Alkylsulfonyl selenofluoromethide reagents, methods of making and using the same

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to an alkylsulfonyl monofluoromethyl selenylating agent, a preparation method and application thereof. The structural formula of the alkylsulfonyl monofluoromethyl selenylating agent is shown as formula (I). The alkylsulfonyl monofluoromethyl selenylating agent is prepared by using common sodium alkylsulfinate as a sulfonylating agent, selenium powder as a selenium source, and monofluoromonochloromethane as a monofluoromethylating agent in a liquid phase through one-step reaction. The preparation method of the alkylsulfonyl monofluoromethyl selenylating agent has the advantages of simple steps, high atom utilization rate, high yield, and simple post-treatment. In addition, based on the prepared alkylsulfonyl monofluoromethyl selenylating agent, a direct monofluoromethyl selenylation reaction of an aromatic amine compound is realized in a photocatalytic system through one-step method, and technical defects existing in a three-step method for preparing a monofluoromethyl selenyl aryl ether compound in the prior art are overcome.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically to alkyl sulfonyl monofluoromethylselenylating reagents, their preparation methods, and applications. Background Technology

[0002] Selenium (Se) is an essential trace element for microorganisms, plants, animals, and humans. Organoselenium compounds are an important class of molecules in organic synthesis. They are widely used in materials, organic reactions, catalysts, chiral ligands, and free radical scavengers, and often exhibit good biological activities, such as anti-fatigue, antioxidant, immune-boosting, and protection against liver and gastric mucosal damage.

[0003] Fluorine atoms possess unique properties; introducing fluorine atoms or fluorine-containing groups into drug molecules not only enhances binding interactions but also helps regulate the molecule's pKa, membrane permeability, metabolic stability, and bioavailability. Monofluoromethyl (CH₂F), as a biomimicry group of hydroxymethyl (CH₂OH) and a metabolically stable bioelectron ester of methyl (CH₃), exhibits lower electron-withdrawing ability than difluoromethyl (CF₂H) and trifluoromethyl (CF₃), and is lipophilic. Therefore, compounds containing CH₂F have wide applications in the pharmaceutical and pesticide fields. Studies have shown that the combination of fluoroalkyl groups with heteroatoms can better regulate the physicochemical properties of compounds. To date, chemists have dedicated themselves to studying monofluoromethoxy (OCH₂F) and monofluoromethylthio (SCH₂F), achieving excellent results in related reaction fields.

[0004] Monofluoromethylselenoyl possesses unique properties in terms of electrical activity, stability, and lipophilicity, and can complement difluoromethylselenoyl and trifluoromethylselenoyl. Existing technologies disclose structural formulas as follows: It is a monofluoromethylselenoylating agent, but its molecular weight is large. When it is used as a monofluoromethylselenoylating agent in the reaction, the relative molecular weight of the removed part is relatively large, which makes its atom utilization rate low. This is not conducive to the one-step deamination monofluoromethylselenoylation reaction of aromatic amines and affects the preparation of monofluoromethylselenoyl aryl ether compounds. Summary of the Invention

[0005] To address the shortcomings of the existing technology, this invention provides a method for preparing and applying alkylsulfonyl monofluoromethylselenylating agents. This invention is the first to propose alkylsulfonyl monofluoromethylselenylating agents, which differ from existing technologies. In comparison, the alkyl sulfonyl monofluoromethylselenoylating reagents of the present invention have small molecular weights. When used as monofluoromethylselenoylating reagents in the reaction, the portion removed has a relatively small molecular weight, resulting in high atomic utilization and facilitating the one-step deamination monofluoromethylselenoylation reaction of aromatic amines.

[0006] Based on the above technical objectives, the present invention adopts the following technical solution: The first objective of this invention is to provide an alkylsulfonyl monofluoromethylselenoylating agent, the structural formula of which is shown in formula (I): Where R is selected from C1 to C2. 10 Alkyl or C1~C 10 The R group of this invention does not contain a benzene ring and has a small molecular weight compared to the prior art.

[0007] A second objective of this invention is to provide a method for preparing the above-mentioned alkylsulfonyl monofluoromethylselenoylating reagent, comprising the following steps: The reaction equation is: .

[0008] In the liquid phase, RSO2Na, selenium powder and chlorofluoromethane are mixed and subjected to a substitution reaction to obtain alkylsulfonyl methylselenylating reagents.

[0009] Preferably, the substitution reaction conditions are: stirring at room temperature for 5 to 6 hours.

[0010] Preferably, the molar ratio of RSO2Na, selenium powder, and monofluorochloromethane is 1:1 to 1.5:1 to 1.5; wherein, if RSO2Na is in excess, it will generate self-redox coupling byproducts, and if selenium powder and monofluorochloromethane are in excess, it will result in waste.

[0011] A third objective of this invention is to provide the application of the above-mentioned alkyl sulfonyl monofluoromethylselenoylating reagents in the preparation of monofluoromethylselenoyl aryl ether compounds.

[0012] Preferably, the structural formula of the monofluoromethylselenoyl aryl ether compound is as follows: , where R 1 It is selected from H, C1-C5 alkyl, C1-C5 alkoxy, halogen, C2-C6 ester, acyl, carboxyl, hydroxyl, cyano, nitro, phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is alkyl, halogen, ester, cyano or nitro.

[0013] Preferably, the monofluoromethylselenoyl aryl ether compound is selected from... , , , , , , , or .

[0014] A fourth objective of this invention is to provide a method for preparing the above-mentioned monofluoromethylselenoyl aryl ether compound, comprising the following steps: The reaction equation is: .

[0015] Aromatic amines Using p-toluenesulfonic acid, tert-butyl nitrite, and alkyl sulfonyl monofluoromethylselenoylating reagents as raw materials, and Acid Red 94 as a photocatalyst, aromatic amines, p-toluenesulfonic acid, tert-butyl nitrite, and alkyl sulfonyl monofluoromethylselenoylating reagents are dissolved together in a solvent. Under the action of the photocatalyst, a deamination monofluoromethylselenoylation reaction is carried out. During the deamination monofluoromethylselenoylation reaction, p-toluenesulfonic acid and tert-butyl nitrite react with aromatic amines to form aryl diazonium salts. At the same time, the photocatalyst undergoes a single-electron transfer with the aryl diazonium salts to form aryl radicals. The aryl radicals react with monofluoromethylselenoyl radicals generated by the alkyl sulfonyl monofluoromethylselenoylating reagents under light irradiation to generate deamination monofluoromethylselenoylation products, yielding monofluoromethylselenoyl aryl ether compounds.

[0016] Among them, R 1 It is selected from H, C1-C5 alkyl, C1-C5 alkoxy, halogen, C2-C6 ester, acyl, carboxyl, hydroxyl, cyano, nitro, phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is alkyl, halogen, ester, cyano or nitro.

[0017] Preferably, the conditions for the deamination-fluoromethylselenoylation reaction are: stirring at room temperature for 4 to 6 hours.

[0018] Preferably, the molar ratio of aromatic amine to alkyl sulfonyl monofluoromethylselenoylating reagent is 1:1.2~1.5; wherein, if the molar ratio of aromatic amine to alkyl sulfonyl monofluoromethylselenoylating reagent is too large, the conversion rate of the deamination monofluoromethylselenoylation reaction of aromatic amine is low; if the molar ratio is too small, it will result in waste of monofluoromethylselenoylating reagent.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Considering that in the existing technology, the monofluoromethylselenylation reaction of aromatic amines can only be introduced indirectly, but this method is lengthy, often requiring three steps, and the reaction conditions are harsh, requiring not only metal catalysts and large amounts of strong bases, but also expensive fluoroiodomethane as the monofluoromethyl source; the present invention provides a new alkylsulfonyl monofluoromethylselenylation reagent, the structural formula of which is shown in formula (I): R is selected from C1~C 10 Alkyl or C1~C 10 The cycloalkyl group has a simple structure and small molecular weight. As a result, the molecular weight of the alkyl sulfonyl monofluoromethylselenoylating reagent is small. When the deamination monofluoromethylselenoylating reaction of aromatic amines is carried out, the molecular weight of the removed part is relatively small, which makes its atom utilization rate high. The preparation of monofluoromethylselenoyl aryl ether compounds can be achieved in one step.

[0020] 2. The alkylsulfonyl monofluoromethylselenoylating reagent of the present invention is prepared by a one-step reaction in the liquid phase using common sodium alkylsulfinate as the sulfonating agent, selenium powder as the selenium source, and monofluorochloromethane as the monofluoromethylating agent. The preparation method of the alkylsulfonyl monofluoromethylselenoylating reagent of the present invention is simple (can be completed in one step), has high atom utilization, high yield, and simple post-processing.

[0021] 3. This invention also provides the application of alkyl sulfonyl monofluoromethylselenoylating reagents, that is, using the alkyl sulfonyl monofluoromethylselenoylating reagents prepared in this invention and aromatic amines as raw materials, the monofluoromethylselenoylation reaction of aromatic amines can be realized in one step. The reaction operation is simple, the steps are short, the cost is low, the product can be obtained at room temperature, the substrate has a wide range of applicability, and it is environmentally friendly. It overcomes the technical defects of existing monofluoromethylselenoylation reactions of aromatic amines, which only have the indirect introduction method, which has harsh conditions, long steps, requires metal catalysts and a large amount of strong bases, and uses expensive fluoroiodomethane as a monofluoromethyl source. Attached Figure Description

[0022] Figure 1 The image shows the proton NMR spectrum of the alkyl sulfonyl fluoromethyl selenylating reagent of Example 1.

[0023] Figure 2 The carbon spectrum of the alkyl sulfonyl monofluoromethylselenylating reagent of Example 1 is shown.

[0024] Figure 3 The fluorine spectrum of the alkyl sulfonyl monofluoromethylselenylating reagent of Example 1 is shown.

[0025] Figure 4 The hydrogen spectrum of the monofluoromethylselenoyl ether used in Experiment Example 3 is shown.

[0026] Figure 5 The carbon spectrum of the monofluoromethylselenoyl ether used in Experiment Example 3 is shown.

[0027] Figure 6 The fluorine spectrum of the monofluoromethylselenoyl ether used in Experiment Example 3 is shown.

[0028] Figure 7 This is a schematic diagram of the structural formula of a monofluoromethylselenoaryl ether compound prepared by the reaction of 2-bromophenylboronic acid and phenylsulfonic acid monofluoromethylselenoester using existing technology. Detailed Implementation

[0029] The following detailed description, in conjunction with embodiments of the present invention and accompanying drawings, provides a clear and complete illustration of the technical solutions in these embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0030] Considering that in the existing technology, the monofluoromethylselenylation reaction of aromatic amines can only be achieved through indirect methods, this method has the problems of being lengthy (requiring three steps), having harsh reaction conditions (requiring metal catalysts and large amounts of strong bases), and requiring the use of expensive fluoroiodomethane as the monofluoromethyl source.

[0031] To address the problems existing in the prior art, this invention provides an alkylsulfonyl monofluoromethylselenoylating agent, the structural formula of which is shown in formula (I): Where R is selected from C1 to C2. 10 Alkyl or C1~C 10 The cycloalkyl group; and using alkyl sulfonyl monofluoromethylselenoylating reagent as a raw material, a monofluoromethylselenoyl aryl ether compound was prepared by one-step reaction with an aromatic amine.

[0032] To address the issue of lengthy steps in existing monofluoromethylselenylation reactions of aromatic amines, this invention uses alkyl sulfonyl monofluoromethylselenylating reagents as raw materials to prepare monofluoromethylselenyl aryl ether compounds via a one-step deamination monofluoromethylselenylation reaction, overcoming the defects of multi-step synthesis. Regarding the issue of harsh reaction conditions, this invention achieves mild conversion through a metal-free, base-free photocatalytic deamination reaction system. And to address the need for expensive fluoroiodomethane, this invention uses alkyl sulfonyl monofluoromethylselenylating reagents as inexpensive monofluoromethyl sources, significantly reducing costs.

[0033] The technical solution of the present invention will be further studied using the following embodiments. The specific research methods and results are shown below: Example 1 The preparation method of alkylsulfonyl monofluoromethylselenylating reagent includes the following steps: The reaction equation is: .

[0034] In a round-bottom flask, 5.0 mmol of sodium methanesulfinate, 6.0 mmol of selenium powder, and 10.0 mL of N,N-dimethylformamide were added sequentially. After securing the flask with an air balloon, the air inside was evacuated. Then, chlorofluoromethane gas was introduced, and the reaction was stopped after stirring at room temperature for 5 hours. The mixture was cooled to room temperature to obtain the crude product. Post-processing: The crude product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R...). f =0.30), the target product 2a was obtained, named: methyl fluoromethyl selenide methanesulfonate, a yellow liquid with a yield of 71%.

[0035] 1 H NMR (400 MHz, CDCl3) δ 6.42 (d,J = 50.1 Hz, 2H), 3.54 (s, 3H); 19 FNMR (376 MHz, CDCl3) δ -189.72 (t, J = 50.9 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ86.6 (d, J = 237.4 Hz), 56.0. HRMS (ESI) for C2H5FO2SSeNa (M+Na) + Calcd: 214.9052, Found: 214.9060. Its proton, carbon, and fluorine spectra are as follows: Figure 1 , Figure 2 and Figure 3 As shown.

[0036] Example 2 The preparation method of alkylsulfonyl monofluoromethylselenylating reagent includes the following steps: The reaction equation is: .

[0037] In a round-bottom flask, 5.0 mmol of sodium ethyl sulfinate, 6.0 mmol of selenium powder, and 10.0 mL of N,N-dimethylacetamide were added sequentially. After securing the flask with an air balloon, the air inside was evacuated. Then, chlorofluoromethane gas was introduced, and the reaction was stopped after stirring at room temperature for 6 hours. The mixture was cooled to room temperature to obtain the crude product. Post-processing: The crude product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R...). f =0.30), and the target product 2b was obtained, named: ethyl sulfonate monofluoromethyl selenide, a yellow liquid with a yield of 79%.

[0038] 1 H NMR (400 MHz, CDCl3) δ 6.38 (d, J = 50.1 Hz, 2H), 3.48 (dd, J = 14.5, 7.2 Hz, 2H), 1.46 (t, J = 7.3 Hz, 3H); 19 F NMR (376 MHz, CDCl3) δ -188.56 (t, J =50.9 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 86.4 (d,J = 234.4 Hz), 62.0, 8.5. HRMS(ESI) for C3H7FO2SSeNa (M+Na) + : Calcd: 228.9208, Found: 228.9215.

[0039] Example 3 A method for preparing alkylsulfonyl monofluoromethylselenylating agents includes the following steps: The reaction equation is: .

[0040] In a round-bottom flask, 5.0 mmol of sodium methanesulfonate, 5.0 mmol of selenium powder, and 10.0 mL of N,N-dimethylformamide were added sequentially. After securing the flask with an air balloon, the air inside was evacuated. Then, chlorofluoromethane gas was introduced, and the reaction was stopped after stirring at room temperature for 6 hours. The mixture was cooled to room temperature to obtain the crude product. Post-processing: The crude product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R...). f =0.30), and the target product 2a was obtained, named: methyl fluoromethyl selenide methanesulfonate, a yellow liquid.

[0041] Example 4 The preparation method of alkylsulfonyl monofluoromethylselenylating reagent includes the following steps: The reaction equation is: .

[0042] In a round-bottom flask, 5.0 mmol of sodium methanesulfonate, 7.5 mmol of selenium powder, and 10.0 mL of N,N-dimethylformamide were added sequentially. After securing the flask with an air balloon, the air inside was evacuated. Then, chlorofluoromethane gas was introduced, and the reaction was stopped after stirring at room temperature for 7 hours. The mixture was cooled to room temperature to obtain the crude product. Post-processing: The crude product was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R...). f =0.30), and the target product 2a was obtained, named: methyl fluoromethyl selenide methanesulfonate, a yellow liquid.

[0043] The following describes the application of monofluoromethylselenomethylmethanesulfonate from Example 1, with specific application methods and results as follows: Application Experiment Example 1 The reaction equation is: .

[0044] In a dry reaction tube, 0.25 mmol of 2-phenylaniline 3a and 0.30 mmol of [unspecified ingredient] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t BuONO, 0.30 mmol of monofluoromethyl selenomethyl methanesulfonate, and 1 mL of DMSO were reacted under green light at room temperature with stirring for 10 h to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R...). f =0.30), and the target product 4a, a yellow liquid, was obtained with a yield of 78%.

[0045] 1 H NMR (400 MHz, CDCl3) δ 7.78 – 7.70 (m, 1H), 7.45 – 7.37 (m, 3H), 7.36 – 7.28 (m, 5H), 5.91 (d, J = 52.1 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -191.68 (t, J = 53.8 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 143.9 (d, J = 2.4 Hz), 141.6, 131.1 (d, J = 1.7 Hz), 130.5 (d, J = 2.5 Hz), 130.2, 129.2, 128.7, 128.3,127.9, 127.5, 83.2 (d, J = 226.5 Hz). HRMS (ESI) for C 13 H 11 FSeNa (M+Na) + : Calcd:288.9902, Found: 288.9910.

[0046] Application Experiment Example 2 The reaction equation is: .

[0047] In a dry reaction tube, 0.25 mmol of 2-chloroaniline 3b and 0.30 mmol of [unspecified ingredient] were added sequentially. p-TsOH, 8 mol% Acid Red 94, 0.30 mmol t BuONO, 0.30 mmol of monofluoromethylselenomethyl methanesulfonate, and 1 mL of DMSO were reacted under green light at room temperature with stirring for 12 h to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R...). f =0.30), the target product 4b was obtained, with a yellow liquid yield of 84%.

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.60 (m, 1H), 7.42 – 7.36 (m, 1H), 7.25 – 7.22 (m, 2H), 6.09 (d, J = 51.7 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -193.45 (t, J = 53.5 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 135.1 (d, J = 2.4 Hz), 131.7, 130.6 (d, J = 2.9 Hz), 129.7, 128.7, 127.9, 81.9 (d, J = 227.6 Hz). HRMS(ESI) for C7H6ClFSeNa (M+Na) + : Calcd: 246.9199, Found: 246.9206.

[0049] Application Experiment Example 3 The reaction equation is: .

[0050] In a dry reaction tube, 0.25 mmol of 2-bromoaniline 3c and 0.30 mmol of [unspecified ingredient] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol tBuONO, 0.30 mmol of monofluoromethyl selenomethyl methanesulfonate, and 1 mL of DMSO were reacted under green light at room temperature with stirring for 10 h to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R...). f =0.30), the target product 4c, a yellow liquid, was obtained with a yield of 86%.

[0051] 1 H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.9, 1.5 Hz, 1H), 7.56 (dd, J =8.0, 1.4 Hz, 1H), 7.29 (td, J = 7.7, 1.3 Hz, 1H), 7.18 – 7.12 (m, 1H), 6.09 (d, J = 51.8 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -193.81 (t, J = 51.9 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 133.2 (d, J = 3.0 Hz), 133.0, 131.4 (d, J = 2.0 Hz), 128.7,128.5, 125.2 (d, J = 2.5 Hz), 82.4 (d, J = 227.8 Hz). HRMS (ESI) for C7H6BrFSeNa(M+Na) + Calcd: 290.8694, Found: 290.8685. Its proton, carbon, and fluorine spectra are as follows: Figure 4 , Figure 5 and Figure 6 As shown.

[0052] Application Experiment Example 4 The reaction equation is: .

[0053] In a dry reaction tube, 0.25 mmol of 2-iodoaniline 3d and 0.30 mmol of [unspecified substance] were added sequentially. p-TsOH, 8 mol% Acid Red 94, 0.30 mmol t BuONO, 0.30 mmol of monofluoromethylselenomethyl methanesulfonate, and 1 mL of DMSO were reacted under white light at room temperature for 10 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R...). f =0.30), the target product was obtained 4d, a yellow liquid, with a yield of 80%.

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.02 – 6.93 (m, 1H), 6.06 (d, J = 51.7 Hz, 2H); 19 FNMR (376 MHz, CDCl3) δ -193.81 (t, J = 52.2 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ139.7, 137.8 (d, J = 2.9 Hz), 130.9 (d, J = 2.0 Hz), 129.4, 128.7, 101.5 (d, J =3.2 Hz), 83.6 (d, J = 228.3 Hz). HRMS (ESI) for C7H6FISeNa (M+Na) + : Calcd:338.8556, Found: 338.8551.

[0055] Application Experiment Example 5 The reaction equation is: .

[0056] In a dry reaction tube, 0.25 mmol of 2-cyanoaniline 3e and 0.30 mmol of [unspecified ingredient] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol tBuONO, 0.30 mmol of monofluoromethylselenomethyl methanesulfonate, and 1 mL of DMSO were reacted under white light at room temperature for 10 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R...). f =0.30), the target product 4e was obtained, a yellow liquid, with a yield of 79%.

[0057] 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 7.7, 1.2Hz, 1H), 7.55 (td, J = 7.8, 1.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 6.09 (d, J =51.4 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -191.52 (t, J = 51.5 Hz, 1F); 13 C NMR (101MHz, CDCl3) δ 134.2 (d, J = 1.5 Hz), 133.9, 133.6 (d, J = 2.5 Hz), 133.5, 128.6,117.7, 116.9 (d, J = 2.4 Hz), 83.2 (d, J = 230.5 Hz). HRMS (ESI) for C8H6FNSeNa (M+Na) + : Calcd: 237.9542, Found: 237.9535.

[0058] Application Experiment Example 6 The reaction equation is: .

[0059] In a dry reaction tube, 0.25 mmol of 3-bromoaniline 3f and 0.30 mmol of [unspecified ingredient] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol tBuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate, and 1 mL of DMSO were reacted under blue light at room temperature with stirring for 10 h to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R...). f =0.30), the target product 4f was obtained, a yellow liquid with a yield of 75%.

[0060] 1 H NMR (400 MHz, CDCl3) δ 7.75 (t, J = 1.7 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.45 (ddd, J = 7.8, 1.8, 0.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.02 (d, J = 51.7Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -190.72 (t, J = 52.4 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 135.4 (d, J = 2.2 Hz), 131.5 (d, J = 2.0 Hz), 131.3 (d, J = 2.6 Hz),131.2, 130.8, 123.1, 83.7 (d, J = 228.5 Hz). HRMS (ESI) for C7H6BrFSeNa (M+Na) + :Calcd: 290.8694, Found: 290.8690.

[0061] Application Experiment Example 7 The reaction equation is: .

[0062] In a dry reaction tube, 3 g of 0.25 mmol of 3-nitroaniline and 0.30 mmol of [unspecified ingredient] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol tBuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate, and 1 mL of DMSO were reacted under blue light at room temperature for 10 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:8, R...). f =0.30), yellow liquid, yielded 4g of the target product, with a yield of 78%.

[0063] 1 H NMR (400 MHz, CDCl3) δ 8.46 (t, J = 1.9 Hz, 1H), 8.18 (ddd, J = 8.2,2.2, 1.0 Hz, 1H), 7.92 (ddd, J = 7.7, 1.5, 1.1 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 6.08 (d, J = 51.6 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -191.23 (t, J = 51.7 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 148.5, 138.6, 131.4 (d, J = 2.1 Hz), 130.2, 127.4 (d, J = 1.3 Hz), 123.0, 83.3 (d, J = 229.5 Hz). HRMS (ESI) for C7H6FNO2SeNa (M+Na) + : Calcd: 257.9440, Found: 257.9449.

[0064] Application Experiment Example 8 The reaction equation is: .

[0065] In a dry reaction tube, 0.25 mmol of 4-nitroaniline was added sequentially for 3 hours, followed by 0.30 mmol of... p -TsOH, 8 mol% Acid Red 94, 0.30 mmol tBuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate, and 1 mL of DMSO were reacted under blue light at room temperature for 10 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:15, R...). f =0.30), the target product was obtained after 4 hours, a yellow liquid, with a yield of 87%.

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 6.07 (d, J = 51.7 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 19 F NMR (376 MHz, CDCl3) δ -191.22 (t, J = 52.2 Hz, 1F); 13 C NMR (101 MHz, CDCl3)δ 166.3, 136.2 (d, J = 2.8 Hz), 131.6 (d, J = 2.2 Hz, 2C), 130.4 (2C), 129.8,83.1 (d, J = 228.2 Hz), 61.3, 14.4. HRMS (ESI) for C 10 H 11 FO2SeNa (M+Na) + : Calcd:284.9801, Found: 284.9809.

[0067] Application Experiment Example 9 The reaction equation is: .

[0068] In a dry reaction tube, 0.25 mmol of 4-ethoxyaniline 3i and 0.30 mmol of [unspecified ingredient] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol tBuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate, and 1 mL of DMSO were reacted under UV light at room temperature for 10 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:15, R...). f =0.30), the target product 4i was obtained, a yellow liquid with a yield of 76%.

[0069] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.93 (d, J = 52.1 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H); 19 F NMR (376 MHz, CDCl3) δ -190.76 (t, J = 52.9 Hz, 1F); 13 C NMR (101 MHz, CDCl3)δ 159.5, 135.9 (d, J = 1.9 Hz, 2C), 119.2 (d, J = 2.4 Hz), 115.6 (2C), 84.8 (d, J =226.9 Hz), 63.7, 14.9. HRMS (ESI) for C9H 12 FOSe (M+H) + : Calcd: 235.0032, Found: 235.0036.

[0070] The alkylsulfonyl monofluoromethylselenoylating reagent of the present invention can also be grafted onto drugs to modify them, or used as an intermediate to prepare new compounds, as shown in application examples 10 and 11: Application Experiment Example 10 The reaction equation is: .

[0071] In a dry reaction tube, 0.25 mmol of ibuprofen derivative 3j and 0.30 mmol of [unspecified substance] were added sequentially.p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t BuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate, and 1 mL of DMSO were reacted under UV light at room temperature for 10 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:15, R...). f =0.30), the target product 4j was obtained, a yellow liquid with a yield of 76%.

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.96 (d, J = 51.9 Hz, 2H), 3.93 (q, J = 7.1 Hz, 1H), 2.47 (d, J = 7.2 Hz, 2H), 1.93 – 1.80 (m, 1H), 1.60 (d, J = 7.2 Hz, 3H), 0.91 (d, J = 6.6 Hz, 6H); 19 F NMR (376 MHz, CDCl3) δ -190.71 (t, J = 52.3 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 173.2, 151.1, 141.1, 137.1, 134.7(d, J = 2.1 Hz, 2C), 129.7 (2C), 127.3 (2C), 126.1 (d, J = 2.4 Hz), 122.6 (2C), 84.2 (d, J = 227.7 Hz), 45.4, 45.2, 30.3, 22.5 (2C), 18.6. HRMS (ESI) forC 20 H 23FO2SeNa (M+Na) + : Calcd: 417.0740, Found: 417.0756.

[0073] Application Experiment Example 11 The reaction equation is: .

[0074] In a dry reaction tube, 0.25 mmol of probenecid derivative 3kJ and 0.30 mmol of [unspecified substance] were added sequentially. p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t BuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate, and 1 mL of DMSO were reacted under UV light at room temperature for 12 h with stirring to obtain the crude product. Post-treatment: 5 mL of water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:8, R...). f =0.30), yielding the target product 4K, a yellow solid with a melting point of 64. o C~65 o C, yield 87%.

[0075] 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 6.03 (d, J = 51.9 Hz, 2H),3.16 – 3.10 (m, 4H), 1.62 – 1.52 (m, 4H), 0.89 (t, J = 7.4 Hz, 6H); 19 F NMR (376MHz, CDCl3) δ -190.69 (t, J = 52.3 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 163.8,150.7, 145.1, 134.8 (d, J= 1.8 Hz, 2C), 132.6, 131.0 (2C), 127.3 (2C), 126.9(d, J = 2.4 Hz), 122.7 (2C), 84.1 (d, J = 228.0 Hz), 50.0 (2C), 22.0 (2C), 11.3(2C). HRMS (ESI) for C 20 H 24 FNO4SSeNa (M+Na) + : Calcd: 496.0468, Found: 496.0480.

[0076] Application Examples 10 and 11 illustrate that the alkyl sulfonyl monofluoromethylselenoylating reagent of the present invention can also modify drugs.

[0077] Application Example 12 The reaction equation is: .

[0078] In a dry reaction tube, 0.25 mmol of 4-cyanoaniline 3l, 0.30 mmol of p-TsOH, 8 mol% Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of monofluoromethyl selenide methanesulfonate 2a, and 1 mL of DMSO were added sequentially. The mixture was stirred under blue light at room temperature for 10 h. Post-treatment: The reaction was quenched with 5 mL of water, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography to obtain the target product 4l, a yellow liquid with a yield of 83%.

[0079] 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.62 – 7.54 (m, 2H), 6.09 (d, J = 51.6 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -191.62 (t, J = 51.7 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 136.9 (d, J = 2.6 Hz), 132.7 (2C), 132.0 (d, J = 2.2Hz, 2C), 118.5, 111.3, 82.7 (d,J = 229.1 Hz). HRMS (ESI) for C8H6FNSeNa (M+Na) + : Calcd: 237.9542, Found: 237.9535.

[0080] Application Example 13 The reaction equation is: .

[0081] In a dry reaction tube, 0.25 mmol of 4-nitroaniline 3m, 0.30 mmol of p-TsOH, 8 mol% Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of monofluoromethyl selenide ethyl sulfonate 2b, and 1 mL of DMSO were added sequentially. The mixture was stirred under blue light at room temperature for 12 h. Post-treatment: The reaction was quenched with 5 mL of water, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography to obtain the target product 4m, a yellow solid with a melting point of 93℃~94℃ and a yield of 89%.

[0082] 1 H NMR (400 MHz, CDCl3) δ 8.19 – 8.13 (m, 2H), 7.75 – 7.69 (m, 2H), 6.12 (d, J = 51.5 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -191.97 (t, J = 51.9 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 147.3, 139.5 (d, J = 1.9 Hz), 131.7 (d, J = 1.2 Hz,2C), 124.2 (2C), 82.6 (d, J = 229.3 Hz). HRMS (ESI) for C7H7FNO2Se (M+H) + :Calcd: 235.9621, Found: 235.9625.

[0083] Application Example 14 The reaction equation is: .

[0084] In a dry reaction tube, 0.25 mmol of 4-bromoaniline 3n, 0.30 mmol of p-TsOH, 8 mol% Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of ethyl sulfonate monofluoromethyl selenide 2b, and 1 mL of DMSO were added sequentially. The mixture was stirred under white light at room temperature for 10 h. Post-treatment: The reaction was quenched with 5 mL of water, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography to obtain the target product 4n, a yellow liquid with a yield of 89%.

[0085] 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.41 (m, 4H), 5.99 (d, J = 51.9 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -190.87 (t, J = 52.0 Hz, 1F); 13 C NMR (101 MHz, CDCl3) δ 134.8 (d, J = 2.1 Hz, 2C), 132.6 (2C), 128.3 (d, J = 2.5 Hz), 122.7,83.8 (d, J = 228.1 Hz). HRMS (ESI) for C7H6BrFSeNa (M+Na) + : Calcd: 290.8694, Found: 290.8703.

[0086] Application Example 15 The reaction equation is: .

[0087] In a dry reaction tube, 0.25 mmol of 4-phenylaniline 3o, 0.30 mmol of p-TsOH, 8 mol% Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of ethyl sulfonate monofluoromethyl selenide 2b, and 1 mL of DMSO were added sequentially. The mixture was stirred under green light at room temperature for 10 h. Post-treatment: The reaction was quenched with 5 mL of water, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, dried, concentrated under reduced pressure, and finally purified by column chromatography to obtain the target product 4o, a white solid with a melting point of 51℃~52℃ and a yield of 85%.

[0088] 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.5 Hz, 2H), 7.59 – 7.55 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.47 – 7.41 (m, 2H), 7.38 – 7.33 (m, 1H), 6.03 (d, J =52.0 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -190.49 (t, J = 52.0 Hz, 1F); 13 C NMR (101MHz, CDCl3) δ 141.2, 140.4, 133.6 (d, J = 2.0 Hz, 2C), 129.0 (2C), 128.4 (d, J =2.5 Hz), 128.1 (2C), 127.8, 127.2 (2C), 84.0 (d, J = 227.5 Hz). HRMS (ESI) for C 13 H 11 FSeNa (M+Na) + : Calcd: 288.9902, Found: 288.9910.

[0089] Existing technology completes the monofluoromethylselenylation reaction of aromatic amine compounds in three steps, and the reaction equation is as follows: .

[0090] The monofluoromethylselenyl aryl ether compound prepared by the existing three-step method is as follows: Among them, 4l, 4m and 4n are obtained by the present invention.

[0091] This invention successfully prepared compounds 4l, 4m, and 4n in a one-step process, as described in Application Examples 12, 13, and 14. This further demonstrates that the present invention overcomes the problems of the existing technology where the monofluoromethylselenylation reaction of aromatic amine compounds relies on indirect methods for introduction. That is, the traditional indirect introduction method is lengthy, usually requiring three steps; and the reaction conditions are harsh, requiring not only metal catalysts and large amounts of strong bases, but also expensive fluoroiodomethane as the monofluoromethyl source.

[0092] In the prior art, 2-bromophenylboronic acid and phenylsulfonic acid monofluoromethyl selenide are reacted to obtain... Figure 7 The compound with the shown structural formula, Figure 7 The present invention includes 4c, 4l, 4m, and 4o obtained by the present invention. The present invention successfully prepared compounds 4c, 4l, 4m, and 4o in a one-step process, as described in Application Examples 3, 12, 13, and 15. Specifically, Application Examples 3, 12, 13, and 15 are all based on the alkylsulfonyl monofluoromethylselenoylating reagents obtained by the present invention. This one-step method achieves the monofluoromethylselenoylation reaction of aromatic amine compounds without the need for monofluoromethylselenoylating reagents prepared by existing technologies. This overcomes the problem that monofluoromethylselenoylating reagents prepared by existing technologies have large molecular weights, resulting in a relatively large amount of removed molecular weight and low atom utilization when applied to the monofluoromethylselenoylation reaction of aromatic amine compounds.

[0093] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of the invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of this invention.

Claims

1. The application of alkyl sulfonyl monofluoromethylselenoylating agents in the one-step preparation of monofluoromethylselenoyl aryl ether compounds in a photocatalytic system, characterized in that, The structural formula of the alkyl sulfonyl monofluoromethylselenoylating reagent is shown in formula (I): ; Wherein, R is selected from C1~C 10 Alkyl groups; The monofluoromethylselenyl aryl ether compound is prepared according to the following steps: The reaction equation is: ; by Using p-toluenesulfonic acid, tert-butyl nitrite, and alkyl sulfonyl monofluoromethylselenoylating agents as raw materials, and Acid Red 94 as a photocatalyst, [the following process is described:] ... p-Toluenesulfonic acid, tert-butyl nitrite and alkyl sulfonyl monofluoromethylselenoylating reagent are dissolved together in a solvent, and a deamination monofluoromethylselenoylation reaction is carried out under the action of a photocatalyst and light to obtain monofluoromethylselenoyl aryl ether compounds. Among them, R 1 It is selected from H, C1-C5 alkyl, C1-C5 alkoxy, halogen, C2-C6 ester, acyl, carboxyl, hydroxyl, cyano, nitro, phenyl or substituted phenyl, wherein the substituent of the substituted phenyl is alkyl, halogen, ester, cyano or nitro.

2. The application according to claim 1, characterized in that, The preparation method of alkylsulfonyl monofluoromethylselenylating reagents includes the following steps: The reaction equation is: ; In the liquid phase, RSO2Na, selenium powder and chlorofluoromethane are mixed and subjected to a substitution reaction to obtain alkylsulfonyl methylselenylating reagents.

3. The application according to claim 2, characterized in that, The substitution reaction conditions are: stirring at room temperature for 5-7 hours.

4. The application according to claim 2, characterized in that, The molar ratio of RSO2Na, selenium powder and monofluorochloromethane is 1:1~1.5:1~1.

5.

5. The application according to claim 1, characterized in that, The molar ratio with the alkyl sulfonyl monofluoromethylselenoylating agent is 1:1.2~1.5.

Images