mL.

[0027] In the process of the present invention, the reaction temperature is -20℃ to 20℃, preferably 0℃; the reaction time is 10h to 48h, preferably 14h; the reaction temperature and reaction time of the present invention can be determined by technicians according to different thiol compounds and actual needs.

[0028] After the reaction of the present invention is completed, the reaction solution is washed with saturated brine and extracted three times with ethyl acetate. The purified sulfonyl fluoride product is obtained by column chromatography.

[0029] The advantages of this invention are as follows: it uses readily available fluorine and mercapto compounds as reaction substrates, commercially available, easily prepared, and air-insensitive dimethyl sulfonium bromide as the reaction reagent, and inexpensive and readily available 2,4,6-trimethylpyridine as the base. After feeding at 0°C, the mixture is allowed to naturally return to room temperature, and sulfonyl fluoride compounds are synthesized simply and efficiently under nitrogen conditions. Compared with other methods for synthesizing sulfonyl fluoride compounds, the reaction raw materials used in this invention (including fluorinating reagents, dimethyl sulfonium bromide, and base) are all inexpensive and readily available. It does not require the use of hazardous strong bases and corrosive acids, and the reaction yield is high. It features low cost, environmental friendliness, safe operation, and ease of industrial application.

[0030] The method of this invention has good compatibility with aliphatic, aromatic, and heterocyclic raw materials. Therefore, there are practically no strict limitations on the substituents in thiol compounds and their derivatives. Attached Figure Description

[0031] Figure 1 The 1H NMR spectrum of benzo[d]thiazole-2-sulfonyl fluoride described in Example 1;

[0032] Figure 2 The carbon NMR spectrum of benzo[d]thiazole-2-sulfonyl fluoride described in Example 1;

[0033] Figure 3 The NMR fluorine spectrum of benzo[d]thiazole-2-sulfonyl fluoride described in Example 1;

[0034] Figure 4 The 1H NMR spectrum of 4-chlorobenzenesulfonyl fluoride described in Example 2;

[0035] Figure 5 The carbon NMR spectrum of 4-chlorobenzenesulfonyl fluoride described in Example 2;

[0036] Figure 6 The NMR fluorine spectrum of 4-chlorobenzenesulfonyl fluoride described in Example 2;

[0037] Figure 7 The 1H NMR spectrum of 4-(tert-butyl)benzenesulfonyl fluoride described in Example 3;

[0038] Figure 8 The 1H NMR spectrum of 2-methoxybenzenesulfonyl fluoride described in Example 4;

[0039] Figure 9 The 1H NMR spectrum of 2,6-dimethylbenzenesulfonyl fluoride described in Example 5;

[0040] Figure 10 The 1H NMR spectrum of 3,4-dimethoxybenzenesulfonyl fluoride described in Example 6;

[0041] Figure 11 The 1H NMR spectrum of 4-fluorobenzenesulfonyl fluoride described in Example 7;

[0042] Figure 12 The image shows the 1H NMR spectrum of benzyl sulfonyl fluoride described in Example 8.

[0043] Figure 13 The 1H NMR spectrum of 4-(tert-butyl)benzylsulfonyl fluoride described in Example 9 is shown.

[0044] Figure 14 The image shows the 1H NMR spectrum of methyl 2-(fluorosulfonyl)benzoate described in Example 10.

[0045] Figure 15 The image shows the 1H NMR spectrum of 4-methoxybenzenesulfonyl fluoride as described in Example 11.

[0046] Figure 16 The image shows the 1H NMR spectrum of pyridine-2-sulfonyl fluoride described in Example 12.

[0047] Figure 17 The NMR spectrum of 2-naphthalene-2-sulfonyl fluoride described in Example 13 is shown in the 1H NMR spectrum. Detailed Implementation

[0048] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0049] All raw materials used in the following specific examples are commercially available, and each reagent is purified using methods known in the art before use when necessary.

[0050] In this invention, "thiol compound" has the meaning commonly understood by those skilled in the art, namely, a compound containing a thiol group (-SH), such as 2-mercaptobenzoxazole, 2-mercaptobenzothiazole and its various derivatives.

[0051] In this invention, "sulfonyl fluoride compounds" has the meaning commonly understood by those skilled in the art, namely, compounds in which sulfur atoms are bonded to oxygen atoms, such as S-(benzo[d]thiazo-2-yl)-N-benzylsulfonyl and its various derivatives.

[0052] All raw materials used in the following specific examples are commercially available, and each reagent is purified using methods known in the art before use when necessary.

[0053] 1 H NMR and 13 All C NMR measurements were performed using a Bruker Avance 400 spectrometer. The test temperature was room temperature, and the solvent was deuterated chloroform. (Reference selection follows.) 1 ¹H NMR: CHCl₃ was 7.260 ppm; 13 C NMR: CHCl3 was 77,000 ppm.

[0054] Example 1: Synthesis of benzo[d]thiazole-2-sulfonyl fluoride

[0055] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, benzo[d]thiazole-2-thiol (167 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 103 mg of benzo[d]thiazole-2-sulfonyl fluoride, with a yield of 95%.

[0056] Product: benzo[d]thiazole-2-sulfonyl fluoride 1 H NMR (400MHz, Chloroform-d) δ8.31–8.26(m,1H),8.07–8.03(m,1H),7.73–7.66(m,2H). 13C NMR (101MHz, Chloroform-d) δ155.9 (d, J = 38.2Hz), 151.8 (d, J = 2.6Hz). 137.0, 129.4, 128.4, 126.1, 122.2. 19 F NMR(376MHz,Chloroform-d)δ64.15.

[0057] Example 2: Synthesis of 4-chlorobenzenesulfonyl fluoride

[0058] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 4-chlorobenzenethiophenol (145 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 60 mg of 4-chlorobenzenesulfonyl fluoride, with a yield of 62%.

[0059] Product 4-chlorobenzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.98–7.93(m,2H),7.63–7.59(m,2H). 13 C NMR (101MHz, Chloroform-d) δ 142.6, 131.3 (d, J = 25.7Hz), 130.1, 129.8. 19 F NMR (376MHz, CDCl3) δ 66.50.

[0060] Example 3: Synthesis of 4-(tert-butyl)benzenesulfonyl fluoride

[0061] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 4-(tert-butyl)benzylthiophenol (166 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 87 mg of 4-(tert-butyl)benzylthiol, with a yield of 77%.

[0062] Product 4-(tert-butyl)benzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.54–7.45(m,1H),7.44–7.36(m,1H),7.36–7.30(m,1H),7.30–7.24(m,1H),1.45–1.01(m,9H). 13 C NMR (101MHz, CDCl3) δ157.5,155.0,140.2,136.3,127.4,126.4,125.7,124.6,35.2,34.9,31.1,31.0. 19 F NMR (376MHz, CDCl3) δ 66.24.

[0063] Example 4: Synthesis of 2-methoxybenzenesulfonyl fluoride

[0064] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 2-methoxybenzenethiophenol (140 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 71 mg of 2-methoxybenzenesulfonyl fluoride, with a yield of 75%.

[0065] Product 2-methoxybenzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.95–7.92(m,1H),7.72–7.68(m,1H),7.1–7.09(m,2H),4.01(s,2H). 13 C NMR (101MHz, CDCl3) δ158.07,137.37,131.23,131.21,120.49,112.74,56.54. 19 F NMR (376MHz, CDCl3) δ 58.57.

[0066] Example 5: Synthesis of 2,6-dimethylbenzenesulfonyl fluoride

[0067] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 2,6-dimethylbenzenethiophenol (138 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 56 mg of 2,6-dimethylbenzenesulfonyl fluoride, with a yield of 61%.

[0068] Product 2,6-dimethylbenzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.45–7.41(m,1H),7.24–7.22(m,2H),2.69(s,6H). 13 C NMR (101MHz, Chloroform-d) δ140.1, 134.0, 132.05 (d, J = 20.1Hz), 131.10 (d, J = 1.4Hz), 22.44 (d, J = 2.1Hz). 19 F NMR (376MHz, CDCl3) δ 67.84.

[0069] Example 6: Synthesis of 3,4-dimethoxybenzenesulfonyl fluoride

[0070] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 3,4-dimethoxybenzenethiophenol (170 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 80 mg of 3,4-dimethoxybenzenesulfonyl fluoride, with a yield of 73%.

[0071] Product 3,4-dimethoxybenzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.66–7.64(m,1H),7.39–7.38(m,1H),7.01(d,J=8.5Hz,1H),3.98(s,3H),3.95(s,3H). 13 C NMR (101MHz, Chloroform-d) δ154.9, 149.5, 123.92 (d, J = 24.6Hz), 123.2, 110.8, 110.1, 56.4, 56.3. 19 FNMR(376MHz,Chloroform-d)δ67.22.

[0072] Example 7: Synthesis of 4-fluorobenzenesulfonyl fluoride

[0073] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 4-fluorobenzenethiophenol (128 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 69 mg of 4-fluorobenzenesulfonyl fluoride, with a yield of 77%.

[0074] Product 4-fluorobenzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ8.08–8.04(m,2H),7.34–7.30(m,2H). 13 C NMR (101MHz, CDCl3) δ168.1,165.6,131.6,131.5,117.3,117.1. 19 F NMR (376MHz, CDCl3) δ66.82,-99.27.

[0075] Example 8: Synthesis of benzyl sulfonyl fluoride

[0076] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, benzyl mercaptan (124 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 76 mg of benzyl sulfonyl fluoride, with a yield of 88%.

[0077] Product: benzyl sulfonyl fluoride 1H NMR (400MHz, Chloroform-d) δ7.49–7.42 (m, 5H), 4.60 (d, J = 3.3Hz, 2H). 13 C NMR (101MHz, Chloroform-d) δ130.6, 129.9, 129.3, 125.4, 56.8 (d, J = 17.6Hz). 19 FNMR (376MHz, CDCl3) δ 51.38.

[0078] Example 9: Synthesis of 4-(tert-butyl)benzylsulfonyl fluoride

[0079] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 4-(tert-butyl)benzyl mercaptan (180 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 82 mg of 4-(tert-butyl)benzylsulfonyl fluoride, with a yield of 71%.

[0080] Product 4-(tert-butyl)benzylsulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.48–7.46(m,2H),7.38–7.36(m,2H),4.58(s,2H),1.34(s,9H). 13 C NMR (101MHz, CDCl3) δ153.1,130.3,126.3,122.3,56.50,56.3,34.7,31.1. 19 F NMR (376MHz, CDCl3) δ 51.12.

[0081] Example 10: Synthesis of methyl 2-(fluorosulfonyl)benzoate

[0082] Dimethyl sulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, methyl 2-mercaptobenzoate (168 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 93 mg of methyl 2-(fluorosulfonyl)benzoate, with a yield of 82%.

[0083] Product 2-(fluorosulfonyl)benzoate: 1 H NMR (400MHz, Chloroform-d) δ8.18–8.13(m,1H),7.90–7.85(m,1H),7.85–7.80(m,1H),7.76–7.71(m,1H),3.99(s,2H). 13 C NMR (101MHz, CDCl3) δ165.7,135.2,133.0,132.0,131.6,130.7,130.5,,53.50. 19 F NMR (376MHz, CDCl3) δ 64.48.

[0084] Example 11: Synthesis of 4-methoxybenzenesulfonyl fluoride

[0085] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, 4-methoxybenzenethiophenol (140 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 46 mg of 4-methoxybenzenesulfonyl fluoride, with a yield of 86%.

[0086] Product 4-methoxybenzenesulfonyl fluoride: 1 H NMR (400MHz, Chloroform-d) δ7.94–7.89(m,2H),7.07–7.03(m,2H),3.90(s,3H). 13 C NMR (101MHz, CDCl3) δ165.2, 130.8, 123.9 (d, J = 24.6Hz), 55.8. 19 FNMR (376MHz, CDCl3) δ 67.31.

[0087] Example 12: Synthesis of pyridine-2-sulfonyl fluoride

[0088] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, pyridine-2-thiol (111 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 97 mg of pyridine-2-sulfonyl fluoride, with a yield of 61%.

[0089] Product: pyridine-2-sulfonyl fluoride 1H NMR (400MHz, Chloroform-d) δ8.8–8.83(m,1H),8.14–8.12(m,1H),8.08–8.04(m,1H),7.73–7.70(m,1H). 13 C NMR (101MHz, CDCl3) δ151.3,151.0,138.7,129.2,124.. 19 F NMR (376MHz, CDCl3) δ 55.84.

[0090] Example 13: Synthesis of naphthalene-2-sulfonyl fluoride

[0091] Dimethylsulfonium bromide (110.9 mg, 0.5 mmol, 1 equiv) was added to a Schlenk reaction tube under nitrogen protection and equipped with a magnetic stirrer. MeCN (5 mL) was added at 0 °C (ice-water bath) to dissolve and form a mixed solution. The mixture was stirred for 5 min, followed by the addition of 2,4,6-trimethylpyridine (95 mg, 0.75 mmol, 1.5 equiv). After a period of reaction, naphthalene-2-thiol (160 mg, 1 mmol, 2 equiv) was added. After stirring for 5 min, potassium hydrofluoric acid (117 mg, 1.5 mmol, 3 equiv) and sodium chlorite (226 mg, 2 mmol, 4 equiv) were added sequentially. The mixture was allowed to return to room temperature and the reaction was continued for 14 h. After the reaction was complete, the reaction solution was washed with water and extracted three times with 10 mL of ethyl acetate each time. The organic phases were combined, concentrated by rotary evaporation, and then subjected to column chromatography to obtain 208 mg of naphthalene-2-sulfonyl fluoride, with a yield of 99%.

[0092] Product: Naphthalene-2-sulfonyl fluoride 1 H NMR (400MHz, Chloroform-d) δ8.58 (d, J = 2.0Hz, 1H), 8.07–7.90 (m, 4H), 7.76–7.72 (m, 1H), 7.69–7.65 (m, 1H). 13 C NMR (101MHz, Chloroform-d) δ135.9, 131.7, 130.8 (d, J = 1.1Hz), 130.3, 130.0, 129.7, 129.5, 128.2, 128.0, 122.0. 19 F NMR (376MHz, CDCl3) δ 66.39.

[0093]

[0094]

[0095] It should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any combination or equivalent transformation made based on the above embodiments shall fall within the scope of protection of the present invention.

Claims

1. A process for synthesizing sulfonyl fluoride compounds, characterized in that, The process method is as follows: ； Wherein, R is a substituent, and the substituent is selected from C6~C6. 15 aliphatic, C6~C 15 Aromatic compounds or 5-10 heteroaryl groups containing 1-5 O, N, S heteroatoms; The oxidant is one of sodium chlorite, NBS, DDQ or H2O2; The base is one of the following: tertiary amine, pyridine, cyclohexylmethylamine, and 2,4,6-trimethylpyridine.

2. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, In the aforementioned process, the substituent R is selected from C6~C6. 15 aliphatic or C6~C 15 Aromatic compounds.

3. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, In the aforementioned process, the molar ratio of dimethyl sulfonium bromide to R-SH is 1:2~3.

4. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, In the aforementioned process, the molar ratio of dimethylsulfonium bromide to the base is 1:1~2; the base is 2,4,6-trimethylpyridine.

5. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, In the aforementioned process, the molar ratio of dimethyl sulfonium bromide to KHF2 is 1:2~3.

6. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, In the synthesis method described above, the molar ratio of dimethyl sulfonium bromide to the oxidant is 1:3~4; the oxidant is sodium chlorite.

7. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, In the process described, the reaction solvent is acetonitrile; the molar concentration of R-SH in the reaction solvent is 0.2 mmol / mL; and the molar concentration of KHF2 in the reaction solvent is 0.3 mmol / mL.

8. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, The reaction temperature in the process is -20℃ to 20℃; the reaction time is 10h to 48h.

9. The synthesis process of sulfonyl fluoride compounds as described in claim 1, characterized in that, After the reaction was complete, the reaction solution was washed with saturated brine and extracted three times with ethyl acetate. The purified sulfonyl fluoride product was obtained by column chromatography.

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