A method for efficiently preparing sulfonyl fluorides

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for efficiently preparing sulfonyl fluorides. The steps of this method are as follows: Step 1: Under a nitrogen atmosphere and at room temperature, electrochemically electrolyze a reaction mixture formed by trimethyl quaternary ammonium salt, a sulfur dioxide source, a fluorine source, an electrolyte, and a solvent using a constant voltage until the reaction is complete; Step 2: Wash and dry the organic phase, and perform vacuum distillation; Purify to obtain the sulfonyl fluoride compound. The present invention utilizes the electrochemical cathodic reduction of trimethyl quaternary ammonium salt to generate aryl or alkyl radicals; and then reacts with the SO2 source to generate aryl or alkyl sulfur dioxide radicals. These radicals can continue to be oxidized at the anode to generate aryl or alkyl sulfur dioxide cations, which then react with fluoride ions to obtain the target product. This reaction has no intermediate links and is simple and convenient to operate. The synthesis of the target product by an electrochemical method broadens the synthesis methods of sulfonyl fluorides.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing organic sulfonyl fluoride by an electrochemical method starting from trimethyl quaternary ammonium salt compounds, a sulfur dioxide source, and a fluorine source. Background Art

[0002] Sulfonyl fluoride compounds are a class of important organic compounds and are widely used in many fields such as organic synthesis, materials science, and molecular pharmacology. Sulfonyl fluoride compounds can be used as recombinant protease activity probes, protease inhibitors, and fluorination reagents, etc. Such as: FSBA, LUF7445, XO44, etc. Therefore, as a class of medical organic molecules, it is an important structural unit in organic synthesis.

[0003]

[0004] Currently, sulfonyl fluoride compounds can be synthesized from different carbon sources such as arylsulfonyl chlorides, thiols, aryl halides, alkenes, and aryl diazonium salts, etc. Some representative examples are introduced as follows:

[0005] (1) Nucleophilic fluorination reaction: Using arylsulfonyl chlorides and heteroarylsulfonyl chlorides, with KF as the fluorine source, the nucleophilic fluorination reaction of sulfonyl chloride is carried out at 30 - 180 °C to prepare sulfonyl fluoride. (Lidia Matesic, Naomi A. Wyatt, Benjamin H. Fraser. J. Org. Chem. 2013, 78, 11262 - 11270.)

[0006] (2) Electrooxidative coupling synthesis of sulfonyl fluoride reaction: This reaction needs to be carried out electrochemically. Using thiols and disulfides as raw materials at room temperature, KF as the F source, and pyridine as the base, the synthesis of sulfonyl fluoride compounds has been successfully achieved (Gabriele Laudadio, Aloisio de A. Bartolomeu, Lucas M. H. M. Verwijlen, Y. Cao, Kleber T. de Oliveira and Timothy Noel. J. Am. Chem. Soc. 2019, 141, 11832 - 11836.)

[0007] (3) Palladium-catalyzed synthesis of sulfonyl fluoride from aryl bromides reaction: This reaction first uses DABSO as the SO2 source, palladium-catalyzed aryl bromides to generate sulfinates, and then uses the electrophilic fluorine source NFSI to in-situ generate sulfonyl fluorides. (Alyn T. Davies, John M. Curto, Scott W. Bagley and Michael C. Willis Chem. Sci., 2017, 8, 1233 - 1237.)

[0008] (4) Imidazolyl photocatalytic ·SO2F reagent fluorosulfonation: An air-stable redox-active imidazole fluorosulfonic acid reagent IMSF is described. A key design feature of this radical fluorosulfonylating reagent is its cationic nature, which gradually forms fluorosulfonyl radicals (·SO2F) through a set reduction process under photocatalytic conditions. This ·SO2F can react with various olefins to generate alkenylsulfonyl fluorides, alkylsulfonyl fluorides, and migratory fluorosulfonation products. (W.-G. Zhang, H.-Y. Li, X.-J. Li, Z.-l. Zou, M.-J. Huang, J.-Y. Liu, X.-C. Wang, S.-Y. Ni, Y. Pan, Y. Wang. Nat. Commun. 2022, 13, 3515.)

[0009] (5) Copper-free Sandmeyer reaction of sulfonyl fluorides: A copper-free Sandmeyer-type fluorosulfonation reaction. Using Na2S2O5 and Selectfluor as the sulfur dioxide and fluorine sources respectively, aryl diazonium salts are converted into sulfonyl fluorides. Starting from aromatic amines, one-pot direct synthesis of sulfonyl fluoride compounds is achieved through in-situ diazotization reactions. (T. Zhong, M.-K. Pang, Z.-D. Chen, B. Zhang, J. Weng, and G. Lu. Org. Lett., 2020, 22, 3072 - 3078.)

[0010] In summary, sulfonyl fluoride compounds have extensive applications in many important fields. However, so far, most of the existing synthesis methods start from methods such as nucleophilic fluorination and transition metal catalysis, using arylsulfonyl chlorides, thiols, aryl halides, olefins, and aryl diazonium salts to achieve the synthesis of sulfonyl fluoride compounds. But they often require relatively harsh conditions, use transition metals, unstable and expensive reagents, have a narrow substrate scope, and are not conducive to industrial production. Therefore, it is of great significance to develop new carbon sources and synthetic methods to synthesize sulfonyl fluorides with different structures under mild conditions. Summary of the Invention

[0011] The present invention proposes a method for synthesizing sulfonyl fluoride compounds with simple method, low cost, and high yield, which broadens the existing synthesis technology.

[0012] An efficient method for preparing sulfonyl fluoride compounds of the present invention specifically comprises the following steps:

[0013]

[0014] Under a nitrogen atmosphere, trimethylammonium salt (1 eq), sulfur dioxide source 2 (Z eq), fluorine source (Y eq), electrolyte (X eq), and solvent were successively added to the electrolytic cell. At room temperature, the mixture was electrolyzed at a constant voltage under magnetic stirring until the raw materials reacted completely (detected by TLC). The reaction mixture was poured into ethyl acetate, washed with water, the organic phase was dried over anhydrous Na2SO4, and distilled under reduced pressure. The sulfonyl fluoride compound 3 was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents. The constant voltage can be achieved by installing carbon rods, platinum electrodes, etc. as the anode and cathode in the reaction mixture.

[0015] The trimethylammonium salt compounds with various substituents contained in the present invention can be prepared by referring to the literature methods. [X. Kong, Y. Wang, Y. Chen, X. Chen, L. Lin, Z.-Y. Cao, Org. Chem. Front., 2022, 9, 1288 - 1294].

[0016] The solvents used in the present invention are common organic solvents such as acetonitrile (CH3CN), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), etc. The amount used is 10 mL - 20 mL of solvent per millimole of trimethylammonium salt.

[0017] The fluorine source used in the present invention can be LiF, KF, NaF, KHF2, etc. Y is any value from 3 to 6.

[0018] The sulfur dioxide source used in the present invention can be bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct (DABSO), potassium metabisulfite, sodium metabisulfite, etc. The value of Z can be any value from 1 to 10.

[0019] The electrolyte used in the present invention is: n-Bu4NClO4, n Bu4NPF6, Et4NOTs, LiClO4, etc. X is any value from 0.5 to 10. In the present invention, R can be an aryl or an alkyl group. The aryl group can be a phenyl group substituted with methyl, ethyl, tert-butyl, methoxy, fluorine, chlorine, bromine, etc. at the para position, or a heteroaryl group such as thiophene, etc.; the alkyl group can be a butyl group or a benzyl group, etc., but is not limited to these groups; X- can be a halogen ion such as chlorine, bromine, iodine, trifluoromethanesulfonate, tetrafluoroborate, etc.

[0020] The constant voltage in the present invention can be -3 V to -5 V.

[0021] The beneficial effects of the present invention are:

[0022] (1) The raw materials used in the present invention are cheap and easily available, and it is easy to realize industrial production.

[0023] (2) The reaction of the present invention has no intermediate steps, is simple and convenient to operate, and does not require an additional oxidation-reduction agent, metal or photocatalyst.

[0024] (3) The present invention synthesizes the target product from trimethyl quaternary ammonium salt raw materials, broadening the synthesis method of sulfonyl fluoride compounds.

[0025] (4) The present invention adopts an electrochemical method to achieve the concept of green chemistry.

[0026] (5) The reaction principle of the present invention is as Figure 1 shown. It uses electrochemical cathodic reduction of trimethyl quaternary ammonium salt to generate aryl or alkyl radicals; then reacts with a SO2 source to generate aryl or alkyl sulfur dioxide radicals. These radicals can continue to be oxidized at the anode to generate aryl or alkyl sulfur dioxide cations, which then react with fluoride ions to obtain the target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the reaction principle diagram of the present invention.

[0028] Figure 2 is the 1H NMR spectrum of 4-(tert-butyl)benzenesulfonyl fluoride prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention will be described in more detail below through specific embodiments, so as to facilitate the understanding of the technical solution of the present invention, but it is not used to limit the protection scope of the present invention.

[0030] In the reaction equations of the following examples, 1 represents trimethyl quaternary ammonium salt.

[0031] Example 1

[0032] Synthesis of 4-(tert-butyl)benzenesulfonyl fluoride 3a:

[0033]

[0034] Under a nitrogen atmosphere, 4-(tert-butyl)phenyl quaternary ammonium salt 1a (0.1 mmol), DABSO (0.1 mmol), KHF2 (0.3 mmol), and n-Bu4NClO4 (0.2 mmol) were successively added to the electrolytic cell, and the solvent acetonitrile (4 mL) was added. A carbon rod was installed as the anode and cathode, and the mixture was electrolyzed at a constant voltage of -3V with magnetic stirring at room temperature. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried with anhydrous sodium sulfate, the organic phase was concentrated, and then subjected to column chromatography with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 17.7 mg of white solid product, with a yield of 82%.

[0035] The data characterization of 4-(tert-butyl)benzenesulfonyl fluoride is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 1.28 (s, 9H); 13 C NMR (101 MHz, Chloroform-d) δ 160.02, 130.0, 129.93 (d, J = 25 Hz), 129.8, 128.3, 126.7, 35.5, 30.9; 19 F NMR (376 MHz, Chloroform-d) δ 66.20; HRMS (ESI) m / z: [M+H] + Calcd for C 10 H 14 FO2S 217.0699; Found 217.0693.

[0036] Example 2

[0037] Synthesis of 4-methylbenzenesulfonyl fluoride 3b:

[0038]

[0039] Under a nitrogen atmosphere, 4-methylphenyl quaternary ammonium salt 1b (0.1 mmol), Na2S2O5 (0.2 mmol), KF (0.6 mmol), and n-Bu4NClO4 (0.1 mmol) were successively added to the electrolytic cell, and the solvent THF (2 mL) was added. A carbon rod was installed as the anode and cathode, and the mixture was electrolyzed at a constant voltage of -4V with magnetic stirring at room temperature. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried with anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was performed. The eluent was (petroleum ether / ethyl acetate = 50 / 1), and 13.3 mg of white solid product was obtained with a yield of 76%.

[0040] The data characterization of 4-methylbenzenesulfonyl fluoride is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.4 Hz, 2H), 7.50–7.37 (m, 2H), 2.49 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 147.1, 130.3, 130.2 (d, J = 24 Hz), 128.4, 21.8; 19 F NMR (376 MHz, Chloroform-d) δ 66.25; HRMS (ESI) m / z: [M+Na]+ Calcd for C7H7FO2SNa 197.0048; Found 197.0043.

[0041] Example 3

[0042] Synthesis of 4-ethylbenzenesulfonyl fluoride 3c:

[0043]

[0044] Under a nitrogen atmosphere, 4-ethylphenyl quaternary ammonium salt 1c (0.1 mmol), Na2S2O5 (0.4 mmol), KF (0.5 mmol), and n-Bu4NClO4 (0.2 mmol) were successively added to the electrolytic cell, and the solvent DMSO (4 mL) was added. A carbon rod was installed as the anode and cathode. At room temperature, the mixture was electrolyzed at a constant voltage of -5V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried with anhydrous sodium sulfate, the organic phase was concentrated, and then subjected to column chromatography with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 13.3 mg of the product as a white solid with a yield of 70%.

[0045] Data characterization of 4-ethylbenzenesulfonyl fluoride is as follows: 1 H NMR (400 MHz, Chloroform-d) δ7.98–7.87 (m, 2H), 7.51–7.39 (m, 2H), 2.78 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ153.2, 130.2 (d, J = 24 Hz), 129.2, 128.6, 29.0, 14.9; 19 F NMR (376 MHz, Chloroform-d) δ66.23; HRMS (EI) m / z: [M+Na] + Calcd for C8H9FO2SNa 211.0205; Found 211.0199.

[0046] Example 4

[0047] Synthesis of 5-bromo-2-methoxybenzenesulfonyl fluoride 3d:

[0048]

[0049] Under a nitrogen atmosphere, 5-bromo-2-methoxyphenyl quaternary ammonium salt 1d (0.1 mmol), K2S2O5 (1.0 mmol), LiF (0.4 mmol), and n-Bu4NClO4 (0.8 mmol) were successively added to the electrolytic cell, and the solvent THF (3 mL) was added. A carbon rod was installed as the cathode and anode. At room temperature, the mixture was electrolyzed at a constant voltage of -4V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 21.0 mg of the product as a white solid with a yield of 78%.

[0050] The data characterization of 5-bromo-2-methoxybenzenesulfonyl fluoride is as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J = 2.5 Hz, 1H), 7.79 (dd, J = 8.9, 2.5 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 4.01 (s, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 157.1, 139.9, 127.9 (d, J = 25 Hz), 114.5, 112.2, 56.90; 19 19F NMR (376 MHz, Chloroform-d) δ 58.93; HRMS (EI) m / z: [M+H] + Calcd for C7H7BrFO3S 268.9283; Found 268.9287.

[0051] Example 5

[0052] Synthesis of 4-methoxybenzenesulfonyl fluoride 3e:

[0053]

[0054] Under a nitrogen atmosphere, 4-methoxyphenyl quaternary ammonium salt 1e (0.1 mmol), Na2S2O5 (0.8 mmol), LiF (0.6 mmol), and n-Bu4NClO4 (0.4 mmol) were successively added to the electrolytic cell, and the solvent DMF (4 mL) was added. A carbon rod was installed as the cathode and anode. At room temperature, the mixture was electrolyzed at a constant voltage of -5V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 15.6 mg of the product as a white solid with a yield of 83%.

[0055] The data characterization of 4-methoxybenzenesulfonyl fluoride is as follows: 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=9.0Hz,2H),7.12–6.98(m,2H),3.92(s,3H); 13 C NMR(101MHz,Chloroform-d)δ165.3,130.8,123.7(d,J=24Hz),114.9,55.9; 19 F NMR(376MHz,Chloroform-d)δ67.26;HRMS(ESI)m / z:[M+Na] + Calcd for C7H7FO3SNa 212.9998;Found 212.9992.

[0056] Example 6

[0057] Synthesis of 3-fluoro-4-methoxybenzenesulfonyl fluoride 3f

[0058]

[0059] Under a nitrogen atmosphere, 3-fluoro-4-methoxyphenyl quaternary ammonium salt 1f (0.1 mmol), Na2S2O5 (0.8 mmol), KF (0.6 mmol), and LiClO4 (1.0 mmol) were successively added to the electrolytic cell, and the solvent THF (4 mL) was added. A carbon rod was installed as the anode and cathode, and the mixture was electrolyzed at a constant voltage of -4V under magnetic stirring at room temperature. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated. Then, column chromatography was performed with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 20.6 mg of the product as a white solid with a yield of 84%.

[0060] The data characterization of 3-fluoro-4-methoxybenzenesulfonyl fluoride is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.81(dt,J=8.7,1.9Hz,1H),7.72(dd,J=9.9,2.3Hz,1H),7.18–7.09(m,1H),4.01(s,3H); 13CNMR(126MHz, Chloroform-d) δ 154.0 (d, J = 8Hz), 151.7 (d, J = 202Hz), 126.4 (d, J = 3Hz), 124.1 (d, J = 21Hz), 116.5 (d, J = 18Hz), 113.3 (d, J = 1Hz), 56.7; 19 F NMR(471MHz, Chloroform-d) δ 67.30, -130.01; HRMS(ESI) m / z: [M + H] + Calcd for C7H7F2O3S 209.0084; Found 209.0085.

[0061] Example 7

[0062] Synthesis of 3 g of 1,3 - benzodioxole - 5 - sulfonyl fluoride:

[0063]

[0064] Under a nitrogen atmosphere, 1 g (0.1 mmol) of 1,3 - benzodioxole quaternary ammonium salt, Na2S2O5 (0.2 mmol), LiF (0.6 mmol), and n - Bu4NPF6 (0.2 mmol) were successively added to the electrolytic cell, and the solvent DMSO (4 mL) was added. A carbon rod was installed as the anode and cathode, and the mixture was electrolyzed at a constant voltage of - 3V with magnetic stirring at room temperature. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried with anhydrous sodium sulfate, the organic phase was concentrated, and then subjected to column chromatography with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 14.3 mg of the product as a white solid with a yield of 70%.

[0065] Data characterization of 1,3 - benzodioxole - 5 - sulfonyl fluoride is as follows: 1 H NMR(500MHz, Chloroform - d) δ 7.61 (ddd, J = 8.3, 1.9, 0.7Hz, 1H), 7.38 (d, J = 2.0Hz, 1H), 6.97 (dd, J = 8.3, 0.9Hz, 1H), 6.16 (s, 2H); 13 C NMR(126MHz, Chloroform - d) δ 154.0, 148.7, 125.5 (d, J = 20Hz), 125.2, 108.8, 108.2, 103.0; 19 F NMR(471MHz, Chloroform - d) δ 66.82; HRMS(ESI) m / z: [M + Na] +Calculated for C7H5FO4SNa 226.9790; Found 226.985.

[0066] Example 8

[0067] Synthesis of 4-fluorobenzenesulfonyl fluoride 3h:

[0068]

[0069] Under a nitrogen atmosphere, 4-fluorophenyl quaternary ammonium salt 1h (0.1 mmol), Na2S2O5 (0.2 mmol), KHF2 (0.6 mmol), and n-Bu4NClO4 (0.2 mmol) were successively added to the electrolytic cell, and the solvent DMF (4 mL) was added. A carbon rod was installed as the anode and cathode. At room temperature, the mixture was electrolyzed at a constant voltage of -3V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 14.7 mg of the product as a white solid with a yield of 82%.

[0070] Data characterization of 4-fluorobenzenesulfonyl fluoride is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.77 (dt, J = 8.0, 1.3 Hz, 1H), 7.66 (dt, J = 7.6, 2.1 Hz, 1H), 7.58 (tdd, J = 8.0, 5.1, 1.2 Hz, 1H), 7.43 (td, J = 8.2, 2.6 Hz, 1H); 13 C NMR (101 MHz, Chloroform-d) δ 162.4 (d, J = 253 Hz), 134.7 (d, J = 18 Hz), 131.7 (d, J = 8 Hz), 124.4 (d, J = 3 Hz), 123.0 (d, J = 21 Hz), 115.9 (d, J = 25 Hz); 19 F NMR (376 MHz, Chloroform-d) δ 65.88, -107.58–-107.66 (m). HRMS (ESI) m / z: [M+H] + Calculated for C6H5F2O2S 178.9978; Found 178.9980.

[0071] Example 9

[0072] Synthesis of 4-chlorobenzenesulfonyl fluoride 3i:

[0073]

[0074] Under a nitrogen atmosphere, 4-chlorophenyl quaternary ammonium salt 1i (0.1 mmol), Na2S2O5 (0.2 mmol), KF (0.6 mmol), and Et4NOTs (0.2 mmol) were successively added to the electrolytic cell, and the solvent acetonitrile (4 mL) was added. A carbon rod was installed as the anode and cathode. At room temperature, the mixture was electrolyzed at a constant voltage of -4 V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then subjected to column chromatography with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 15.0 mg of the product as a white solid with a yield of 77%.

[0075] The data characterization of 4-chlorobenzenesulfonyl fluoride is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 8.8 Hz, 2H), 7.63 (s, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 142.7, 131.4 (d, J = 26 Hz), 130.1, 129.9; 19 F NMR (376 MHz, Chloroform-d) δ 66.42; HRMS (ESI) m / z: [M+H] + Calcd for C6H5 35 ClFO2S 194.9683; Found 194.9680.

[0076] Example 10

[0077] Synthesis of 3-bromobenzenesulfonyl fluoride 3j:

[0078]

[0079] Under a nitrogen atmosphere, 3-bromophenyl quaternary ammonium salt 1j (0.1 mmol), K2S2O5 (0.2 mmol), NaF (0.6 mmol), and n-Bu4NPF6 (0.2 mmol) were successively added to the electrolytic cell, and the solvent THF (4 mL) was added. A carbon rod was installed as the anode and cathode. At room temperature, the mixture was electrolyzed at a constant voltage of -5 V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then subjected to column chromatography with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 18.7 mg of the product as a white solid with a yield of 78%.

[0080] The data characterization of 3-bromobenzenesulfonyl fluoride is as follows: 11H NMR (400 MHz, Chloroform-d) δ 8.15 (t, J = 1.7 Hz, 1H), 7.93 (dd, J = 21.0, 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H); 13 13C NMR (101 MHz, Chloroform-d) δ 138.8, 134.8 (d, J = 25.4 Hz), 131.3, 131.2, 127.0, 123.6; 19 19F NMR (376 MHz, Chloroform-d): δ 66.2; HRMS (ESI) m / z: [M+H] + Calcd for C6H5BrFO2S 238.9178; Found 238.9178.

[0081] Example 11

[0082] Synthesis of 2-methylbenzenesulfonyl fluoride 3k:

[0083]

[0084] Under a nitrogen atmosphere, 2-methylphenyl quaternary ammonium salt 1k (0.1 mmol), Na2S2O5 (0.2 mmol), LiF (0.6 mmol), and n-Bu4NClO4 (0.2 mmol) were successively added to the electrolytic cell, and the solvent THF (4 mL) was added. A carbon rod was installed as the anode and cathode, and the mixture was electrolyzed at a constant voltage of -4V with magnetic stirring at room temperature. After the reaction was monitored by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated. Then, column chromatography was performed with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 12.7 mg of the product as a white solid with a yield of 73%.

[0085] The data characterization of 2-methylbenzenesulfonyl fluoride is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 8.04 (d, J = 8.0 Hz, 1H), 7.63 (td, J = 7.6, 1.3 Hz, 1H), 7.44–7.39 (m, 2H), 2.70 (s, 3H); 13 13C NMR (126 MHz, Chloroform-d) δ 139.2, 135.4, 133.0, 132.5 (d, J = 22.7 Hz), 130.2 (d, J = 1.7 Hz), 126.8, 20.4 (d, J = 1.2 Hz); 1919F NMR (471 MHz, Chloroform-d) δ 60.3; HRMS (ESI) m / z: [M+H] + Calcd for C7H8FO2S 175.0229; Found 175.0221.

[0086] Example 12

[0087] Synthesis of 2-methoxybenzenesulfonyl fluoride 3l:

[0088]

[0089] Under a nitrogen atmosphere, 2-methoxyphenyl quaternary ammonium salt 1l (0.1 mmol), Na2S2O5 (0.2 mmol), KF (0.6 mmol), and LiClO4 (0.2 mmol) were successively added to an electrolytic cell, and the solvent acetonitrile (4 mL) was added. A carbon rod was installed as the anode and cathode. At room temperature, the mixture was electrolyzed with a constant voltage of -4V under magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then purified by column chromatography with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 13.3 mg of the product as a white solid, with a yield of 80%.

[0090] Data characterization of 2-methoxybenzenesulfonyl fluoride is as follows: 1 1H NMR (400 MHz, Chloroform-d): δ 7.94 (dd, J = 8.1, 1.6 Hz, 1H), 7.74–7.67 (m, 1H), 7.12 (dd, J = 7.9, 6.0 Hz, 2H), 4.01 (s, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 160.7, 137.2, 131.3, 122.5, 118.7, 113.0, 55.8; 19 19F NMR (376 MHz, Chloroform-d): δ 58.5; HRMS (ESI) m / z: [M+H] + Calcd for C7H8FO3S 191.0178; Found 191.0173.

[0091] Example 13

[0092] Synthesis of thiophene-2-sulfonyl fluoride 3m:

[0093]

[0094] Under a nitrogen atmosphere, 1m (0.1 mmol) of thiophene quaternary ammonium salt, 0.2 mmol of K2S2O5, 0.6 mmol of KF, and 0.2 mmol of LiClO4 were successively added to the electrolytic cell, and 4 mL of acetonitrile as the solvent was added. Carbon rods were installed as the anode and cathode. At room temperature, the mixture was electrolyzed at a constant voltage of -5V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with the eluent (petroleum ether / ethyl acetate = 50 / 1) to obtain 13.3 mg of white solid product with a yield of 80%.

[0095] The data characterization of thiophene-2-sulfonyl fluoride is as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.93 (dt, J = 3.9, 1.4 Hz, 1H), 7.88 (dd, J = 5.0, 1.4 Hz, 1H), 7.24 (ddd, J = 4.9, 3.9, 0.9 Hz, 1H); 13 C NMR (126 MHz, Chloroform-d) δ 136.9, 136.6, 131.4 (d, J = 23 Hz), 128.2; 19 F NMR (471 MHz, Chloroform-d) δ 71.76; HRMS (ESI) m / z: [M+H] + Calcd for C4H4FO2S2 166.9637; Found 166.9641.

[0096] Example 14

[0097] Synthesis of benzylsulfonyl fluoride 3n:

[0098]

[0099] Under a nitrogen atmosphere, 1n (0.2 mmol) of benzyl quaternary ammonium salt, 0.2 mmol of K2S2O5, 0.6 mmol of NaF, and 0.2 mmol of n-Bu4NPF6 were successively added to the electrolytic cell, and 4 mL of THF as the solvent was added. Carbon rods were installed as the anode and cathode. At room temperature, the mixture was electrolyzed at -5V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with the eluent (petroleum ether / ethyl acetate = 50 / 1) to obtain 14.6 mg of white solid product with a yield of 84%.

[0100] The data characterization of benzylsulfonyl fluoride is as follows:1 1H NMR (400 MHz, Chloroform-d) δ 7.44 (p, J = 1.9 Hz, 5H), 4.59 (d, J = 3.2 Hz, 2H); 13 13C NMR (101 MHz, Chloroform-d) δ 130.7, 129.9, 129.3, 125.5, 56.9 (d, J = 18 Hz); 19 19F NMR (376 MHz, Chloroform-d) δ 51.42; HRMS (ESI) m / z: [M+Na] + Calcd for C7H7FO2SNa 197.0048; Found 197.0043.

[0101] Example 15

[0102] Synthesis of 2-(1,3-dioxoisoindol-2-yl)ethane-1-sulfonyl fluoride 3o:

[0103]

[0104] Under a nitrogen atmosphere, 2-(1,3-dioxoisoindol-2-yl)ethyl quaternary ammonium salt 1o (0.1 mmol), K2S2O5 (0.6 mmol), NaF (0.6 mmol), and n-Bu4NClO4 (0.9 mmol) were successively added to the electrolytic cell, and the solvent DMF (4 mL) was added. A carbon rod was installed as the anode and cathode, and the mixture was electrolyzed at -4 V with magnetic stirring at room temperature. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated. Then, column chromatography was performed with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 20.2 mg of the product as a white solid with a yield of 78%.

[0105] Data characterization of 2-(1,3-dioxoisoindol-2-yl)ethane-1-sulfonyl fluoride is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 7.89 (dd, J = 5.5, 3.1 Hz, 2H), 7.77 (dd, J = 5.5, 3.1 Hz, 2H), 4.28 (t, J = 6.7 Hz, 2H), 3.84 (td, J = 6.6, 4.6 Hz, 2H); 13 13C NMR (126 MHz, Chloroform-d) δ 167.3, 134.6, 131.6, 123.8, 48.1 (d, J = 14 Hz), 32.0; 1919F NMR (471 MHz, Chloroform-d) δ 56.03; HRMS (ESI) m / z: [M+Na] + Calcd for C 10 H8FNO4SNa 280.0056; Found 280.0061.

[0106] Example 16

[0107] Synthesis of p-toluenesulfonyl fluoride 3p:

[0108]

[0109] Under a nitrogen atmosphere, p-methylbenzyl quaternary ammonium salt 1p (0.1 mmol), K2S2O5 (0.2 mmol), NaF (0.6 mmol), and n-Bu4NClO4 (0.05 mmol) were successively added to the electrolytic cell, and the solvent DMSO (4 mL) was added. The anode and cathode were installed, and the mixture was electrolyzed at -3V under magnetic stirring at room temperature. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated. Then, column chromatography was performed with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 14.3 mg of the product as a white solid with a yield of 76%.

[0110] Data characterization of p-toluenesulfonyl fluoride is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 7.34–7.29 (m, 1H), 7.25 (t, J = 3.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 4.55 (d, J = 3.1 Hz, 2H), 2.38 (s, 3H); 13 13C NMR (126 MHz, Chloroform-d) δ 139.2, 131.3, 130.7, 129.2, 127.7, 125.3, 56.8 (d, J = 14 Hz), 21.3; 19 19F NMR (376 MHz, Chloroform-d) δ 51.46; HRMS (ESI) m / z: [M+Na] + Calcd for C8H9FO2SNa 211.0205; Found 211.0199.

[0111] Example 17

[0112] Synthesis of butane-1-sulfonyl fluoride 3q:

[0113]

[0114] Under a nitrogen atmosphere, n-butyl quaternary ammonium salt 1q (0.1 mmol), K2S2O5 (0.2 mmol), NaF (0.6 mmol), and n-Bu4NClO4 (0.2 mmol) were successively added to the electrolytic cell, and the solvent acetonitrile (4 mL) was added. Carbon rods were installed as the anode and cathode. At room temperature, the mixture was electrolyzed at -5 V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 9.6 mg of the product as a white solid with a yield of 68%.

[0115] The data characterization of butane-1-sulfonyl fluoride is as follows: 1 H NMR (500 MHz, Chloroform-d) δ 3.40–3.32 (m, 2H), 1.96–1.88 (m, 2H), 1.52 (q, J = 7.5 Hz, 2H), 0.98 (td, J = 7.3, 1.4 Hz, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 50.5 (d, J = 13 Hz), 25.2, 21.0, 13.08, 13.07; 19 F NMR (471 MHz, Chloroform-d) δ 52.79; HRMS (ESI) m / z: [M+H] + Calcd for C4H 10 FO2S 141.0386; Found 141.0380.

[0116] Example 18

[0117] Synthesis of ethyl 3-(fluorosulfonyl)benzoate 3r:

[0118]

[0119] Under a nitrogen atmosphere, 3-(ethoxycarbonyl)phenyl quaternary ammonium salt 1r (0.1 mmol), Na2S2O5 (0.2 mmol), KF (0.6 mmol), and Et4NOTs (0.2 mmol) were successively added to the electrolytic cell, and the solvent acetonitrile (4 mL) was added. Carbon rods were installed as the anode and cathode. At room temperature, the mixture was electrolyzed at -4 V with magnetic stirring. After the reaction was detected by TLC and the raw materials were completely consumed, the reaction was stopped. The reaction mixture was poured into ethyl acetate, washed twice with water, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and then column chromatography was carried out with an eluent of (petroleum ether / ethyl acetate = 50 / 1) to obtain 18.6 mg of the product as a white solid with a yield of 80%.

[0120] The data characterization of ethyl 3-(fluorosulfonyl)benzoate is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.66(s,1H),8.44(d,J=7.8Hz,1H),8.18(d,J=7.9Hz,1H),7.74(t,J=7.9Hz,1H),4.45(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ164.1,136.3,133.6(d,J=25.6Hz),132.4,132.0,130.0,129.5,62.1,14.2; 19 F NMR(376MHz,Chloroform-d)δ66.00;HRMS(ESI)m / z:[M+H] + Calcd for C9H 10 FO4S 233.0284;Found 233.0282.

[0121] The above-described embodiments are only preferred embodiments of the present invention and do not limit the scope of implementation of the present invention. Therefore, all equivalent changes or modifications made according to the structure, features, and principles described in the scope of the present invention patent should be included in the scope of the present invention's patent application.

Claims

1. A method for efficiently preparing sulfonyl fluoride compounds, characterized in that, Including: Step 1: Under a nitrogen atmosphere and at room temperature, electrolyze a reaction mixture formed by trimethylammonium salt 1, a sulfur dioxide source 2, a fluorine source, an electrolyte, and a solvent using a constant voltage until the reaction is complete; the reaction equation is as follows: ； Wherein R is an aryl group, an alkyl group, or a benzyl group. The aryl group is a phenyl group with a methyl, ethyl, tert-butyl, methoxy, fluorine, chlorine, or bromine substitution at the para position, or the aryl group is a thiophene, and the alkyl group is a butyl group; X is bromine or iodine; The fluorine source is LiF, KF, or NaF; The sulfur dioxide source is potassium metabisulfite or sodium metabisulfite; Step 2: Wash and dry the organic phase, and perform vacuum distillation; purify to obtain the sulfonyl fluoride compound 3.

2. The method for efficiently preparing a sulfonyl fluoride compound according to claim 1, wherein The constant voltage is formed by installing carbon rods or platinum electrodes as the anode and cathode in the reaction mixture.

3. A method for efficiently preparing a sulfonyl fluoride compound according to claim 1, characterized in that, The constant voltage is -3 V to -5 V.

4. A method for efficiently preparing sulfonyl fluoride compounds according to claim 1, characterized in that, The solvent is acetonitrile, N , N N,N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide, and the dosage thereof is 10 mL to 20 mL of the solvent corresponding to each millimole of the trimethyl quaternary ammonium salt.

5. A method for efficiently preparing a sulfonyl fluoride compound according to claim 1, characterized in that, The dosage of the fluorine source is 3 to 6 equivalents.

6. A method for efficiently preparing a sulfonyl fluoride compound according to claim 1, characterized in that, The dosage of the sulfur dioxide source is 1 to 10 equivalents.

7. The method for efficiently preparing a sulfonyl fluoride compound according to claim 1, characterized in that, The electrolyte is n Bu4NClO4, n Bu4NPF6, Et4NOTs or LiClO4, and the dosage of the electrolyte is 0.5 to 10 equivalents.

8. A method for efficiently preparing a sulfonyl fluoride compound according to claim 1, wherein Step 2 specifically is: Pour the reaction mixture into ethyl acetate, wash with water, dry the organic phase with anhydrous Na2SO4, and perform vacuum distillation; use petroleum ether and ethyl acetate as eluents, and purify through silica gel chromatography to obtain the sulfonyl fluoride compound 3.

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