Preparation method of aryl sulfonyl fluoride compound

Abstract

The invention discloses a preparation method of an aryl sulfonyl fluoride compound, which specifically comprises the following steps of: reacting aryl thiocyanate as shown in a formula (1) as a substrate in a solvent under the atmosphere of an additive, a fluorine source and gas, and obtaining the aryl sulfonyl fluoride compound as shown in 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 aryl sulfuryl fluoride compound is synthesized from simple and easily available aryl 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 an arylsulfonyl fluoride compound. 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] However, most of the new methods currently available often use expensive metal catalysis, photocatalysis, and electrocatalysis, 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 generates RS by selecting different bases. - The attack on aryl thiocyanate produces RSSR dithiocyanate intermediate, which is then oxidized and fluorinated to obtain the final product, thus synthesizing aryl sulfonyl fluoride compounds.

[0006] The purpose of this invention is to provide a method for preparing arylsulfonyl fluoride compounds, using aryl thiocyanate as a substrate. The synthetic route is as follows:

[0007] The specific method is as follows: In a solvent, the aryl thiocyanate shown in formula (1) is used as a substrate and reacts with additives, F source and gas atmosphere. After the reaction is completed, the aryl sulfonyl fluoride compound 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 solvent is any one or more of water, methanol, and acetonitrile.

[0011] In one embodiment of the present invention, the additive (alkali) is any one or more of triethylamine, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, DBU (1,8-diazabicyclo[5.4.0]undecene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), and LiHMDS (lithium bis(trimethylsilyl)amino).

[0012] In one embodiment of the present invention, the amount of additive used is 0.5-2 eq of the aryl thiocyanate shown in formula (1).

[0013] Preferably, the values ​​are 0.5eq, 1eq, 1.5eq, or 2eq.

[0014] In one embodiment of the present invention, the fluorine source is any one or more of Selectfluor reagent and NFSI reagent.

[0015] In one embodiment of the present invention, the amount of fluorine source is 4-12 eq of the aryl thiocyanate shown in formula (1).

[0016] Preferably, the equivalence is 4eq, 6eq, 8eq, 10eq, or 12eq.

[0017] In one embodiment of the invention, the gaseous environment includes nitrogen, oxygen, or air.

[0018] In one embodiment of the present invention, the reaction temperature is 60-100°C. In one embodiment of the present invention, the reaction temperature is 60°C, 80°C or 100°C.

[0019] In one embodiment of the present invention, the reaction time is 1-5 hours.

[0020] In one embodiment of the present invention, the reaction time is 1h, 2h, 3h, 4h or 5h.

[0021] In one embodiment of the present invention, the steps of a novel green and economical preparation method are as follows: At room temperature, aryl thiocyanate (0.5 mmol, 1 eq), DBU (0.5 mmol, 1 eq), acetonitrile (2 mL) and water (0.2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 80 °C for two hours in air. After the aryl thiocyanate was consumed, selectfluor (3.25 mmol, 6.5 eq) was added, and the reaction was continued at 80 °C for two more hours. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain pure aryl sulfonyl fluoride compound.

[0022] The main separation method used in the above methods is rapid column chromatography, which yields the final product, arylsulfonyl fluoride compound.

[0023] Beneficial effects: The reaction mechanism of this invention is as follows: Under the action of a base, RS- attacks aryl thiocyanate to generate RSSR dithiocyanate intermediate, which is then oxidized and fluorinated to obtain the final product, thus synthesizing aryl sulfonyl fluoride compound.

[0024] The method of this invention uses an aryl thiocyanate compound as a substrate, DBU as a base, and selectfluor as a fluorinating agent in an air atmosphere to synthesize an aryl sulfonyl fluoride compound in one step, thereby obtaining the target compound.

[0025] The method of this invention uses inexpensive and readily available slelctfluor 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.

[0026] The synthesis method of this invention synthesizes aryl sulfonyl fluoride compounds from readily available aryl thiocyanates under relatively simple conditions, which have wide applications in the fields of medicine, pesticides and petrochemicals. Attached Figure Description

[0027] Figure 1 This is a synthetic route diagram of the method of the present invention; Figure 2 4-Methylbenzenesulfonyl fluoride was prepared as described in Example 1. 1 H NMR spectrum; Figure 3 4-Methylbenzenesulfonyl fluoride was prepared as described in Example 1. 13 C NMR spectrum; Figure 4 4-Methylbenzenesulfonyl fluoride was prepared as described in Example 1. 19 F NMR spectrum; Figure 5 4-Methoxybenzenesulfonyl fluoride was prepared as described in Example 2. 1 H NMR spectrum; Figure 6 4-Methoxybenzenesulfonyl fluoride was prepared as described in Example 2. 13 C NMR spectrum; Figure 7 4-Methoxybenzenesulfonyl fluoride was prepared as described in Example 2. 19 F NMR spectrum. Detailed Implementation

[0028] The following are specific embodiments of the present invention.

[0029] The synthesis route diagram of this invention embodiment is as follows: Figure 1 As shown: Example 1: Synthesis of 4-methylbenzenesulfonyl fluoride

[0030] At room temperature, p-tolyl thiocyanate (0.5 mmol, 1 eq), DBU (0.5 mmol, 1 eq), acetonitrile (2 mL), and water (0.2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 80 °C in air until p-tolyl thiocyanate disappeared from the TLC plate. Selectfluor (3.25 mmol, 6.5 eq) was then added, and the reaction was continued at 80 °C for two more hours. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain the target product in 77.4 mg, with a yield of 89%.

[0031] 1 H NMR (400 MHz, Chloroform-d) d 7.88 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 2.49 (s, 3H). 19 F NMR (376 MHz, Chloroform-d) d 66.31. 13 C NMR (101 MHz, Chloroform-d) d 147.25, 130.38, 130.08 (d, J = 24.1Hz), 128.53, 21.94. Example 2: Synthesis of 4-methoxybenzenesulfonyl fluoride At room temperature, p-methoxyphenyl thiocyanate (0.5 mmol, 1 eq), DBU (0.5 mmol, 1 eq), acetonitrile (2 mL), and water (0.2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 80 °C in air until p-methoxyphenyl thiocyanate disappeared from the TLC plate. Selectfluor (3.25 mmol, 6.5 eq) was then added, and the reaction was continued at 80 °C for two hours. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain the target product, 62.7 mg, in a yield of 66%.

[0032] 1 H NMR (400 MHz, Chloroform-d) d 7.96 – 7.90 (m, 2H), 7.09 – 7.03 (m, 2H), 3.91 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) d 165.35, 130.97, 124.25 (d, J = 24.8Hz), 115.01, 56.03. 19 F NMR (376 MHz, Chloroform-d) d 67.23. Example 3: Synthesis of 4-tert-butylbenzenesulfonyl fluoride At room temperature, p-tert-butylphenyl thiocyanate (0.5 mmol, 1 eq), DBU (0.5 mmol, 1 eq), acetonitrile (2 mL), and water (0.2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 80 °C in air until p-tert-butylphenyl thiocyanate disappeared from the TLC plate. Selectfluor (3.25 mmol, 6.5 eq) was added, and the reaction was continued at 80 °C for two hours. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain the target product in 79.9 mg, with a yield of 74%.

[0033] 1 H NMR (400 MHz, Chloroform-d) d 7.93 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 1.36 (s, 9H). 19 F NMR (376 MHz, Chloroform-d) d 66.26. Example 4: Synthesis of 4-fluorobenzenesulfonyl fluoride At room temperature, p-fluorophenyl thiocyanate (0.5 mmol, 1 eq), DBU (0.5 mmol, 1 eq), acetonitrile (2 mL), and water (0.2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 80 °C in air until p-fluorophenyl thiocyanate disappeared from the TLC plate. Selectfluor (3.25 mmol, 6.5 eq) was then added, and the reaction was continued at 80 °C for two more hours. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain the target product, yielding 40.9 mg in 46% yield.

[0034] 1 H NMR (400 MHz, Chloroform-d) d 8.09 – 8.02 (m, 2H), 7.32 (ddd, J =8.9, 7.8, 0.8 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) d 166.99 (d, J = 259.8 Hz), 133.41 (d, J = 8.7 Hz), 131.68 (d, J = 10.1 Hz), 117.37 (d, J = 23.1 Hz). 19 F NMR (376 MHz, Chloroform-d) d 66.79, -99.29. Example 5: Synthesis of 4-iodobenzenesulfonyl fluoride At room temperature, p-iodophenylthiocyanate (0.5 mmol, 1 eq), DBU (0.5 mmol, 1 eq), acetonitrile (2 mL), and water (0.2 mL) were added to a 10 mL Schlenk tube that had been dried in an oven. The mixture was reacted at 80 °C in air until p-iodophenylthiocyanate disappeared from the TLC plate. Selectfluor (3.25 mmol, 6.5 eq) was then added, and the reaction was continued at 80 °C for two hours. The mixture was concentrated under reduced pressure and then purified by rapid column chromatography to obtain the target product in 80.8 mg, with a yield of 53%.

[0035] 1 H NMR (400 MHz, Chloroform-d) d8.04 – 7.97 (m, 2H), 7.74 – 7.68 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) d 138.01, 131.50 (d, J = 25.5 Hz), 128.45, 103.06. 19 F NMR (376 MHz, CDCl3) d 66.30. Example 6: Investigating the effect of additives (bases) on the synthesis of arylsulfonyl fluoride Referring to Example 1, the additive (base) DBU was replaced with triethylamine, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, DBN, and LiHMDS, respectively, while other conditions remained unchanged, to obtain the corresponding arylsulfonyl fluorides; the effect of different additives (bases) on the yield of synthesized arylsulfonyl fluorides is shown in Table 1.

[0036] Table 1

[0037] The results showed that replacing DBU in Example 1 with triethylamine, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, DBN, and LiHMDS as additives (bases) resulted in a lower product yield than in Example 1, with a yield not exceeding 76%.

[0038] Example 7: Investigating the effect of DBU equivalent on the synthesis of arylsulfonyl fluoride Referring to Example 1, the amount of additive (base) DBU was replaced by 0.5 eq, 1.5 eq, and 2 eq, respectively. Other conditions remained unchanged, and the corresponding arylsulfonyl fluorides were obtained. The effects of different additives (bases) on the yield of the synthesized arylsulfonyl fluorides are shown in Table 2.

[0039] Table 2

[0040] The results showed that replacing 1 eq of DBU in Example 1 with 0.5 eq, 1.5 eq, or 2 eq resulted in a lower product yield than in Example 1, with a yield not exceeding 60%.

[0041] Example 8: Investigating the effect of solvent selection on the synthesis of arylsulfonyl fluoride.

[0042] Referring to Example 1, the solvent was replaced by methanol / water, methanol, and acetonitrile respectively, while other conditions remained unchanged, to prepare the corresponding arylsulfonyl fluorides; the effect of different solvents on the yield of synthesized arylsulfonyl fluorides is shown in Table 3.

[0043] Table 3

[0044] The results showed that using methanol, acetonitrile, or acetonitrile / water (as in Example 2) as solvents resulted in a lower product yield than in Example 1, with a yield not exceeding 46%.

[0045] Example 9: Investigating the effect of reaction temperature on the synthesis of arylsulfonyl fluoride. Referring to Example 1, the reaction temperature was changed from 80℃ to 25℃, 60℃, and 100℃ respectively, while other conditions remained unchanged, to obtain the corresponding aryl sulfonyl fluorides; the effect of different reaction temperatures on the yield of synthesized aryl sulfonyl fluorides is shown in Table 4.

[0046] Table 4

[0047] The results showed that replacing 80°C in Example 1 with 25°C, 60°C, and 100°C resulted in a lower product yield than in Example 1, with a yield not exceeding 73%.

Claims

1. A method for preparing an arylsulfonyl fluoride compound, characterized in that, The synthetic route using aryl thiocyanates as substrates is as follows: The specific method is as follows: In a solvent, the aryl thiocyanate shown in formula (1) is used as a substrate and reacts with additives, a fluorine source and a gas atmosphere. After the reaction is completed, the aryl sulfonyl fluoride compound 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 solvent is any one or more of water, methanol, and acetonitrile.

3. The preparation method according to claim 1, characterized in that, The additives are any one or more of the following: triethylamine, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, DBU, DBN, and LiHMDS.

4. The preparation method according to claim 1, characterized in that, The amount of additive used is 0.5-2 eq of the aryl thiocyanate shown in formula (1).

5. The preparation method according to claim 1, characterized in that, The fluorine source can be any one or more of Selectfluor reagent, NFSI reagent, etc.

6. The preparation method according to claim 1, characterized in that, The amount of fluorine source used is 4-12 eq of aryl thiocyanate as shown in formula (1).

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

8. The preparation method according to claim 1, characterized in that, The reaction temperature is 60-100℃.

9. The preparation method according to claim 1, characterized in that, The reaction time is 1-5 hours.

Images