A process for the preparation of perfluoroalkyl aryl sulfides
By preparing aryl sulfenyl chloride in an aprotic solvent and using a phase transfer catalyst to improve the solubility of F- ions, the problem of synthesizing perfluoroalkyl aryl sulfides in the prior art has been solved, realizing the efficient and low-cost synthesis of perfluoroalkyl aryl sulfides, which has broad application value.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- XIAN MODERN CHEM RES INST
- Filing Date
- 2023-09-28
- Publication Date
- 2026-05-15
AI Technical Summary
Existing technologies struggle to efficiently synthesize perfluoroalkyl aryl sulfides with long chains and high molecular weights. Furthermore, they exhibit low reactivity, require expensive highly reactive fluoroalkylating reagents, employ complex synthetic routes, and face harsh reaction conditions due to the easy poisoning of transition metal catalysts by sulfur atoms.
Arylsulfenyl chloride was prepared by reacting thiophenol with a chlorinating agent in an aprotic solvent. Then, in the presence of fluoride and a phase transfer catalyst, it was reacted with perfluoro-2-methyl-2-pentene. The phase transfer catalyst was used to enhance the solubility and addition activity of F- ions, thereby achieving efficient coupling between C6 perfluoroalkyl groups and the S atoms of thiophenol.
The efficient synthesis of perfluoroalkyl aryl sulfides has been achieved, with low raw material costs, a simple synthesis process, and ideal yields, making it suitable for applications in multiple fields.
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Figure CN117326994B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of fluorine-containing materials and relates to a method for preparing a perfluoroalkyl aryl sulfide. Background Technology
[0002] Sulfur-containing organic compounds possess unique biological activities such as antibacterial and anticancer properties, and are widely used in medicinal and pesticide chemistry. Fluorine-containing organic compounds, due to the special properties of their CF bonds, have significant value in pharmaceuticals, surfactants, and other functional materials. Perfluoroalkyl sulfides, containing both sulfur and fluorine elements, exhibit a significant advantage in lipophilicity among fluorine-containing functional groups, thus attracting considerable attention in research related to drug molecule modification.
[0003] Currently, perfluoroalkyl sulfides are mainly synthesized through the perfluoroalkylation of sulfur atoms. Among them, trifluoromethylation is the most studied and has the most methods. It is possible to achieve the trifluoromethylation of sulfur atoms through several major reaction strategies such as free radical, nucleophilic, and electrophilic reactions, and then synthesize trifluoromethyl sulfides.
[0004] However, due to the scarcity of sources, difficulty in synthesis, and significant steric hindrance leading to low reactivity, the coupling reaction of long-chain, high-molecular-weight perfluoroalkyl groups with sulfur atoms still has considerable research potential. Methods for introducing C2 or higher perfluoroalkyl groups onto sulfur atoms remain very limited. Highly reactive fluoroalkylating agents such as Togni and Umemoto reagents are expensive, have complex synthetic routes, and various transition metal catalysts used in coupling reactions are easily poisoned by sulfur atoms in the substrate, resulting in harsh reaction conditions and numerous limitations in application. Summary of the Invention
[0005] To address the deficiencies or shortcomings of existing technologies, this invention provides a method for preparing perfluoroalkyl aryl sulfides, wherein the structural formula of the perfluoroalkyl aryl sulfide is shown in formula (I):
[0006]
[0007] In formula (Ⅰ), R is 4-Cl, 4-CH3, 4-OCH3, 4-F, 4-Br or 4-C(CH3)3;
[0008] The preparation method includes the following steps:
[0009] (1) A terephthalamide chloride is prepared by reacting thiophenol with a chlorinating agent in a first solvent; wherein the chlorinating agent is selected from thionyl chloride, sulfonyl chloride, phosphoryl chloride, alkyl acyl chloride, alkyl sulfonyl chloride or chloroimide; and the first solvent is an aprotic solvent.
[0010] (2) In the presence of fluoride and phase transfer catalyst, the arylsulfonyl chloride prepared in step (1) is reacted with perfluoro-2-methyl-2-pentene (D-2) in a second solvent to prepare the compound (1,1,1,3,3,4,4,5,5,5-decafluoro-2-trifluoromethylpent-2-yl) (aryl) sulfide shown in formula (1); the fluoride is selected from alkali metal fluoride salts, alkaline earth metal fluoride salts, alkyl ammonium fluoride or alkyl fluorinated silicate; the phase transfer catalyst is alkyl ammonium chloride, aryl ammonium chloride, alkyl ammonium bromide or crown ether; the second solvent is an aprotic solvent.
[0011] An alternative is that the molar ratio of the thiophenol to the chlorinating agent is 1:1 to 2.
[0012] An optional approach is that the reaction temperature in step (1) is 0 to 30°C (preferably, the reaction in step 1 is carried out in an ice-water bath), and the reaction time is 0.25 to 24 h.
[0013] Optionally, the molar ratio of the arylsulfonyl chloride to perfluoro-2-methyl-2-pentene is 1:1 to 10; the molar ratio of the fluoride to the arylsulfonyl chloride is 0.5 to 3:1 (preferably 2 to 3:1); and the molar ratio of the phase transfer catalyst to the arylsulfonyl chloride is 0.01 to 0.5:1 (preferably 0.05 to 0.2:1).
[0014] An optional approach is to use a reaction temperature of 0 to 100°C and a reaction time of 1 to 48 hours in step (2).
[0015] Alternatively, the thiophenol may be selected from 4-chlorothiophenol, 4-methylthiophenol, 4-methoxythiophenol, 4-fluorothiophenol, 4-bromothiophenol, or 4-tert-butylthiophenol.
[0016] Alternatively, the chlorinating agent may be selected from sulfonyl chloride, sulfonyl chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, or trichloroisocyanuric acid. Preferably, it may be N-chlorosuccinimide, trichloroisocyanuric acid, N-chlorophthalimide, or 1,3-dichloro-5,5-dimethylhydantoin.
[0017] Alternatively, the first solvent may be selected from dichloromethane, diethyl ether, ethyl acetate, acetone, carbon tetrachloride, or n-hexane. Preferably, it is dichloromethane diethyl ether, ethyl acetate, acetone, or carbon tetrachloride.
[0018] Alternatively, the fluoride may be selected from sodium fluoride, potassium fluoride, cesium fluoride, calcium fluoride, TBAF, or TBAT. Preferably, cesium fluoride is used.
[0019] Alternatively, the phase transfer catalyst is selected from 15-crown-5, 18-crown-6, dibenzo-18-crown-6, dicyclohexano-18-crown-6, or dibenzo-24-crown-8. Preferably, it is dibenzo-24-crown-8 or dicyclohexano-24-crown-8.
[0020] Alternatively, the second solvent may be selected from acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, or N-methylpyrrolidone. Preferably, it may be acetonitrile, N,N-dimethylformamide, or N-methylpyrrolidone.
[0021] In a preferred embodiment, the first solvent is selected from dichloromethane, diethyl ether, ethyl acetate, acetone, or carbon tetrachloride; the fluoride is selected from cesium fluoride; the phase transfer catalyst is selected from dibenzo-24-crown-8 or dicyclohexano-24-crown-8; and the second solvent is selected from acetonitrile, N,N-dimethylformamide, or N-methylpyrrolidone. The preparation method of this invention uses inexpensive and widely available raw materials, has a simple synthesis process, and achieves ideal yields. This method enables efficient coupling of C6 perfluoroalkyl groups with the sulfur atom of thiophenols, and the synthesized perfluoroalkyl aryl sulfides have research and application value in many fields.
[0022] In a preferred embodiment, the present invention uses crown ethers to counteract alkali metal ions (Na+). + K + Cs + ) to perform complexation, thereby effectively improving F - The solubility of the ion in organic solvents and its addition activity to D-2 promote the generation of perfluoro-1,1-dimethylbutyl anion, thereby increasing the yield of its nucleophilic substitution reaction with arylsulfonyl chloride. Attached Figure Description
[0023] Figure 1 (1,1,1,3,3,4,4,5,5,5-decafluoro-2-trifluoromethylpentan-2-yl)(4-chlorophenyl) sulfide prepared in Example 1 1 H NMR spectrum.
[0024] Figure 2 (1,1,1,3,3,4,4,5,5,5-decafluoro-2-trifluoromethylpentan-2-yl)(4-chlorophenyl) sulfide prepared in Example 1 19 F NMR spectrum. Detailed Implementation
[0025] Unless otherwise specified, the scientific and technical terms used in this invention are for the understanding of those skilled in the art. It should also be understood that temperatures and concentrations mentioned herein are approximate values used for illustrative purposes. While similar or equivalent methods and materials to those described herein can be used in the implementation of this disclosure, some suitable methods and materials are described below. Publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in part, and in case of conflict, this document shall prevail. Furthermore, the materials, methods, solution concentrations, and examples described are exemplary only and are not intended to be limiting. In specific embodiments, those skilled in the art can optimize the proportions, concentrations, and operating parameters of the substances involved in the methods using conventional experimental periods based on the disclosure of this invention to achieve the objectives of this invention.
[0026] The present invention will be further described in detail below through specific embodiments, but this is not intended to limit the invention in any way. All substances used in the following embodiments are commercially available products.
[0027] Example 1:
[0028] Step (1): Add 0.167 g (1.25 mmol) of N-chlorosuccinimide and 5 mL of dichloromethane to a 10 mL reaction tube, stir to dissolve, maintain the temperature at 0 °C in an ice-water bath, slowly add 0.145 g (1 mmol) of 4-chlorothiophenol, seal the reaction for 4 h, remove the solvent under reduced pressure, wash the solid obtained from the reaction with 10 mL of n-hexane three times, filter to remove the white solid, remove the solvent under reduced pressure to obtain 4-chlorobenzenesulfonyl chloride, which can be used directly for subsequent reactions without further purification;
[0029] In step (2), under N2 protection, 0.3 g (2 mmol) of dry cesium fluoride, 90 mg (0.2 mmol) of dibenzo-24-crown-8, 1.5 g (5 mmol) of perfluoro-2-methyl-2-pentene, and 3 mL of acetonitrile were added to a 25 mL reaction tube. The reaction was carried out at 60 °C for 0.5 h under sealed stirring. Then, under N2 protection, 4-chlorobenzenesulfonyl chloride synthesized in step (1) was added, and the reaction was continued at 60 °C with sealed stirring for 2 h. After cooling to room temperature, the reaction product was poured into 50 mL of water and extracted three times with 10 mL of diethyl ether. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. The product (1,1,1,3,3,4,4,5,5,5-decafluoro-2-trifluoromethylpentan-2-yl)(4-chlorophenyl) sulfide was obtained by column chromatography (n-hexane) with a yield of 0.32 g and a yield of 70%.
[0030] Product structure is shown below Figure 1 and Figure 2 The characterization data are as follows:
[0031] 1H NMR (500MHz, Chloroform-d) δ7.67 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H).
[0032] 19 F NMR (471MHz, Chloroform-d) δ -61.13 (p, J = 10.9, 10.3Hz), -80.20 (dd, J = 25.0, 12.0Hz), -104.94 (dq, J = 27.0, 13.9Hz), -122.12 (p, J = 12.2, 11.4Hz).
[0033] The above data proves that the product obtained in this embodiment is (1,1,1,3,3,4,4,5,5,5-decafluoro-2-trifluoromethylpentan-2-yl)(4-chlorophenyl) sulfide.
[0034] Examples 2-6:
[0035] Examples 2-6 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the chlorinating agent in step (1) of Example 1 was N-chlorosuccinimide, while in Examples 2-6 it was sulfoxide, sulfonyl chloride, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, and trichloroisocyanuric acid, respectively. The reaction results of Examples 2-6 are shown in Table 1.
[0036] Table 1. Reaction results of Examples 2-6
[0037] Example Chlorination reagent Perfluoroalkyl aryl sulfides yield / % 2 sulfoxide 45.1 3 sulfonyl chloride 52.3 4 N-chlorophthalimide 66.2 5 1,3-Dichloro-5,5-dimethylhydantoin 61.5 6 Trichloroisocyanuric acid 64.1
[0038] Examples 7-11:
[0039] Examples 7-11 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the first solvent in step (1) of Example 1 was dichloromethane, while in Examples 7-11 it was diethyl ether, ethyl acetate, acetone, carbon tetrachloride, and n-hexane, respectively. The reaction results of Examples 7-11 are shown in Table 2.
[0040] Table 2 Reaction results of Examples 7-11
[0041] Example First solvent Perfluoroalkyl aryl sulfides yield / % 7 Diethyl ether 50.2 8 Ethyl acetate 56.3 9 acetone 58.9 10 Carbon tetrachloride 68.2 11 n-Hexane 30.1
[0042] Examples 12-14:
[0043] Examples 12-14 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the molar ratio of 4-chlorothiophenol to N-chlorosuccinimide in step (1) of Example 1 was 1:1.25, while in Examples 12-14 it was 1:1, 1:1.5, and 1:2, respectively. The reaction results of Examples 12-14 are shown in Table 3.
[0044] Table 3 Reaction results of Examples 12-14
[0045] Example 4-Chlorothiophenol: N-Chlorosilicate (molar ratio) Perfluoroalkyl aryl sulfides yield / % 12 1:1 61.2 13 1:1.5 68.2 14 1:2 66.9
[0046] Examples 15-18:
[0047] Examples 15-18 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the fluoride in step (2) of Example 1 was cesium fluoride and the phase transfer catalyst was dibenzo-24-crown-8, while the fluorides in Examples 15-18 were sodium fluoride and potassium fluoride, and the crown ethers were 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and dicyclohexano-18-crown-6, respectively. The reaction results of Examples 15-18 are shown in Table 4.
[0048] Table 4 Reaction results of Examples 15-18
[0049] Example Fluorides Crown ethers Perfluoroalkyl aryl sulfides yield / % 15 Sodium fluoride 15-crown-5 14 16 Potassium fluoride 18-crown-6 43 17 Potassium fluoride Dibenzo-18-crown-6 42 18 Potassium fluoride Dicyclohexano-18-crown-6 40
[0050] Comparative Examples 1-3:
[0051] Comparative Examples 1-3 were prepared using the same method as in Example 1, except that the fluoride in Example 1 was cesium fluoride and the crown ether was dibenzo-24-crown-8, while the fluorides in Comparative Examples 1-3 were calcium fluoride, TBAF, and TBAT, and the crown ethers were 15-crown-5, 18-crown-6, and dibenzo-18-crown-6, respectively. The reaction results of Comparative Examples 1-3 are shown in Table 5.
[0052] Table 5. Effects of alkaline earth metal fluorides, organic fluorides, and crown ethers on the reaction.
[0053]
[0054]
[0055] Comparative Examples 1 and 2 failed to achieve the conversion of the substrate to perfluoroalkyl aryl sulfides, while the yields of Comparative Examples 3 and 4 were lower. This may be because the cation radius of alkaline earth metal fluorides such as calcium fluoride does not match the size of the crown ether vacancy, resulting in a poor solvation effect and increased Fo. -Solubility in the organic phase; organofluorine compounds such as TBAF and TBAT have good solubility, but their steric hindrance reduces the attack efficiency of perfluoroalkyl anions on the substrate sulfenyl chloride, thus affecting the nucleophilic reaction. Comparative Example 4:
[0056] The preparation method of this comparative example differs from that of Example 1 in that dibenzo-24-crown-8 is not added to the reaction system in step (2); 0.18 g of product is obtained, with a yield of 40%. The same method as in Example 1 is used to verify that the obtained product is (1,1,1,3,3,4,4,5,5,5-decafluoro-2-trifluoromethylpentan-2-yl)(4-chlorophenyl) sulfide.
[0057] Comparative Examples 5-9:
[0058] Comparative Examples 5-9 were prepared using the same preparation method as in Example 1, except that the fluoride in Example 1 was cesium fluoride, while the fluorides in Comparative Examples 5-9 were calcium fluoride, TBAF, TBAT, potassium fluoride, and sodium fluoride, respectively. The yields of the products are shown in Figure 6.
[0059] Table 6
[0060] Comparative Example Fluorides Perfluoroalkyl aryl sulfides yield / % 5 Calcium fluoride 0 6 TBAF 0 7 TBAT 30.8 8 Potassium fluoride 43.5 9 Sodium fluoride 14.5
[0061] Examples 19-23:
[0062] Examples 19-23 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the second solvent in step (2) of Example 1 was acetonitrile, while in Examples 19-23 it was N,N-dimethylformamide, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, and N-methylpyrrolidone, respectively. The reaction results of Examples 19-23 are shown in Table 7.
[0063] Table 7 Reaction results of Examples 19-23
[0064] Example Second solvent Perfluoroalkyl aryl sulfides yield / % 19 N,N-Dimethylformamide 52 20 Tetrahydrofuran 22 21 Ethylene glycol dimethyl ether 26 22 1,4-Dioxane 19 23 N-Methylpyrrolidone 49
[0065] Examples 24-29:
[0066] Examples 24-29 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the molar ratio of 4-chlorobenzenesulfonyl chloride to cesium fluoride in step (2) of Example 1 was 1:2, while in Examples 24-26 it was 1:1, 1:1.5, and 1:3, respectively; the molar ratio of dibenzo-24-crown-8 to 4-chlorobenzenesulfonyl chloride in Example 1 was 0.1:1, while in Examples 27-29 it was 0.05:1, 0.08:1, and 0.2:1, respectively. The reaction results of Examples 24-29 are shown in Table 8.
[0067] Table 8 Reaction results of Examples 24-29
[0068]
[0069]
[0070] Examples 30-34:
[0071] Examples 30-34 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the thiophenol in step (1) of Example 1 was 4-chlorobenzylthiophenol, while in Examples 30-34 it was 4-methylbenzylthiophenol, 4-methoxybenzylthiophenol, 4-fluorobenzylthiophenol, 4-bromobenzylthiophenol, and 4-tert-butylbenzylthiophenol, respectively. The reaction results of Examples 30-34 are shown in Table 9.
[0072] Table 9 Reaction results of Examples 30-34
[0073] Example raw material thiophenol Perfluoroalkyl aryl sulfides yield / % 30 4-Methylthiophenol 82 31 4-Methoxythiophenol 79 32 4-Fluorothiophenol 80 33 4-Bromothiophenol 63 34 4-tert-butylthiophenol 72
[0074] Examples 34-37:
[0075] Examples 34-37 prepared perfluoroalkyl aryl sulfides using the same preparation method as in Example 1, except that the crown ether in Example 1 was dibenzo-24-crown-8, while the crown ethers in this set of examples were 15-crown-5, 18-crown-6, and dibenzo-18-crown-6, respectively. The reaction results are shown in Table 10.
[0076] Table 10
[0077] Example Crown ethers Perfluoroalkyl aryl sulfides yield / % 34 18-crown-6 35.7 35 Dibenzo-18-crown-6 45.2 36 Dicyclohexano-18-crown-6 41.3 37 Dicyclohexano-24-crown-8 56.2
[0078] The above description is only a partial embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention shall fall within the scope of the technical solution of the present invention.
Claims
1. A method for preparing a perfluoroalkyl aryl sulfide, characterized in that, The structural formula of the perfluoroalkyl aryl sulfide is shown in Formula (Ⅰ): Ⅰ In formula (Ⅰ), R is 4-Cl, 4-CH3, 4-OCH3, 4-F, 4-Br or 4-C(CH3)3; The preparation method includes the following steps: (1) A thiophenol is reacted with a chlorinating agent in a first solvent to prepare an aryl sulfenyl chloride; the chlorinating agent is selected from thionyl chloride, sulfonyl chloride, phosphoryl chloride, alkyl acyl chloride, alkyl sulfonyl chloride or chloroimide; the first solvent is an aprotic solvent; (2) In the presence of fluoride and phase transfer catalyst, the arylsulfonyl chloride prepared in step (1) is reacted with perfluoro-2-methyl-2-pentene in a second solvent to prepare the compound shown in formula (1); The fluoride is selected from cesium fluoride; the phase transfer catalyst is selected from dibenzo-24-crown-8.
2. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The molar ratio of thiophenol to chlorinating agent is 1:1~2.
3. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The reaction temperature in step (1) is 0~30℃ and the reaction time is 0.25~24h.
4. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The molar ratio of the arylsulfonyl chloride to perfluoro-2-methyl-2-pentene is 1:1 to 10; the molar ratio of the fluoride to the arylsulfonyl chloride is 0.5 to 3:1; and the molar ratio of the phase transfer catalyst to the arylsulfonyl chloride is 0.01 to 0.5:
1.
5. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The reaction temperature in step (2) is 0~100℃ and the reaction time is 1~48h.
6. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The thiophenol is selected from 4-chlorothiophenol, 4-methylthiophenol, 4-methoxythiophenol, 4-fluorothiophenol, 4-bromothiophenol, or 4-tert-butylthiophenol.
7. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The chlorinating agent is selected from sulfoxide, sulfonyl chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid.
8. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The first solvent is selected from dichloromethane, diethyl ether, ethyl acetate, acetone, carbon tetrachloride, or n-hexane.
9. The method for preparing perfluoroalkyl aryl sulfides according to claim 1, characterized in that, The second solvent is selected from acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, or... N-methylpyrrolidone.