Arylsulfonyl fluoride and preparation method using aryliodonium salt as raw material

Abstract

The present invention relates to an arylsulfonyl fluoride and a preparation method using an aryliodonium salt as a raw material, comprising: mixing the aryliodonium salt, a sulfur dioxide source, a fluorine source, and a photosensitizer in an organic solvent in an inert gas atmosphere, and stirring the mixture for reaction under light conditions to obtain the arylsulfonyl fluoride; wherein the aryliodonium salt has the following structural formula: #imgabs0# wherein R 1 、R 2 wherein the anion X is H, alkyl, halide, methoxy, cyano, or trifluoromethyl, respectively; and the anion X is a hexafluorophosphate anion, a trifluoromethanesulfonate anion, or a p-toluenesulfonate anion, etc. Compared with the prior art, the present invention, based on a novel strategy of "free radical sulfur dioxide insertion fluorination," achieves efficient, metal-free photocatalytic synthesis of arylsulfonyl fluorides at room temperature. This method has the advantages of mild reaction conditions, simple operation, and good yields. It is also highly applicable to both symmetrical and asymmetrical aryliodonium salts, and the gram-scale reaction provides more possibilities for introducing sulfonyl fluoride groups into drug molecules.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to an arylsulfonyl fluoride and a preparation method using an aryliodonium salt as a raw material. Background Art

[0002] Sulfonyl fluoride compounds possess a unique balance of reactivity and stability, resistance to reduction, and high thermodynamic stability to nucleophilic substitution reactions, making them important applications in organic synthesis, biopharmaceuticals, polymer materials, and other fields [Angew. Chem. Int. Ed., 2019, 58, 957; RSC Med. Chem., 2020, 11, 10]. In 2014, Professor Sharpless's research group reported a novel click chemistry reaction—the hexavalent sulfur (VI) fluoride exchange (SuFEx) reaction [Angew. Chem. Int. Ed., 2014, 53, 9430]. Sulfonyl fluoride-containing molecules are involved in nearly every field of modern chemistry. However, current methods for introducing sulfonyl fluoride groups into organic molecules are relatively limited, hindering further research and application of the SuFEx click reaction. Therefore, the development of more methods for synthesizing sulfonyl fluorides is urgently needed. With the development of click chemistry (SuFEx) reactions, the research and application of arylsulfonyl fluoride compounds have increased significantly. In chemical biology and molecular pharmacology, they can be used as reaction probes, irreversible covalent inhibitors of proteins, or warheads for probes [J.Am.Chem.Soc., 2017, 139, 680.]. Methods for preparing various arylsulfonyl fluoride compounds have also been widely reported.

[0003] The most classic method for preparing arylsulfonyl fluorides is the nucleophilic fluorine-chlorine exchange reaction of arylsulfonyl chlorides [J.Org.Chem., 1977, 42, 2031.]. However, arylsulfonyl chlorides are unstable, water-sensitive, and difficult to prepare. Arylsulfonyl fluorides can also be prepared by simple oxidative fluorination or electrochemical methods based on the conversion of various sulfur-containing functional groups [Green Chem., 2016, 18, 1224; J.Am.Chem.Soc., 2019, 141, 11832.], but substrate availability limits their widespread application. Furthermore, transition metal-catalyzed methods can also effectively synthesize various arylsulfonyl fluorides [J.Org.Chem., 2017, 82, 2294.]. However, the use of transition metals can cause environmental pollution and are unfriendly to the natural environment. Therefore, the development of new synthetic methods for the environmentally friendly preparation of various high-value arylsulfonyl fluorides is of great significance.

[0004] Photochemical synthesis methods are currently widely used. Unlike metal-catalyzed reactions, organic photoredox catalysts have attracted research from fields ranging from chemical biology to pharmaceuticals to materials science. Organic photoredox catalysis offers not only "metal-free" alternatives to transition metal catalysis but also unique chemistries that react efficiently and a wide range of substrates that are unreactive in most synthetic environments [Chem. Rev., 2016, 116, 10075.].

[0005] There are few reports on photochemical synthesis of arylsulfonyl fluorides. Recently, Tlili's group reported a visible light-mediated method for synthesizing arylsulfonyl fluorides via a single electron transfer process using aryl diazonium salts as substrates and a cyanoaromatic hydrocarbon as an organic photoredox catalyst [Chem.–Eur. J., 2021, 27, 8704.]. As highly reactive compounds, aryl diazonium salts are widely used to prepare polyfunctionalized aromatic compounds through the Sandmeyer reaction. However, aryl diazonium salts are generally unstable and easily decompose or even explode when heated or violently vibrated, posing a potential risk.

[0006] Based on the above research background, developing mild reaction conditions and synthesizing arylsulfonyl fluorides from stable substrates is an urgent problem to be solved. Summary of the Invention

[0007] The purpose of the present invention is to provide an arylsulfonyl fluoride and a preparation method using an aryliodonium salt as a raw material.

[0008] The purpose of the present invention can be achieved by the following technical solutions:

[0009] Aryl iodonium salts are a class of stable and highly reactive substances that can serve as precursors of aryl radicals under light irradiation. The present invention provides an efficient and mild method for preparing aryl sulfonyl fluoride from aryl iodonium salts by achieving metal-free catalysis under visible light induction. The method comprises:

[0010] In an inert gas atmosphere, an aryl iodonium salt, a sulfur dioxide source, a fluorine source, and a photosensitizer are mixed in an organic solvent and stirred to react under light conditions to obtain an aryl sulfonyl fluoride;

[0011] Wherein, the structural formula of the aryl iodonium salt is as follows:

[0012]

[0013] Correspondingly, the structural formula of the arylsulfonyl fluoride is as follows:

[0014] or

[0015] Where R 1 、R 2 One or more combinations of H, C1-C10 linear or branched alkyl, F, Cl, Br, I, methoxy, nitro, cyano, acetylamino, trifluoromethyl, trifluoromethoxy or biphenyl;

[0016] The anion X is one of a hexafluorophosphate anion, a trifluoromethanesulfonate anion, a p-toluenesulfonate anion, and a tetrafluoroborate anion.

[0017] Furthermore, the sulfur dioxide source is one of 4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct (DABSO), thiourea dioxide, sulfur dioxide, 4-(dimethylamino)pyridin-1-ium-1-sulfinate, potassium metabisulfite, sodium metabisulfite (Na2S2O5) or sodium dithionite (Na2S2O4).

[0018] Furthermore, the fluorine source is one of N-fluorobisbenzenesulfonamide (NFSI), selective fluorination reagent (Selectfluor), 1-fluoropyridine tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridine tetrafluoroborate, potassium fluoride, potassium bifluoride, sodium fluoride, cesium fluoride, silver fluoride or copper fluoride.

[0019] Furthermore, the photosensitizer is one of camphorquinone (CQ), 10-hexyl-7-(thiophene-3-yl)-10H-phenothiazine-3-carboxaldehyde (Ps), 7,7'-((10-hexyl-10H-phenothiazine-3,7-diyl)bis(acetylene-2,1-diyl))bis(10-hexyl-10H-phenothiazine-3-carboxaldehyde) (PCPCHO), Eosin Y (Eosin Y), Fluorecein, curcumin, Rose Bengal, Rhodamine B, anthraquinone, 2,4,6-triphenylpyran tetrafluoroborate, Michler's ketone, tetrachlorobenzoquinone, 10-phenylphenothiazine or 2,4,6-trimethylbenzoyl-diphenylphosphine oxide (TPO).

[0020] Furthermore, the organic solvent is one of acetonitrile, 1,2-dichloroethane (DCE), dichloromethane (DCM), ethyl acetate, n-hexane, ethanol (EtOH), tert-butanol, toluene, acetone, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), chlorobenzene or chloroform.

[0021] Furthermore, during the stirring reaction, the reaction temperature is room temperature and the reaction time is 1-48 hours.

[0022] Furthermore, the molar ratio of the aryl iodonium salt, the sulfur dioxide source, the fluorine source, and the photosensitizer is 1:(0.5-5):(1.2-5):(0.01-0.1).

[0023] Furthermore, in the lighting conditions, the light source used is one of an ultraviolet lamp, a blue light lamp (blue LED), an incandescent lamp (CFL), and a green light lamp (green LED).

[0024] Furthermore, when a blue light lamp is selected as the light source, the power of the blue light lamp is 20W and the wavelength of the blue light is 440-445nm.

[0025] An arylsulfonyl fluoride is prepared by the method described above.

[0026] Photochemical synthesis has garnered widespread attention and application in recent years as a green, environmentally friendly, and highly efficient organic synthesis method. This method involves the reaction of a photosensitizer with an aryl iodonium salt under photocatalytic conditions to form an aryl radical. This reaction simultaneously captures sulfur dioxide from a sulfur dioxide source to form an arylsulfonyl radical, which is then nucleophilically attacked by fluoride anions to yield an arylsulfonyl fluoride. The reaction is mild, simple to operate, requires minimal materials, and does not require transition metal catalysis. It exhibits good applicability to both symmetric and asymmetric substrates.

[0027] The present invention limits the process conditions during the reaction, such as reaction temperature, reaction time and the ratio of the addition amounts of the various raw materials. If the conditions are not within the scope of the claims of the present invention, the reaction can still proceed smoothly to obtain the arylsulfonyl fluoride compound, but the yield will be reduced.

[0028] Compared with the prior art, the present invention has the following characteristics:

[0029] 1) Based on the "free radical sulfur dioxide insertion fluorination" strategy, the present invention achieves an efficient synthesis of aryl iodonium salts to aryl sulfonyl fluorides with good yields;

[0030] 2) The present invention synthesizes arylsulfonyl fluoride under light conditions, and the reaction does not require transition metal catalysis, resulting in green synthesis, mild conditions, and simple operation;

[0031] 3) The method for synthesizing arylsulfonyl fluoride of the present invention has good applicability to various symmetrical and asymmetrical aryliodonium salt substrates. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the 4-isopropylbenzenesulfonyl fluoride compound in Example 3 of the present invention;

[0033] Figure 2is the nuclear magnetic resonance fluorine spectrum of the 4-isopropylbenzenesulfonyl fluoride compound in Example 3 of the present invention;

[0034] Figure 3 This is the carbon NMR spectrum of the 4-isopropylbenzenesulfonyl fluoride compound in Example 3 of the present invention. DETAILED DESCRIPTION

[0035] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0036] An arylsulfonyl fluoride, the preparation method of which comprises:

[0037]

[0038] In an inert gas atmosphere, an aryl iodonium salt, a sulfur dioxide source, a fluorine source, and a photosensitizer are mixed in an organic solvent at a molar ratio of 1:(0.5-5):(1.2-5):(0.01-0.1), and the mixture is stirred at room temperature under illumination for 1-48 hours to obtain an aryl sulfonyl fluoride.

[0039] The aryl group in the aryliodonium salt can be any one or more of phenyl, substituted phenyl, condensed ring aryl, substituted condensed ring aryl, aromatic heterocycle or aromatic heterocycle derivative group, wherein the substituted phenyl, substituted condensed ring aryl, substituted aromatic heterocycle or aromatic heterocycle derivative group can be single substituted or multi-substituted;

[0040] Preferably, the aryl iodonium salt structural formula is as follows:

[0041]

[0042] Where R 1 、R 2 One or more combinations of H, C1-C10 linear or branched alkyl, F, Cl, Br, I, methoxy, nitro, cyano, acetylamino, trifluoromethyl, trifluoromethoxy or biphenyl;

[0043] The anion X is one of a hexafluorophosphate anion, a trifluoromethanesulfonate anion, a p-toluenesulfonate anion, and a tetrafluoroborate anion.

[0044] The sulfur dioxide source is one of 4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct, thiourea dioxide, sulfur dioxide, 4-(dimethylamino)pyridin-1-ium-1-sulfinate, potassium metabisulfite, sodium metabisulfite or sodium dithionite; and preferably 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO).

[0045] The fluorine source is one of N-fluorobisbenzenesulfonamide (NFSI), selective fluorination reagent (Selectfluor), 1-fluoropyridine tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridine tetrafluoroborate, potassium fluoride, potassium bifluoride, sodium fluoride, cesium fluoride, silver fluoride or copper fluoride; and preferably potassium bifluoride.

[0046]

[0047] The photosensitizer is one of camphorquinone (CQ), 10-hexyl-7-(thiophen-3-yl)-10H-phenothiazine-3-carboxaldehyde (Ps), 7,7'-((10-hexyl-10H-phenothiazine-3,7-diyl)bis(acetylene-2,1-diyl))bis(10-hexyl-10H-phenothiazine-3-carboxaldehyde) (PCPCHO), eosin Y (Eosin Y), fluorescein (Fluorecein), curcumin, tetrachlorotetraiodine fluorescein disodium (RoseBengal), rhodamine B, anthraquinone, 2,4,6-triphenylpyran boron tetrafluoride salt, Michler's ketone, tetrachlorobenzoquinone, 10-phenylphenothiazine or 2,4,6-trimethylbenzoyl-diphenylphosphine oxide (TPO); and preferably camphorquinone (CQ).

[0048] The organic solvent is one of acetonitrile, 1,2-dichloroethane (DCE), dichloromethane (DCM), ethyl acetate, n-hexane, ethanol (EtOH), tert-butanol, toluene, acetone, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), chlorobenzene or chloroform; and preferably acetonitrile.

[0049] In the illumination conditions, the light source used is one of an ultraviolet lamp, a blue light lamp (blue LED), an incandescent lamp (CFL), and a green light lamp (greenLED). Preferably, when a blue light lamp is selected as the light source, the power of the blue light lamp is 20W and the wavelength of the blue light is 440-445nm.

[0050] Compared with the existing technology, the present invention is based on the "free radical sulfur dioxide insertion fluorination" strategy to achieve efficient synthesis of aryl sulfonyl fluorides without metal photocatalysis at room temperature. It has the advantages of mild reaction conditions, simple operation, and good yield. It has good applicability for both symmetrical and asymmetrical aryl iodonium salts. The gram-scale reaction provides more possibilities for introducing sulfonyl fluoride groups into drug molecules.

[0051] This embodiment is implemented based on the technical solution of the present invention, and provides detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments. Table 1 shows the specifications and manufacturers of commercially available reagents used in the article. Diaryliodonium salts were prepared according to the literature (J.Org.Chem.2008,73,4602-4607; Synlett 2008,2008,592-596; Adv.Synth.Catal.2007,349,2610-2618; Chem.Commun.2007,2521-2523; Chem.–Eur.J.2021,27,5790-5795; Org.Lett.2014,16,6408-6411; Performance Study of Epoxy Photoinitiator System of Aromatic Ionium Salts [D]. Beijing University of Chemical Technology, 2015).

[0052] Table 1 Experimental drugs and manufacturers

[0053]

[0054]

[0055]

[0056] Example 1: Synthesis of 4-methylbenzenesulfonyl fluoride

[0057]

[0058] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor were added 181.6 mg (0.4 mmol) of bis(4-methylphenyl)iodonium hexafluorophosphate (V), 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Then, 4.0 mL of anhydrous acetonitrile was added via syringe under an argon atmosphere. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 4-methylbenzenesulfonyl fluoride (white solid, 75%). 1 H NMR (400MHz, CDCl3): δ7.89 (d, J = 8.2Hz, 2H), 7.42 (d, J = 8.0Hz, 2H), 2.49 (s, 3H); 19F NMR (376MHz, CDCl3): δ66.3ppm. GC-MS (EI): m / z=174.0 (M + ).

[0059] Comparative Example 1:

[0060] Compared with Example 1, the only difference is that the sulfur dioxide source (ie, DABSO) is replaced by potassium metabisulfite, sodium metabisulfite, sodium dithionite, and thiourea dioxide, and the rest is the same as Example 1.

[0061] By nuclear magnetic resonance fluorine spectrum detection, trace yields can be obtained using the above sulfur dioxide sources. The results are shown in Table 2.

[0062] Table 2

[0063]

[0064]

[0065] Comparative Example 2:

[0066] Compared with Example 1, the only difference is that the fluorine source (i.e., KHF2) is replaced by an equimolar amount of a selective fluorination reagent (Selectfluor), 1-fluoropyridine tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridine tetrafluoroborate, potassium fluoride, sodium fluoride, silver fluoride, and copper fluoride. The rest is the same as in Example 1.

[0067] The yield was reduced as shown in Table 3 by nuclear magnetic resonance fluorine spectrum detection.

[0068] Table 3

[0069]

[0070] Comparative Example 3:

[0071] Compared with Example 1, the only difference is that the photosensitizer (ie, CQ) is replaced by equimolar amounts of Ps, PCPCHO, TPO, Eosin Y, Fluorecein, Rose Bengal, etc., and the rest is the same as Example 1.

[0072] The yields were all lower than 70% as determined by nuclear magnetic resonance fluorine spectroscopy, as shown in Table 4.

[0073] Table 4

[0074]

[0075]

[0076] Comparative Example 4:

[0077] Compared with Example 1, the only difference is that the solvent (ie, acetonitrile) is replaced by equal volumes of dichloromethane, 1,2-dichloroethane, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene, and acetone, and the rest is the same as Example 1.

[0078] The yields were all lower than 14% as determined by nuclear magnetic resonance fluorine spectroscopy, as shown in Table 5.

[0079] Table 5

[0080]

[0081] Comparative Example 5: Effect of light wavelength on substrate

[0082] Compared with Example 1, the only difference is that the light source (ie, the blue light lamp) is replaced by a green light lamp (LED) or an incandescent lamp (CFL) of equal power, and the rest is the same as Example 1.

[0083] The results of nuclear magnetic resonance fluorine spectrum showed that the yield was significantly reduced to only 53% when using green light, while the yield did not change significantly when using CFL lamp. The results are shown in Table 6.

[0084] Table 6

[0085]

[0086]

[0087] Comparative Example 6:

[0088] Compared with Example 1, the only difference is that the stirring reaction time is adjusted (originally 24 hours), and the rest is the same as Example 1.

[0089] The results of nuclear magnetic resonance fluorine spectroscopy are shown in Table 7. When the reaction time is less than 8 hours, the fluorine spectrum yield is less than 39%, possibly because the time is too short and the reaction raw materials may not be completely converted. Compared with Example 1, the yields are relatively close when the reaction time is more than 12 hours.

[0090] Table 7

[0091]

[0092] In summary, the optimal conditions for the reaction are: 1.0 equivalent of aryl iodonium salt substrate, 1.2 equivalents of DABSO, 2.0 equivalents of potassium bifluoride, 0.05 equivalents of camphorquinone (CQ), and 0.1 M acetonitrile, in an argon atmosphere, under irradiation with a blue light lamp (20 W, 440-445 nm), and stirring at room temperature for 24 hours.

[0093] Based on the above optimal conditions, a series of sulfonyl fluorides with electron-withdrawing groups, electron-pushing groups and heterocyclic aromatic groups were synthesized.

[0094] Example 2: Synthesis of 2-methylbenzenesulfonyl fluoride

[0095]

[0096] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor were added 158.4 mg (0.4 mmol) of di(2-methylbenzene)iodonium tetrafluoroborate, 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 2-methylbenzenesulfonyl fluoride (colorless liquid, 58%). 1 H NMR (400MHz, CDCl3): δ8.03 (d, J = 7.9Hz, 1H), 7.63 (t, J = 7.2Hz, 1H), 7.41 (t, J = 8.6Hz, 2H), 2.69 (s, 3H); 19 F NMR (376MHz, CDCl3): δ60.2ppm. GC-MS (EI): m / z=174.0 (M + ).

[0097] Example 3: Synthesis of benzenesulfonyl fluoride

[0098]

[0099] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor were added 170.4 mg (0.4 mmol) of diphenyliodonium hexafluorophosphate (V), 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon two to three times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to separate the product benzenesulfonyl fluoride (light yellow liquid, 71%). The NMR characterization results of the product are shown in FIG. Figure 1-3 shown.

[0100] 1 H NMR (400MHz, CDCl3): δ8.02 (d, J = 8.0Hz, 2H), 7.79 (t, J = 7.5Hz, 1H), 7.64 (t, J = 7.8Hz, 2H); 19 F NMR (376MHz, CDCl3): δ65.8ppm. GC-MS (EI): m / z=160.0 (M + ).

[0101] Example 4: Synthesis of 4-isopropylbenzenesulfonyl fluoride

[0102]

[0103] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor, were added 204.1 mg (0.4 mmol) of bis(4-isopropylphenyl)iodonium hexafluorophosphate (V), 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 4-isopropylbenzenesulfonyl fluoride (colorless liquid, 70%).1 H NMR (400MHz, CDCl3): δ7.93 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.2Hz, 2H), 3.04 (hept, J = 6.9Hz, 1H), 1.29 (d, J = 6.9Hz, 6H); 19 F NMR (376 MHz, CDCl3): δ 66.2; 13 C NMR (101MHz, CDCl3): δ157.8, 130.4 (d, J = 22Hz), 128.8, 127.9, 34.6, 23.6ppm. HRMS (FI) m / z: [M] + Calcd for C9H 11 FO2S 202.0464; Found 202.0459.

[0104] Example 5: Synthesis of 4-tert-Butylbenzenesulfonyl fluoride

[0105]

[0106] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor, were added 215.2 mg (0.4 mmol) of bis(4-tert-butylphenyl)iodonium hexafluorophosphate (V), 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 4-tert-butylbenzenesulfonyl fluoride (white solid, 48%). 1 H NMR (400MHz, CDCl3): δ7.94 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 1.37 (s, 9H); 19 F NMR (376MHz, CDCl3): δ66.2ppm. GC-MS (EI): m / z=216.0 (M + ).

[0107] Example 6: Synthesis of 2,4,6-trimethylbenzenesulfonyl fluoride

[0108]

[0109] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor, were added 205.7 mg (0.4 mmol) of bis(2,4,6-trimethylphenyl)iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 2,4,6-trimethylbenzenesulfonyl fluoride (white solid, 69%). 1 H NMR (400MHz, CDCl3): δ7.03(s,2H),2.65–2.62(m,6H),2.35(s,3H); 19 F NMR (376MHz, CDCl3): δ68.2ppm. GC-MS (EI): m / z=202.0 (M + ).

[0110] Example 7: Synthesis of 4-methoxybenzenesulfonyl fluoride

[0111]

[0112] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor, were added 205.0 mg (0.4 mmol) of bis(4-methoxyphenyl)iodonium-4-methylbenzenesulfonate, 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 4-methoxybenzenesulfonyl fluoride (yellow liquid, 16%). 1H NMR (400MHz, CDCl3): δ7.95 (d, J = 9.1Hz, 2H), 7.06 (d, J = 9.0Hz, 2H), 3.92 (s, 3H); 19 F NMR (376MHz, CDCl3): δ67.3ppm. GC-MS (EI): m / z=190.0 (M + ).

[0113] Example 8: Synthesis of 4-fluorobenzenesulfonyl fluoride

[0114]

[0115] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor was added 186.5 mg (0.4 mmol) of bis(4-fluorophenyl)iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon two to three times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 4-fluorobenzenesulfonyl fluoride (colorless liquid, 74%). 1 H NMR (400MHz, CDCl3): δ8.06 (dd, J=9.0, 4.8Hz, 2H), 7.32 (t, J=8.5Hz, 2H); 19 F NMR (376MHz, CDCl3): δ66.74, -99.34 (tt, J = 8.4, 4.9Hz) ppm. GC-MS (EI): m / z = 177.9 (M + ).

[0116] Example 9: Synthesis of 4-chlorobenzenesulfonyl fluoride

[0117]

[0118] To an oven-dried, 10-mL sealed tube equipped with a magnetic rotor were added 197.6 mg (0.4 mmol) of bis(4-chlorophenyl)iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) of 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) of KHF2, and 3.3 mg (0.02 mmol) of CQ. The system was then evacuated using a double-chamber tube and purged with argon 2-3 times. Under an argon atmosphere, 4.0 mL of anhydrous acetonitrile was added via syringe. The reaction tube was sealed and placed under blue light (20 W, 440-445 nm) for 24 hours with stirring at room temperature. The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to isolate the product 4-chlorobenzenesulfonyl fluoride (white solid, 62%). 1 H NMR (400MHz, CDCl3): δ7.96 (d, J = 8.7Hz, 2H), 7.62 (d, J = 8.8Hz, 2H); 19 F NMR (376MHz, CDCl3): δ66.5ppm. GC-MS (EI): m / z=193.9(M + ).

[0119] Example 10: Reaction of the Asymmetric Substrate (4-(tert-butyl)phenyl)(phenyl)iodonium triflate

[0120]

[0121] 194.5 mg (0.4 mmol) (4-(tert-butyl)phenyl)(phenyl)iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) 1,4-diazabicyclo[2.2.2]octane-1,4-disulfonate (DABSO), 62.5 mg (0.8 mmol) KHF2 and 3.3 mg (0.02 mmol) CQ were added to a 10 mL sealed tube equipped with a magnetic rotor and dried in an oven. The system was then evacuated using a double row tube and argon was replaced 2-3 times, and 4.0 mL of anhydrous acetonitrile was added by syringe under an argon atmosphere. After the reaction tube was sealed, it was placed under irradiation with a blue light lamp (20 W, 440-445 nm) and stirred at room temperature for 24 hours. The internal standard 4-(trifluoromethoxy)anisole was added before treatment. 19The crude yield of the target product was measured by F NMR spectroscopy (benzenesulfonyl fluoride: 51%; 4-tert-butylbenzenesulfonyl fluoride: 30%). The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin-layer chromatography. After removing the solvent under reduced pressure on a rotary evaporator, the crude product was purified by silica gel column chromatography to obtain a mixture of two fluorosulfonylated products, benzenesulfonyl fluoride and 4-tert-butylbenzenesulfonyl fluoride, with a combined yield of 75% (4:3). 19 F NMR (376MHz, CDCl3): δ66.2, 65.9ppm.

[0122] Example 11: Reaction of asymmetric substrate (4-iodophenyl)(phenyl)iodonium triflate

[0123]

[0124] 222.4 mg (0.4 mmol) (4-iodophenyl) (phenyl) iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) 1,4-diazabicyclo [2.2.2] octane-1,4-disulfonium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) KHF2 and 3.3 mg (0.02 mmol) CQ were added to a 10 mL sealed tube equipped with a magnetic rotor and oven-dried. The system was then evacuated using a double-row tube and argon was replaced 2-3 times, and 4.0 mL of anhydrous acetonitrile was added by syringe under an argon atmosphere. After the reaction tube was sealed, it was placed under irradiation with a blue light lamp (20 W, 440-445 nm) and stirred at room temperature for 24 hours. The internal standard 4- (trifluoromethoxy) anisole was added before treatment, and the reaction was carried out by 19 The crude yield of the target product was measured by F NMR spectroscopy (benzenesulfonyl fluoride: 33%; 4-iodobenzenesulfonyl fluoride: 44%). The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin layer chromatography. After removing the solvent under reduced pressure on a rotary evaporator, the crude product was purified by silica gel column chromatography to obtain two mixed fluorosulfonylation products, benzenesulfonyl fluoride and 4-iodobenzenesulfonyl fluoride, with a combined yield of 67% (1.7:4). 19 F NMR (376MHz, CDCl3): δ66.2, 65.9ppm.

[0125] Example 12: Reaction of the asymmetric substrate (4-methoxyphenyl)(phenyl)iodonium triflate

[0126]

[0127] 184.1 mg (0.4 mmol) (4-methoxyphenyl) (phenyl) iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) 1,4-diazabicyclo [2.2.2] octane-1,4-disulfonate (DABSO), 62.5 mg (0.8 mmol) KHF2 and 3.3 mg (0.02 mmol) CQ were added to a 10 mL sealed tube dried in an oven equipped with a magnetic rotor. The system was then evacuated using a double row tube and argon was replaced 2-3 times, and 4.0 mL of anhydrous acetonitrile was added by syringe under an argon atmosphere. After the reaction tube was sealed, it was placed under irradiation with a blue light lamp (20 W, 440-445 nm) and stirred at room temperature for 24 hours. The internal standard 4- (trifluoromethoxy) anisole was added before treatment, and the reaction was carried out by 19 The crude yields of the target products were measured by F NMR spectroscopy (benzenesulfonyl fluoride: 43%; 4-methoxybenzenesulfonyl fluoride: 15%). The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to obtain two separated fluorosulfonylation products, benzenesulfonyl fluoride (37%) and 4-methoxybenzenesulfonyl fluoride (13%). 1 HNMR (400MHz, CDCl3): δ8.02 (d, J = 8.0Hz, 2H), 7.79 (t, J = 7.5Hz, 1H), 7.64 (t, J = 7.6Hz, 2H); 19 F NMR (376MHz, CDCl3): δ65.8ppm.4-methoxybenzenesulfonyl fluoride: 1 H NMR (400MHz, CDCl3): δ7.94 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 3.92 (s, 3H); 19 F NMR (376MHz, CDCl3): δ67.2ppm.

[0128] Example 13: Reaction of the asymmetric substrate (4-nitrophenyl)(phenyl)iodonium triflate

[0129]

[0130] 190.1 mg (0.4 mmol) (4-nitrophenyl)(phenyl)iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) 1,4-diazabicyclo[2.2.2]octane-1,4-disulfonium-1,4-disulfinate (DABSO), 62.5 mg (0.8 mmol) KHF2 and 3.3 mg (0.02 mmol) CQ were added to a 10 mL sealed tube equipped with a magnetic rotor and oven-dried. The system was then evacuated using a double-row tube and argon was replaced 2-3 times, and 4.0 mL of anhydrous acetonitrile was added by syringe under an argon atmosphere. After the reaction tube was sealed, it was placed under irradiation with a blue light lamp (20 W, 440-445 nm) and stirred at room temperature for 24 hours. The internal standard 4-(trifluoromethoxy)anisole was added before treatment, and the reaction was carried out by 19 The crude yields of the target products were measured by F NMR spectroscopy (benzenesulfonyl fluoride: 17%; 4-nitrobenzenesulfonyl fluoride: 27%). The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to obtain the two separated fluorosulfonylation products, benzenesulfonyl fluoride and 4-nitrobenzenesulfonyl fluoride (28%). 19 F NMR (376MHz, CDCl3): δ65.9ppm.p-nitrobenzenesulfonyl fluoride: 1 H NMR (400MHz, CDCl3): δ8.49 (d, J = 8.3Hz, 2H), 8.25 (d, J = 8.8Hz, 2H); 19 F NMR (376MHz, CDCl3): δ66.2ppm.

[0131] Example 14: Reaction of the asymmetric substrate (4-cyanophenyl)(4-methoxyphenyl)iodonium triflate

[0132]

[0133] 194.1 mg (0.4 mmol) (4-cyanophenyl) (4-methoxyphenyl) iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) 1,4-diazabicyclo [2.2.2] octane-1,4-disulfonate (DABSO), 62.5 mg (0.8 mmol) KHF2 and 3.3 mg (0.02 mmol) CQ were added to a 10 mL sealed tube dried in an oven equipped with a magnetic rotor. The system was then evacuated using a double row tube and argon was replaced 2-3 times, and 4.0 mL of anhydrous acetonitrile was added by syringe under an argon atmosphere. After the reaction tube was sealed, it was placed under irradiation with a blue light lamp (20 W, 440-445 nm) and stirred at room temperature for 24 hours. The internal standard 4- (trifluoromethoxy) anisole was added before treatment, and the reaction was carried out by 19 The crude yields of the target products were measured by F NMR spectroscopy (4-cyanobenzenesulfonyl fluoride: 63%; 4-methoxybenzenesulfonyl fluoride: 15%). The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin layer chromatography. After removing the solvent under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to obtain two separated fluorosulfonylation products, 4-cyanobenzenesulfonyl fluoride (54%) and 4-methoxybenzenesulfonyl fluoride. p-cyanobenzenesulfonyl fluoride: 1 H NMR (400MHz, CDCl3): δ8.16 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H); 19 F NMR (376MHz, CDCl3): δ66.0ppm.4-methoxybenzenesulfonylfluoride: 19 F NMR (376MHz, CDCl3): δ67.2ppm.

[0134] Example 15: Reaction of the asymmetric substrate (4-methoxyphenyl)(pyridin-3-yl)iodonium triflate

[0135]

[0136] 184.5 mg (0.4 mmol) (4-methoxyphenyl) (pyridin-3-yl) iodonium trifluoromethanesulfonate, 115.3 mg (0.48 mmol) 1,4-diazabicyclo [2.2.2] octane-1,4-disulfonate (DABSO), 62.5 mg (0.8 mmol) KHF2 and 3.3 mg (0.02 mmol) CQ were added to a 10 mL sealed tube dried in an oven equipped with a magnetic rotor. The system was then evacuated using a double row tube and argon was replaced 2-3 times, and 4.0 mL of anhydrous acetonitrile was added by syringe under an argon atmosphere. After the reaction tube was sealed, it was placed under irradiation with a blue light lamp (20 W, 440-445 nm) and stirred at room temperature for 24 hours. The internal standard 4- (trifluoromethoxy) anisole was added before treatment, and the reaction was carried out by 19 The crude yield of the target product was measured by F NMR spectroscopy (pyridine-3-sulfonyl fluoride: 28%; 4-methoxybenzenesulfonyl fluoride: 7%). The reaction mixture was then filtered through 200-300 mesh silica gel and monitored by thin layer chromatography. After the solvent was removed under reduced pressure using a rotary evaporator, the crude product was purified by silica gel column chromatography to obtain two separated fluorosulfonylation products, pyridine-3-sulfonyl fluoride (23%) and 4-methoxybenzenesulfonyl fluoride (5%). 1 H NMR (400MHz, CDCl3): δ9.23 (s, 1H), 9.00 (d, J = 4.7Hz, 1H), 8.30 (dt, J = 8.1, 1.9Hz, 1H), 7.61 (dd, J = 8.1, 4.9Hz, 1H); 19 F NMR (376MHz, CDCl3): δ67.9ppm.4-methoxybenzenesulfonyl fluoride: 1 H NMR (400MHz, CDCl3): δ7.95 (d, J = 9.1Hz, 2H), 7.06 (d, J = 9.0Hz, 2H), 3.92 (s, 3H); 19 F NMR (376MHz, CDCl3): δ67.2ppm.

[0137] The above examples demonstrate that the compounds shown in Table 7 can be effectively synthesized by the method of the present invention.

[0138] Table 7

[0139]

[0140]

[0141] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A method for preparing arylsulfonyl fluoride, characterized in that: include: In an inert gas atmosphere, an aryl iodonium salt, a sulfur dioxide source, a fluorine source, and a photosensitizer are mixed in an organic solvent and stirred to react under light conditions to obtain an aryl sulfonyl fluoride; Wherein, the structural formula of the aryl iodonium salt is as follows: or ; Correspondingly, the structural formula of the arylsulfonyl fluoride is as follows: and ,or and ; Where R 1 、R 2 One or more combinations of H, C1-C10 linear or branched alkyl, F, Cl, Br, I, methoxy, nitro, cyano, acetylamino, trifluoromethyl, trifluoromethoxy or biphenyl; R 3 is one of a fused ring aromatic group, a substituted fused ring aromatic group, an aromatic heterocycle, or an aromatic heterocycle derivative group; Anion X is one of hexafluorophosphate anion, trifluoromethanesulfonate anion, p-toluenesulfonate anion or tetrafluoroborate anion; The sulfur dioxide source is one of 4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct, thiourea dioxide, sulfur dioxide, 4-(dimethylamino)pyridin-1-ium-1-sulfinate, potassium metabisulfite, sodium metabisulfite or sodium dithionite; The fluorine source is one of N-fluorobisbenzenesulfonamide, selective fluorination reagent, 1-fluoropyridine tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridine tetrafluoroborate, potassium fluoride, potassium bifluoride, sodium fluoride, cesium fluoride, silver fluoride or copper fluoride; During the stirring reaction, the reaction temperature is room temperature and the reaction time is 1-48 h; In the lighting conditions described, the light source used is a blue light lamp with a power of 20W and a blue light wavelength of 440~445 nm.

2. The method for preparing an arylsulfonyl fluoride according to claim 1, wherein The photosensitizer is camphorquinone, 10-hexyl-7-(thiophen-3-yl)-10 H -phenothiazine-3-carboxaldehyde, 7,7'-((10-hexyl-10 H -phenothiazine-3,7-diyl)bis(acetylene-2,1-diyl))bis(10-hexyl-10 H -phenothiazine-3-carboxaldehyde), eosin Y, fluorescein, curcumin, disodium tetrachlorofluorescein, rhodamine B, anthraquinone, 2,4,6-triphenylpyranyl boron tetrafluoride salt, Michler's ketone, tetrachlorobenzoquinone, 10-phenylphenothiazine or 2,4,6-trimethylbenzoyl-diphenylphosphine oxide.

3. The method for preparing an arylsulfonyl fluoride according to claim 1, wherein The organic solvent is one of acetonitrile, 1,2-dichloroethane, dichloromethane, ethyl acetate, n-hexane, ethanol, tert-butanol, toluene, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, chlorobenzene or chloroform.

4. The method for preparing an arylsulfonyl fluoride according to claim 1, wherein The molar ratio of the aryl iodonium salt, the sulfur dioxide source, the fluorine source, and the photosensitizer is 1: (0.5-5): (1.2-5): (0.01-0.1).

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