Preparation method of benzylsulfonyl fluoride compound

Abstract

The invention discloses a preparation method of a benzylsulfonyl fluoride compound, which comprises the following steps: taking benzylthiocyanate as a substrate, in a solvent, taking benzylthiocyanate shown as a formula (1) as a substrate, reacting under the action of an additive, an F source and a gas atmosphere, and obtaining the benzylsulfonyl fluoride compound shown as a formula (2) after the reaction is finished, in the formulas (1) and (2), R is selected from one or more of H, alkyl, aryl, halogen, cyano, nitryl, alkoxy, acyl and amido. According to the method disclosed by the invention, the target product can be synthesized by only 4-8 hours, so that the target product can be obtained with relatively high yield, and the method is relatively rapid and efficient. According to the synthesis method disclosed by the invention, the benzyl sulfuryl fluoride compound is synthesized from simple and easily available benzyl thiocyanate under relatively simple conditions, and the fluorine-containing building block compound which is widely applied to the fields of medicines, pesticides and petrochemical engineering is realized.

Description

Technical Field

[0001] This invention relates to the field of chemical and daily chemical products, and in particular to a method for preparing sulfonyl fluoride compounds using benzyl thiocyanate as a substrate. Background Technology

[0002] In recent years, sulfonyl fluorides have attracted increasing attention from the academic community. Due to their favorable balance between reactivity and stability, sulfonyl fluorides have become an important framework in organic synthesis, pharmaceutical medicine, and materials science. Sulfonyl fluorides are also a key component of the next-generation "fluorine-sulfur exchange" concept proposed by Nobel laureate Sharpless. SuFEx click chemistry utilizes the strong nucleophilicity and electrophilicity between sulfur and fluorine to efficiently and selectively modify and functionalize organic molecules. Therefore, over the past decade, there has been an urgent need to study the synthesis and modification of sulfonyl fluorides, leading to the development of many complex synthetic methods for sulfonyl fluorides.

[0003] These synthetic reactions often use expensive metal catalysts, photocatalysts, and electrocatalysts, or reagents with low boiling points and high toxicity such as ClSO2F, ESF, and SO2F. Summary of the Invention

[0004] [Technical Issues] A preparation method that does not require expensive and complex catalytic systems and simultaneously achieves fluorosulfonation is provided.

[0005] [Technical Solution] This invention synthesizes benzylsulfonyl fluoride compounds by reacting solid sodium hypochlorite pentahydrate with acetic acid to produce hypochlorous acid, generating a sulfonyl chloride intermediate from the thiocyanate group of hypochlorous acid, followed by fluorine-chlorine exchange to obtain the final product.

[0006] The purpose of this invention is to provide a method for preparing benzyl sulfonyl fluoride compounds, using benzyl thiocyanate as a substrate, and the synthetic route is as follows:

[0007] The specific method is as follows: In a solvent, benzyl thiocyanate as shown in formula (1) is used as a substrate and reacts under the action of additives, F source and gas atmosphere. After the reaction is completed, benzyl sulfonyl fluoride compound as shown in formula (2) is obtained. In formulas (1) and (2), R is selected from one or more of H, alkyl, aryl, halogen, cyano, nitro, alkoxy, acyl, and amide.

[0008] In one embodiment of the present invention, R is C. 1-6 Alkyl groups, such as methyl, ethyl, tert-butyl, or isopropyl.

[0009] In one embodiment of the present invention, R is an aryl group, such as phenyl or naphthyl.

[0010] In one embodiment of the present invention, the additive is one or more of sodium hypochlorite pentahydrate, TCICA (trichloroisocyanuric acid), NBS (N-bromosuccinimide), and NCS (N-chlorosuccinimide).

[0011] In one embodiment of the present invention, the molar ratio of benzyl thiocyanate shown in formula (1) to the additive is 1:3-8.

[0012] In one embodiment of the present invention, the fluorine source is any one or more of KF, KHF2, CsF, TEA·3HF reagent, and TBAF reagent.

[0013] In one embodiment of the present invention, the molar ratio of benzyl thiocyanate of formula (1) to fluorine source is 1:6-12.

[0014] In one embodiment of the invention, the gaseous environment includes nitrogen, oxygen, or air.

[0015] In one embodiment of the present invention, the reaction temperature is 0-40°C.

[0016] In one embodiment of the present invention, the reaction time is 2-6 hours.

[0017] In one embodiment of the present invention, the steps of a novel green and economical preparation method are as follows: In a 10 mL Schlenk tube that had been dried in an oven, benzyl thiocyanate (0.5 mmol, 1 eq), KF (5 mmol, 10 eq), and acetic acid (2 mL) were added. The mixture was reacted at 0 °C in air with the addition of NaOCl·5H₂O (2 mmol, 4 eq), and the reaction was allowed to return to room temperature for 4 h. The mixture was then extracted with 10 mL of ethyl acetate and 20 mL of water. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain pure benzyl sulfonyl fluoride.

[0018] The main separation method used in the above methods is rapid column chromatography, which yields the final product benzylsulfonyl fluoride compound.

[0019] Beneficial effects: This invention provides a method for preparing benzyl sulfonyl fluoride compounds.

[0020] The reaction mechanism of this invention is as follows: solid sodium hypochlorite pentahydrate reacts with acetic acid to produce hypochlorous acid. The thiocyanate group of hypochlorous acid generates a sulfonyl chloride intermediate, which is then exchanged with fluorine to obtain the final product, thus synthesizing benzylsulfonyl fluoride compound.

[0021] The method of this invention uses benzyl thiocyanate compound as substrate, sodium hypochlorite pentahydrate as additive, KF as fluorinating agent, and acetic acid as solvent in an air atmosphere to synthesize benzyl sulfonyl fluoride compound in one step, yielding the target compound.

[0022] The method of this invention uses inexpensive and readily available KF as the fluorination reagent, which has wide substrate applicability, simple and readily available raw materials, and low economic cost. In addition, the method of this invention can achieve the synthesis of the target product with good yield in only 4-8 hours of reaction, which is faster and more efficient.

[0023] The synthesis method of this invention synthesizes benzyl sulfonyl fluoride compounds from readily available benzyl thiocyanate under relatively simple conditions, which have wide applications in the fields of medicine, pesticides and petrochemicals. Attached Figure Description

[0024] Figure 1 This is a synthetic route diagram of the method of the present invention; Figure 2 Benzylsulfonyl fluoride was prepared as described in Example 1. 1 H NMR spectrum; Figure 3 Benzylsulfonyl fluoride was prepared as described in Example 1. 13 C NMR spectrum; Figure 4 Benzylsulfonyl fluoride was prepared as described in Example 1. 19 F NMR spectrum; Figure 5 [1,1'-biphenyl]-4-ylmethanesulfonyl fluoride was prepared as described in Example 2. 1 H NMR spectrum; Figure 6 [1,1'-biphenyl]-4-ylmethanesulfonyl fluoride was prepared as described in Example 2. 13 C NMR spectrum; Figure 7 [1,1'-biphenyl]-4-ylmethanesulfonyl fluoride was prepared as described in Example 2. 19 F NMR spectrum. Detailed Implementation

[0025] The following are specific embodiments of the present invention.

[0026] The synthesis route diagram of this invention embodiment is as follows: Figure 1 As shown; Example 1: Synthesis of benzyl sulfonyl fluoride

[0027] At room temperature, benzyl thiocyanate (0.5 mmol, 1 eq), KF (5 mmol, 10 eq), and acetic acid (2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 0°C in air with the addition of NaOCl·5H₂O (2 mmol, 4 eq), and the reaction was allowed to return to room temperature for 4 h. Extraction was performed with 10 mL of ethyl acetate and 20 mL of water. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain pure benzyl sulfonyl fluoride. 52.2 mg was obtained, with a yield of 70%.

[0028] 1 H NMR (400 MHz, Chloroform-d) δ 7.45 (t, J = 2.5 Hz, 5H), 4.60 (d, J = 3.2 Hz, 2H). 19 F NMR (376 MHz, Chloroform-d) δ 51.40. 13 C NMR (101 MHz, Chloroform-d) δ 130.79, 130.05, 129.46, 125.64, 57.10, 56.93. Example 2: Synthesis of [1,1'-biphenyl]-4-ylmethanesulfonyl fluoride

[0029] At room temperature, [1,1'-biphenyl]-4-ylmethane thiocyanate (0.5 mmol, 1 eq), KF (5 mmol, 10 eq), and acetic acid (2 mL) were added to an oven-dried 10 mL Schlenk tube. The mixture was reacted at 0°C in air with the addition of NaOCl·5H₂O (2 mmol, 4 eq), and the reaction was allowed to return to room temperature for 4 h. Extraction was performed with 10 mL ethyl acetate and 20 mL water. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain pure [1,1'-biphenyl]-4-ylmethanesulfonyl fluoride. 93.8 mg was obtained, with a yield of 75%.

[0030] 1 H NMR (400 MHz, DMSO-d6) δ7.75 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 7.7Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4Hz, 1H), 5.41 (d, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 141.12, 139.25, 131.45, 128.93, 127.81, 127.15, 126.76, 125.81, 54.94 (d, J = 14.5 Hz). 19 F NMR (376 MHz, DMSO) δ 51.57. Example 3: Synthesis of (4-bromophenyl)methanesulfonyl fluoride

[0031] At room temperature, (4-bromophenyl)methane thiocyanate substrate (0.5 mmol, 1 eq), KF (5 mmol, 10 eq), and acetic acid (2 mL) were added to an oven-dried 10 mL Schlenk tube. The reaction was carried out under air atmosphere (0 °C) with the addition of NaOCl·5H₂O (2 mmol, 4 eq), and the mixture was allowed to return to room temperature for 4 h. Extraction was performed with 10 mL ethyl acetate and 20 mL of water. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain pure (4-bromophenyl)methanesulfonyl fluoride. 79.7 mg was obtained, with a yield of 63%.

[0032] 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 4.55 (d, J = 3.1 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 132.77 , 132.32 , 124.67 (d, J = 5.5Hz), 56.35 (d, J = 18.5 Hz). 19F NMR (376 MHz, CDCl3) δ 51.73 (s). Example 4: Investigating the effect of fluorine source on the synthesis of benzylsulfonyl fluoride Referring to Example 1, the fluorinating reagent KF was replaced with KHF2, CsF, TEA·3HF, and TBAF reagents, respectively, while keeping other conditions unchanged, to prepare the corresponding benzylsulfonyl fluorides. The effects of different fluorinating reagents on the yield of benzylsulfonyl fluorides are shown in Table 1.

[0033] Table 1

[0034] The results showed that replacing KF in Example 1 with KHF2, CsF, TEA·3HF and TBAF reagents as fluorinating agents resulted in a lower product yield than in Example 1, with a yield of no more than 67%.

[0035] Example 5: Investigating the effect of pentahydrate and sodium hypochlorite equivalents on the synthesis of benzylsulfonyl fluoride. Referring to Example 1, the equivalents of pentahydrate and sodium hypochlorite were replaced from 4 to 3, 5, 6, 7, and 8, respectively, while other conditions remained unchanged, to prepare the corresponding benzylsulfonyl fluorides. The effects of different equivalents of pentahydrate and sodium hypochlorite on the yield of benzylsulfonyl fluoride synthesis are shown in Table 2.

[0036] Table 2

[0037] The results showed that replacing the 4 equivalents in Example 1 with 3, 5, 6, 7 and 8 equivalents resulted in a lower product yield than in Example 1, with a yield of no more than 70%.

[0038] Example 6: Investigating the effect of gaseous atmosphere on the synthesis of benzylsulfonyl fluoride Referring to Example 1, the air atmosphere was replaced with oxygen and nitrogen, while other conditions remained unchanged, to prepare the corresponding benzylsulfonyl fluoride. The effect of the gas atmosphere on the yield of the synthesized benzylsulfonyl fluoride is shown in Table 3.

[0039] Table 3

[0040] The results showed that replacing the air in Example 1 with oxygen and nitrogen resulted in a lower product yield than in Example 1, with a yield of no more than 68%.

Claims

1. A method for preparing a benzylsulfonyl fluoride compound, characterized in that, The synthetic route using benzyl thiocyanate as a substrate is as follows: The specific method is as follows: In a solvent, benzyl thiocyanate as shown in formula (1) is used as a substrate and reacts under the action of additives, F source and gas atmosphere. After the reaction is completed, benzyl sulfonyl fluoride compound as shown in formula (2) is obtained. In formulas (1) and (2), R is selected from one or more of H, alkyl, aryl, halogen, cyano, nitro, alkoxy, acyl, and amide.

2. The preparation method according to claim 1, characterized in that, The additive is one or more of sodium hypochlorite pentahydrate, trichloroisocyanuric acid, N-bromosuccinimide, and N-chlorosuccinimide.

3. The preparation method according to claim 1, characterized in that, The molar ratio of benzyl thiocyanate to additive shown in formula (1) is 1:3-8.

4. The preparation method according to claim 1, characterized in that, The fluorine source is any one or more of KF, KHF2, CsF, TEA·3HF reagent, and TBAF reagent.

5. The preparation method according to claim 1, characterized in that, The molar ratio of benzyl thiocyanate to fluorine source shown in formula (1) is 1:6-12.

6. The preparation method according to claim 1, characterized in that, The gaseous environment includes nitrogen, oxygen, or air.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 0-40℃.

8. The preparation method according to claim 1, characterized in that, The reaction time is 2-6 hours.

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