Alkyl sulfonyl monofluoromethylselenylation reagent as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an alkylsulfonyl monofluoromethylselenylation reagent as well as a preparation method and application thereof. The structural formula of the alkyl sulfonyl monofluoromethylselenylation reagent is as shown in formula (I): # imgabs0 #, and the alkyl sulfonyl monofluoromethylselenylation reagent is prepared by taking common sodium alkyl sulfinate as a sulfonylation reagent, selenium powder as a selenium source and monofluoromethane chloride as a monofluoromethylation reagent through one-step reaction in a liquid phase. The preparation method of the alkylsulfonyl monofluoromethylselenylation reagent has the advantages of simple and convenient steps, high atom utilization rate, high yield and simple post-treatment. Besides, based on the prepared alkyl sulfonyl monofluoromethylselenylation reagent, in a photocatalytic system, direct monofluoromethylselenylation reaction of an arylamine compound is achieved through a one-step method, and the technical defects existing in preparation of a monofluoromethylselenylation aryl ether compound through a three-step method in the prior art are overcome.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to an alkylsulfonyl monofluoromethylselenoylating reagent and a preparation method and application thereof. Background Art

[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 excellent biological activities, such as anti-fatigue, antioxidant, immune, 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 but also helps modulate the molecule's pKa, membrane permeability, metabolic stability, and bioavailability. The monofluoromethyl group (CH2F), a biomimetic of the hydroxymethyl group (CH2OH) and a metabolically stable bioelectron-removing counterpart of the methyl group (CH3), exhibits less electron-withdrawing power than the difluoromethyl group (CF2H) and trifluoromethyl group (CF3), resulting in lipophilicity. Consequently, CH2F-containing compounds have broad applications in pharmaceuticals and pesticides. Research has shown that combining fluoroalkyl groups with heteroatoms can further modulate the physicochemical properties of compounds. Chemists have dedicated significant research to the study of monofluoromethoxy (OCH2F) and monofluoromethylthio (SCH2F), achieving remarkable results in related reactions.

[0004] The monofluoromethylselenyl group is unique in terms of electrical properties, stability and fat solubility, and can complement the difluoromethylselenyl group and the trifluoromethylselenyl group. However, its molecular weight is large. When used as a fluoromethylselenylating agent in the reaction, the relative molecular weight of the removed part is large, resulting in low atomic utilization, which is not conducive to the one-step deamination fluoromethylselenylation reaction of aromatic amines and affects the preparation of fluoromethylselenyl aryl ether compounds. Summary of the Invention

[0005] In view of the above-mentioned deficiencies in the prior art, the present invention provides a preparation method and application of an alkylsulfonyl monofluoromethyl selenylating agent. The present invention proposes an alkylsulfonyl monofluoromethyl selenylating agent for the first time, which is different from the prior art. In comparison, the alkylsulfonyl monofluoromethylselenylating agent of the present invention has a small molecular weight. When used as a monofluoromethylselenylating agent in a reaction, the removed portion has a relatively small molecular weight, resulting in a high atomic utilization rate, thereby facilitating the one-step deamination monofluoromethylselenylation reaction of aromatic amines.

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

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

[0008] In liquid phase, RSO2Na, selenium powder and monofluoromonochloromethane are mixed to carry out substitution reaction to obtain alkylsulfonyl monofluoromethylselenoylation reagent.

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

[0010] Preferably, the molar ratio of RSO2Na, selenium powder and monofluoromonochloromethane is 1:1~1.5:1~1.5; wherein, if RSO2Na is excessive, self-redox coupling byproducts will be generated, and if selenium powder and monofluoromonochloromethane are excessive, waste will be caused.

[0011] The third object of the present invention is to provide the use of the above-mentioned alkylsulfonyl monofluoromethylselenoylating agent in the preparation of monofluoromethylselenoyl aryl ether compounds.

[0012] Preferably, the structural formula of the monofluoromethylselenyl aryl ether compound is , where R 1 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 monofluoromethylselenyl aryl ether compound is selected from 、 、 、 、 、 、 、 or .

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

[0015] Aromatic amine , p-toluenesulfonic acid, tert-butyl nitrite and an alkylsulfonyl monofluoromethylselenoylating agent are used as raw materials, Acid Red 94 is used as a photocatalyst, aromatic amine, p-toluenesulfonic acid, tert-butyl nitrite and an alkylsulfonyl monofluoromethylselenoylating agent are dissolved together in a solvent, and a deamination monofluoromethylselenoylation reaction is carried out under the action of the photocatalyst. During the deamination monofluoromethylselenoylation reaction, p-toluenesulfonic acid and tert-butyl nitrite react with aromatic amine to form an aryl diazonium salt, and simultaneously, the photocatalyst and the aryl diazonium salt undergo single electron transfer to form an aryl free radical, which reacts with the monofluoromethylselenoyl free radical generated by the alkylsulfonyl monofluoromethylselenoylating agent under light to generate a deamination monofluoromethylselenoylation product, thereby obtaining a monofluoromethylselenoaryl ether compound.

[0016] Among them, R 1 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 deamination-fluoromethylselenoylation reaction is carried out under the following conditions: stirring at room temperature for 4 to 6 hours.

[0018] Preferably, the molar ratio of aromatic amine to alkylsulfonyl monofluoromethylselenylating agent is 1:1.2~1.5; wherein, if the molar ratio of aromatic amine to alkylsulfonyl monofluoromethylselenylating agent is too large, the conversion rate of the deamination monofluoromethylselenylation reaction of aromatic amine is low; if the molar ratio is too small, the monofluoromethylselenylating agent is wasted.

[0019] Compared with the prior art, the present invention has the following beneficial effects: 1. Considering the disadvantages of the prior art that the monofluoromethylselenoylation reaction of aromatic amines can only be introduced by an indirect method, which is tedious and often requires three steps, harsh reaction conditions, and requires not only the use of a metal catalyst and a large amount of strong base, but also the use of expensive iodomethane as a monofluoromethyl source; the present invention provides a new alkylsulfonyl monofluoromethylselenoylation 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; due to the simple structure and small molecular weight of the R group, the molecular weight of the alkylsulfonyl monofluoromethylselenoylating reagent is small. When the deamination monofluoromethylselenoylation reaction of the aromatic amine is carried out, the relative molecular weight of the removed part is small, so that its atomic utilization rate is high, and the preparation of the monofluoromethylselenoyl aryl ether compound is achieved in one step.

[0020] 2. The alkylsulfonyl monofluoromethylselenoylating agent of the present invention is prepared by a one-step liquid-phase reaction using common sodium alkylsulfinate as the sulfonylating agent, selenium powder as the selenium source, and monochloromonofluoromethane as the monofluoromethylating agent. The preparation method of the alkylsulfonyl monofluoromethylselenoylating agent of the present invention features simple steps (complete in one step), high atom utilization, high yield, and simple post-processing.

[0021] 3. The present invention also provides an application of an alkylsulfonyl monofluoromethylselenoylating agent, that is, using the alkylsulfonyl monofluoromethylselenoylating agent prepared by the present invention and aromatic amine as raw materials, a monofluoromethylselenoylation reaction of aromatic amine is achieved in one step, and 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 the existing monofluoromethylselenoylation reaction of aromatic amine, which only has an indirect introduction method, harsh conditions, long steps, the need for a metal catalyst and a large amount of strong base, and the use of expensive iodomethane as a monofluoromethyl source. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the hydrogen spectrum of the alkylsulfonyl monofluoromethylselenoylating agent of Example 1.

[0023] Figure 2 This is the carbon spectrum of the alkylsulfonyl monofluoromethylselenoylating agent of Example 1.

[0024] Figure 3 This is the fluorine spectrum of the alkylsulfonyl monofluoromethylselenoylating agent of Example 1.

[0025] Figure 4 This is the hydrogen spectrum of monofluoromethylselenyl aryl ether obtained in Experimental Example 3.

[0026] Figure 5 This is the carbon spectrum of monofluoromethylselenyl aryl ether obtained in Experimental Example 3.

[0027] Figure 6 This is the fluorine spectrum of monofluoromethylselenyl aryl ether obtained in Experimental Example 3.

[0028] Figure 7 The present invention is a schematic diagram of the structural formula of a monofluoromethylselenoyl aryl ether compound prepared by reacting 2-bromophenylboronic acid and monofluoromethylselenophenylsulfonate in the prior art. DETAILED DESCRIPTION

[0029] The following is a detailed description of the technical solutions in the embodiments of the present invention, using preferred embodiments and accompanying drawings in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0030] Considering that in the existing technology, the monofluoromethylselenoylation reaction of aromatic amines can only be achieved through an indirect method, this method has the problems of lengthy procedures (requiring three steps), harsh reaction conditions (requiring a metal catalyst and a large amount of strong base), and the need to use expensive iodomethane as a monofluoromethyl source.

[0031] In view of the problems existing in the above-mentioned prior art, the present invention provides an alkylsulfonyl monofluoromethylselenylating agent, the structural formula of which is shown in formula (I): ; wherein R is selected from C1~C 10 Alkyl or C1~C 10 and using an alkylsulfonyl fluoromethylselenoylating agent as a raw material to react with aromatic amine in one step to prepare a fluoromethylselenoyl aryl ether compound.

[0032] To address the problem of lengthy steps in existing fluoromethylselenylation reactions of aromatic amines, the present invention uses an alkylsulfonyl fluoromethylselenylation reagent as a raw material to prepare a fluoromethylselenyl aryl ether compound through a one-step deamination fluoromethylselenylation reaction, thereby overcoming the drawbacks of multi-step synthesis. To address the problem of harsh reaction conditions, the present invention achieves a mild conversion through a metal-free, strong base-free photocatalytic deamination reaction system. To address the need to use expensive fluoroiodomethane, the present invention uses an alkylsulfonyl fluoromethylselenylation reagent as an inexpensive fluoromethyl source, significantly reducing costs.

[0033] The following examples are used to further study the technical solution of the present invention. The specific research methods and results are as follows: Example 1 The preparation method of an alkylsulfonyl monofluoromethylselenoylating agent comprises the following steps: The reaction equation is: .

[0034] 5.0 mmol sodium methanesulfinate, 6.0 mmol selenium powder and 10.0 mL N,N-dimethylformamide were added to a round-bottom flask in sequence. After the air in the reaction flask was pierced with an air balloon, the air in the reaction flask was evacuated and then filled with monochlorofluoromethane gas. After stirring at room temperature for 5 h, the reaction was stopped and cooled to room temperature to obtain a crude product. Post-treatment: The crude product was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried, concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R f =0.30) to obtain the target product 2a, named: methylsulfonic acid monofluoromethyl selenyl ester, as 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 hydrogen spectrum, carbon spectrum and fluorine spectrum are as follows Figure 1 、 Figure 2 and Figure 3 shown.

[0036] Example 2 The preparation method of an alkylsulfonyl monofluoromethylselenoylating agent comprises the following steps: The reaction equation is: .

[0037] 5.0 mmol sodium ethylsulfinate, 6.0 mmol selenium powder and 10.0 mL N,N-dimethylacetamide were added to a round-bottom flask in sequence. After the air in the reaction flask was pierced with an air balloon, the air in the reaction flask was evacuated, and then monochlorofluoromethane gas was filled in. After stirring at room temperature for 6 h, the reaction was stopped and cooled to room temperature to obtain a crude product. Post-treatment: The crude product was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried, concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R f =0.30) to obtain the target product 2b, named: ethylsulfonic acid monofluoromethyl selenyl ester, as a yellow liquid in 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 The preparation method of an alkylsulfonyl monofluoromethylselenoylating agent comprises the following steps: The reaction equation is: .

[0040] 5.0 mmol sodium methanesulfinate, 5.0 mmol selenium powder and 10.0 mL N,N-dimethylformamide were added to a round-bottom flask in sequence. After the air in the reaction flask was pierced with an air balloon, the air in the reaction flask was evacuated, and then monochlorofluoromethane gas was filled in. After stirring at room temperature for 6 h, the reaction was stopped and cooled to room temperature to obtain a crude product. Post-treatment: The crude product was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried, concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R f =0.30) to obtain the target product 2a, named: methylsulfonic acid monofluoromethyl selenyl ester, as a yellow liquid.

[0041] Example 4 The preparation method of an alkylsulfonyl monofluoromethylselenoylating agent comprises the following steps: The reaction equation is: .

[0042] 5.0 mmol sodium methanesulfinate, 7.5 mmol selenium powder and 10.0 mL N,N-dimethylformamide were added to a round-bottom flask in sequence. After the air in the reaction flask was pierced with an air balloon, the air in the reaction flask was evacuated and then filled with monochlorofluoromethane gas. After stirring at room temperature for 7 h, the reaction was stopped and cooled to room temperature to obtain a crude product. Post-treatment: The crude product was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried, concentrated under reduced pressure, and then separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:10, R f =0.30) to obtain the target product 2a, named: methylsulfonic acid monofluoromethyl selenyl ester, as a yellow liquid.

[0043] The following application is carried out using the fluoromethyl selenyl methanesulfonate of Example 1. The specific application method and results are as follows: Application Experiment Example 1 The reaction equation is: .

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

[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, 0.30 mmol of p-TsOH, 8 mol% Acid Red 94, 0.30 mmol t -BuONO, 0.30mmol methylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted at room temperature under green light for 12h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R f =0.30) to obtain the target product 4b as a yellow liquid in 84% yield.

[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, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t-BuONO, 0.30mmol methylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted at room temperature under green light for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R f =0.30) to obtain the target product 4c as a yellow liquid in 86% yield.

[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 hydrogen spectrum, carbon spectrum and fluorine spectrum are as follows Figure 4 、 Figure 5 and Figure 6 shown.

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

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

[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, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t-BuONO, 0.30mmol methylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted under white light at room temperature for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R f =0.30) to obtain the target product 4e as a yellow liquid in 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, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t-BuONO, 0.30mmol ethylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted at room temperature under blue light for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:60, R f =0.30) to obtain the target product 4f as a yellow liquid in 75% yield.

[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 = 51.7 Hz, 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, 0.25 mmol of 3-nitroaniline 3g, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t-BuONO, 0.30mmol ethylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted at room temperature under blue light for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:8, R f =0.30), a yellow liquid, to give 4 g of the target product in 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 3h, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t-BuONO, 0.30mmol ethylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted under blue light at room temperature for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:15, R f =0.30) to obtain the target product 4h as a yellow liquid in 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] 0.25 mmol of 4-ethoxyaniline 3i, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t-BuONO, 0.30mmol ethylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted under violet light at room temperature for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:15, R f =0.30) to obtain the target product 4i as a yellow liquid in 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 agent of the present invention can also be grafted onto drugs to modify the drugs, or used as an intermediate to prepare new compounds, as shown in Application Experimental Examples 10 and 11: Application Experiment Example 10 The reaction equation is: .

[0071] 0.25 mmol of ibuprofen derivative 3j, 0.30 mmol of p-TsOH, 8 mol% Acid Red 94, 0.30 mmol t -BuONO, 0.30mmol ethylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted under violet light at room temperature for 10h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:15, R f =0.30) to obtain the target product 4j as a yellow liquid in 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 3k, 0.30 mmol of p -TsOH, 8 mol% Acid Red 94, 0.30 mmol t -BuONO, 0.30mmol ethylsulfonic acid monofluoromethyl selenyl ester and 1mL DMSO were stirred and reacted under violet light at room temperature for 12h to obtain a crude product; post-treatment: 5mL water was added to the crude product to quench the reaction, followed by extraction with ethyl acetate (20mL×3), the organic phases were combined, dried, concentrated under reduced pressure, and finally separated and purified by column chromatography. The eluent for column chromatography was ethyl acetate / petroleum ether (1:8, R f =0.30), the target product 4k was obtained as 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 Example 10 and Application Example 11 illustrate that the alkylsulfonyl monofluoromethylselenoylating agent of the present invention can also modify drugs.

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

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

[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] To a dry reaction tube, 0.25 mmol of 4-nitroaniline 3m, 0.30 mmol of p-TsOH, 8 mol% of Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of fluoromethylselenoethyl 2b, and 1 mL of DMSO were added sequentially. The mixture was stirred and reacted under blue light illumination at room temperature for 12 hours. Post-treatment: 5 mL of water was added to quench the reaction, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure. Finally, the desired product 4m was isolated and purified by column chromatography to obtain a yellow solid with a melting point of 93–94°C in an 89% yield.

[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] To a dry reaction tube, 0.25 mmol of 4-bromoaniline 3n, 0.30 mmol of p-TsOH, 8 mol% of Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of fluoromethylselenoethyl 2b, and 1 mL of DMSO were added sequentially. The reaction was stirred at room temperature under white light for 10 hours. Post-treatment: 5 mL of water was added to quench the reaction, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure. Finally, the desired product 4n was isolated and purified by column chromatography to obtain a yellow liquid in 89% yield.

[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] To a dry reaction tube, 0.25 mmol of 4-phenylaniline 3o, 0.30 mmol of p-TsOH, 8 mol% of Acid Red 94, 0.30 mmol of t-BuONO, 0.30 mmol of ethylsulfonic acid monofluoromethylselenoester 2b, and 1 mL of DMSO were added sequentially. The reaction was stirred at room temperature under green light illumination for 10 h. Workup: 5 mL of water was added to quench the reaction, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried, and concentrated under reduced pressure. Finally, the desired product 4o was isolated and purified by column chromatography to obtain a white solid with a melting point of 51–52°C in an 85% yield.

[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] The prior art completes the monofluoromethylselenoylation reaction of aromatic amine compounds through a three-step process, and the reaction equation is as follows: .

[0090] The monofluoromethylselenyl aryl ether compound prepared by the three-step method of the prior art is: ; Among them, including 4l, 4m and 4n prepared by the present invention.

[0091] The present invention successfully prepared compounds 41, 4m, and 4n by a one-step process, as described above in Application Example 12, Application Example 13, and Application Example 14. This further demonstrates that the present invention overcomes the problems of the prior art in which the monofluoromethylselenoylation reaction of aromatic amine compounds relies on an indirect introduction method, namely, the traditional indirect introduction method has lengthy steps, usually requiring three steps; and the reaction conditions are harsh, requiring not only the use of a metal catalyst and a large amount of strong base, but also the use of expensive iodomethane as a monofluoromethyl source.

[0092] In the prior art, 2-bromophenylboronic acid and phenylsulfonic acid monofluoromethyl selenol are reacted to obtain Figure 7 The compound of the structural formula shown, Figure 7 Among them, 4c, 4l, 4m, and 4o prepared by the present invention are included. The present invention successfully prepares compounds 4c, 4l, 4m, and 4o by a one-step method. The preparation method is as described in Application Example 3, Application Example 12, Application Example 13, and Application Example 15. Specifically, Application Example 3, Application Example 12, Application Example 13, and Application Example 15 are all based on the alkylsulfonyl monofluoromethylselenylating reagent prepared by the present invention. The one-step method achieves the monofluoromethylselenylation reaction of aromatic amine compounds without using the monofluoromethylselenylating reagent prepared by the prior art. This overcomes the problem that the monofluoromethylselenylating reagent prepared by the prior art has a large molecular weight. When used in the monofluoromethylselenylation reaction of aromatic amine compounds, the relative molecular weight of the removed portion is large, resulting in low atomic utilization.

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

Claims

1. An alkylsulfonyl monofluoromethylselenoylating agent, characterized in that The structural formula of the alkylsulfonyl monofluoromethylselenoylating agent is shown in formula (I): ; Among them, R is selected from C1~C 10 Alkyl or C1~C 10 of a cycloalkyl group.

2. A method for preparing the alkylsulfonyl monofluoromethylselenoylating agent according to claim 1, characterized in that: The steps include: The reaction equation is: ; In liquid phase, RSO2Na, selenium powder and monofluoromonochloromethane are mixed to carry out substitution reaction to obtain alkylsulfonyl monofluoromethylselenoylation reagent.

3. The method for preparing the alkylsulfonyl monofluoromethylselenoylating agent according to claim 2, wherein: The substitution reaction conditions are: stirring the reaction at room temperature for 5h~7h.

4. The method for preparing the alkylsulfonyl monofluoromethylselenoylating agent according to claim 2, wherein: The molar ratio of RSO2Na, selenium powder and monochlorofluoromethane is 1:1~1.5:1~1.

5.

5. Use of the alkylsulfonyl monofluoromethylselenoylating agent according to claim 1 in the preparation of monofluoromethylselenoyl aryl ether compounds.

6. The use according to claim 5, characterized in that The structural formula of the monofluoromethylselenyl aryl ether compound is , where R 1 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.

7. The use according to claim 6, characterized in that The monofluoromethylselenoaryl ether compound is selected from 、 、 、 、 、 、 、 or .

8. The use according to claim 5, characterized in that The monofluoromethylselenoaryl ether compound is prepared according to the following steps: The reaction equation is: ; Will , p-toluenesulfonic acid, Acid Red 94, tert-butyl nitrite and an alkylsulfonyl fluoromethylselenoylating agent are dissolved in a solvent to carry out a deamination fluoromethylselenoylation reaction to obtain a fluoromethylselenoyl aryl ether compound; Among them, R 1 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.

9. The use according to claim 8, characterized in that The conditions for the deamination-fluoromethylselenoylation reaction are: stirring at room temperature for 4h~6h.

10. The use according to claim 8, characterized in that The molar ratio of the alkylsulfonyl monofluoromethylselenoylating agent is 1:1.2~1.5.

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