A method for one-pot preparation of aryl crown ether compounds

Abstract

The application discloses a method for preparing aryl crown ether compounds by one-pot method, and comprises the following steps: reacting polyglycol and sulfonyl fluoride or chlorofluorosulfonyl in an organic solvent under the action of alkali to obtain polyglycol difluorosulfonyl ester; and reacting dihydroxy aryl compounds and polyglycol difluorosulfonyl ester in an organic solvent under the action of a catalyst and alkali to obtain aryl crown ether compounds. The method uses the commonly used and economical sulfonyl fluoride or chlorofluorosulfonyl as a reagent, and can prepare various aryl crown ether compounds by one-pot method. The product obtained by the synthesis method has the advantages of simple operation, low cost and high yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic compound synthesis, and particularly relates to a one-pot method for preparing aryl crown ether compounds. BACKGROUND

[0002] Aryl crown ethers are a special class of crown ether compounds with one or more cyclic ether units and an aromatic substituent group introduced at a specific position of the ring. These compounds are widely used in various fields due to their unique molecular structure and excellent selectivity, including chemical sensing, ion selectivity, drug delivery, separation technology, etc. At the same time, aryl crown ethers also show important application potential in supramolecular chemistry and materials science.

[0003] Although aryl crown ethers have broad application prospects, their synthesis methods have many shortcomings. Traditional synthesis routes usually include multiple steps such as di-p-toluene sulfonate esterification reaction, aryl functionalization, cyclization reaction and post-treatment, which not only increases the complexity of synthesis, but also reduces the yield. For example, the commonly used aryl ether synthesis method includes Friedel-Crafts reaction, iodination reaction, and other coupling reactions, which often require high temperature, long reaction time, and may generate a large amount of by-products.

[0004] Especially, the use of p-toluenesulfonyl chloride, although widely used for preparing di-p-toluene sulfonate esterification of polyglycol chains, has the disadvantages of low atomic utilization, complex reaction steps, selectivity and yield problems, and harsh reaction conditions, which limits its practical application. The treatment of waste and by-products generated during the synthesis process also poses a challenge to environmental protection. SUMMARY

[0005] The purpose of this section is to summarize some aspects of the embodiments of the present application and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of the specification to avoid obscuring the purpose of this section, abstract and title, and such simplifications or omissions cannot be used to limit the scope of the present application.

[0006] In view of the above and / or problems existing in the prior art, the present application is proposed.

[0007] One of the purposes of the present application is to provide a one-pot method for preparing aryl crown ether compounds, which uses polyglycol difluorosulfonyl ester to prepare aryl crown ether, improves the yield, and avoids the separation cost caused by column chromatography.

[0008] To solve the above technical problems, the present application provides the following technical scheme: a one-pot method for preparing aryl crown ether compounds, comprising,

[0009] The polyglycol reacts with thionyl fluoride or chlorofluorosulfonyl in the presence of base A in organic solvent A to obtain polyglycol difluorosulfonyl ester of formula I;

[0010]

[0011] wherein n = 1-5;

[0012] The dihydroxy aryl compound reacts with polyglycol difluorosulfonyl ester of formula I in the presence of catalyst and base B in organic solvent B to obtain aryl crown ether compound.

[0013] The dihydroxy aryl compound is selected from one of the following compounds:

[0014]

[0015] The aryl crown ether compound is one of the following compounds:

[0016]

[0017] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 are one of hydrogen, aliphatic group, halogen, alkoxy, nitro, cyano, aryl, and n = 0-6.

[0018] As a preferred scheme of the method for preparing aryl crown ether compound in one pot of the present application, wherein: the base A is any one or more of inorganic base and / or organic base; including one of triethylamine, cesium carbonate, diisopropylethylamine.

[0019] The polyglycol is any one of diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol.

[0020] The molar ratio of polyglycol to base A is 1:1-20.

[0021] As a preferred scheme of the method for preparing aryl crown ether compound in one pot of the present application, wherein: the organic solvent A is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl pyrrolidone, methyl tert-butyl ether and chloroform.

[0022] As a preferred scheme of the method for preparing aryl crown ether compound in one pot of the present application, wherein: the thionyl fluoride or chlorofluorosulfonyl is a gas, and the thionyl fluoride or chlorofluorosulfonyl gas is introduced into the mixture of polyglycol, base A and organic solvent A to react, and the introduction of thionyl fluoride or chlorofluorosulfonyl gas is stopped when the content of glycol in the system is less than 0.3%.

[0023] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the molar ratio of the dihydroxy aryl compound to the polyglycol difluorosulfonyl ester is 1:0.2-20.

[0024] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium cyanide sulfate, and tetrabutylammonium chloride.

[0025] The amount of the catalyst added is 1-50 mol% of the dihydroxy aryl compound.

[0026] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the base B is any one or more of inorganic bases and / or organic bases, including one of sodium hydroxide, sodium hydride, and potassium carbonate.

[0027] The amount of the base B added is 100-2000 mol% of the polyglycol difluorosulfonyl ester.

[0028] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the organic solvent B is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl pyrrolidone, methyl tert-butyl ether, and chloroform.

[0029] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the reaction temperature is -10-100°C, and the reaction time is 1-24 hours.

[0030] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the method further comprises a step of purifying the reaction product aryl crown ether compound.

[0031] As a preferred scheme of the method for preparing the aryl crown ether compound by the one-pot method of the present application, the dihydroxy aryl compound can be a chiral dihydroxy aryl compound, can be racemic, or can have chirality.

[0032] Compared with the prior art, the present application has the following beneficial effects:

[0033] The present application effectively uses sulfuryl fluoride or chlorofluorosulfonyl instead of p-toluenesulfonyl chloride, and the sulfuryl fluoride or chlorofluorosulfonyl itself is low in price, thereby saving cost. The present application uses polyglycol difluorosulfonyl ester to prepare the aryl crown ether, improves the yield, avoids the separation cost caused by column chromatography, reduces the overall process production cost, and improves market competitiveness. BRIEF DESCRIPTION OF DRAWINGS

[0034] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the following embodiment description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without any creative effort based on these drawings. Among them:

[0035] Figure 1 NMR chart of the product aryl crown ether compound in the embodiment 2 of the present application;

[0036] Figure 2 NMR chart of the product aryl crown ether compound in the embodiment 3 of the present application. DETAILED DESCRIPTION

[0037] In order to make the above-mentioned objects, features and advantages of the present application more apparent and easy to understand, the specific embodiments of the present application will be described in detail below with the description of the embodiments.

[0038] In the following description, many specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be practiced in other manners different from those described herein, and those skilled in the art can make similar generalizations without departing from the scope of the present application. Therefore, the present application is not limited to the specific embodiments disclosed below.

[0039] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. The "in one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an independent or alternative embodiment mutually exclusive with other embodiments.

[0040] Unless otherwise specified, the raw materials used in the embodiments are commercially available.

[0041] Embodiment 1

[0042] (1) Tetraethylene glycol (6.47 g, 33.3 mmol) and triethylamine (9.26 mL, 66.6 mmol) were added to a 250 mL round-bottom flask containing 50 mL of dichloromethane. The temperature was lowered to 0°C, and sulfuryl fluoride was introduced into the reaction solution and stirred at room temperature for 2 hours. When the content of glycol in the system was less than 0.3%, the introduction of sulfuryl fluoride gas was stopped. After the reaction was completed, nitrogen was introduced into the reaction system to purge the residual sulfuryl fluoride gas in the system, and a tetraethylene glycol difluorosulfonyl ester solution was obtained.

[0043] The reaction formula is:

[0044]

[0045] (2) Under nitrogen protection, sodium hydroxide (40.0 mg, 1.0 mmol), tetrabutylammonium bromide (8.1 mg) were added into the solution of catechol (55.0 mg, 0.5 mmol) in 10 mL dichloromethane at 0 °C for 30 min. Then, tetraglycol difluorosulfonate solution (1.0 mmol) was added, and the reaction was carried out at reflux for 3 h. The reaction was extracted with dichloromethane for three times, washed with saturated sodium chloride aqueous solution for three times, and dried over anhydrous sodium sulfate. After the organic solvent was removed by rotary evaporation, the product was obtained as white solid (125 mg, 93%).1H NMR (500 MHz, Chloroform-d) δ 6.92-6.85 (m, 4H), 4.18-4.11 (m, 4H), 3.94-3.89 (m, 4H), 3.74-3.79 (m, 8H).

[0046] The reaction formula is:

[0047]

[0048] Example 2

[0049] (1) Tetraglycol (7.93 g, 33.3 mmol) and triethylamine (9.26 mL, 66.6 mmol) were added to a 250 mL round-bottom flask containing 50 mL dichloromethane. The temperature was lowered to 0 °C, and sulfuryl fluoride was introduced into the reaction system, and stirred at room temperature for 2 h. When the content of glycol in the system was less than 0.3%, the introduction of sulfuryl fluoride gas was stopped. After the reaction was completed, nitrogen was introduced into the reaction system to blow off the residual sulfuryl fluoride gas in the system, and a tetraglycol difluorosulfonate solution was obtained.

[0050] The reaction formula is:

[0051]

[0052] (2) Under nitrogen protection, sodium hydride (40.0 mg, 1.0 mmol), tetrabutylammonium chloride (7.0 mg) were added to S-1,1'-bi-2-naphthol (144.6 mg, 0.5 mmol) in dichloromethane solution 10 mL at 0 °C for 30 min. Subsequently, pentaethylene glycol difluorosulfonate solution (1.0 mmol) was added, and the reaction was completed after refluxing for 3 h. Extraction was performed three times with dichloromethane, and the organic phase was washed three times with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removing the organic solvent by rotary evaporation, the product was obtained as a colorless oil (144 mg, 96%).1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 9.0 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 9.0 Hz, 2H), 7.30 (ddd, J = 8.1, 6.5, 1.2 Hz, 2H), 7.19 (ddd, J = 8.1, 6.6, 1.3 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.19 (ddd, J = 10.9, 7.2, 4.1 Hz, 2H), 4.02 (dt, J = 10.5, 4.4 Hz, 2H), 3.64 - 3.55 (m, 6H), 3.52 - 3.46 (m, 6H), 3.37 (t, J = 4.4 Hz, 4H). The1H NMR spectrum is shown in Figure 1 .

[0053] The reaction formula is:

[0054]

[0055] Example 3

[0056] (1) The pentaethylene glycol difluorosulfonate solution was prepared in the same manner as in Example 2.

[0057] (2) Under nitrogen, potassium carbonate (138.2 mg, 1.0 mmol), tetrabutylammonium hydrogen sulfate (8.5 mg) were added to (R)-spirodiphenol (126.2 mg, 0.5 mmol) in acetonitrile 10 mL at 0 °C for 30 min. Then, pentaethylene glycol difluorosulfonate solution (1.0 mmol) was added and the reaction was heated to 60 °C for 5 h. The reaction was extracted with dichloromethane three times, washed with saturated aqueous sodium chloride three times, and dried over anhydrous sodium sulfate. The filtrate was evaporated to remove the organic solvent to give the product as colorless oil (225 mg, 99%).1H NMR (500 MHz, Chloroform-d) δ 7.08 (t, J = 7.7 Hz, 2H), 6.83 (dd, J = 7.5, 1.0 Hz, 2H), 6.67 (d, J = 8.0 Hz, 2H), 4.05 (ddd, J = 10.4, 6.8, 4.8 Hz, 2H), 3.88 (dt, J = 10.2, 4.8 Hz, 2H), 3.66 - 3.60 (m, 2H), 3.56 - 3.45 (m, 8H), 3.33 - 3.20 (m, 6H), 2.99 (dd, J = 8.9, 4.9 Hz, 4H), 2.31 (dt, J = 12.5, 9.3 Hz, 2H), 2.15 (ddd, J = 12.5, 6.2, 4.6 Hz, 2H). The1H NMR spectrum is shown in Figure 1. Figure 2

[0058]

[0059]

[0060] Example 4

[0061] (1) Pentaethylene glycol difluorosulfonate solution was prepared in the same manner as in Example 1.

[0062] (2) Under nitrogen, sodium hydride (40 mg, 1.0 mmol), tetrabutylammonium hydrogen sulfate (8.5 mg) were added to 2,2'-biphenol (126.2 mg, 0.5 mmol) in methyltetrahydrofuran 10 mL at 0 °C for 30 min. Then, pentaethylene glycol difluorosulfonate solution (1.0 mmol) was added and the reaction was heated to 60 °C for 5 h. The reaction was extracted with dichloromethane three times, washed with saturated aqueous sodium chloride three times, and dried over anhydrous sodium sulfate. The filtrate was evaporated to remove the organic solvent to give the product as white solid (169 mg, 98%).1H NMR (500 MHz, Chloroform-d) δ 7.23 (m, 2H), 7.15 (dd, 2H, J = 12.3 Hz, 3.0 Hz), 6.95 (m, 4H), 4.21 (m, 2H), 3.95 (m, 2H), 4.66 (m, 12H). ​​

[0063] The reaction formula is:

[0064]

[0065] Example 5

[0066] (1) Preparation of tetraglycol difluorosulfonate solution, the method is the same as example 1.

[0067] (2) Under nitrogen protection, sodium hydride (40.0 mg, 1.0 mmol), tetrabutylammonium chloride (7.0 mg) were added to 1,8-dihydroxynaphthalene (80.1 mg, 0.5 mmol) in dichloroethane solution 10 mL at 0℃ for 30 min. Then, tetraglycol difluorosulfonate solution (1.0 mmol) was added, and the reaction was completed after refluxing for 3 h. Extracted with dichloromethane three times, washed with saturated aqueous sodium chloride three times, and dried over anhydrous sodium sulfate. After removing the organic solvent by rotary evaporation, the product was obtained as a white solid (151 mg, 95%).1H NMR (500 MHz, Chloroform-d) δ 7.45-7.10 (m, 4H), 6.91-6.59 (m, 4H), 4.32-3.38 (m, 16H).

[0068] The reaction formula is:

[0069]

[0070] Example 6

[0071] (1) Preparation of tetraglycol difluorosulfonate solution, the method is the same as example 1.

[0072] (2) Under nitrogen protection, sodium hydride (40.0 mg, 1.0 mmol), tetrabutylammonium chloride (7.0 mg) were added into (S)-6,6'-dibromofluoranthen-9-one (222.1 mg, 0.5 mmol) in acetonitrile solution 10 mL at 0 °C for 30 min. Subsequently, tetraglycol difluorosulfonate solution (1.0 mmol) was added, and the reaction was completed after refluxing for 3 h. The reaction solution was extracted with dichloromethane for three times, washed with saturated sodium chloride aqueous solution for three times, and dried over anhydrous sodium sulfate. After removing the organic solvent by rotary evaporation, the product was obtained as a white solid (310 mg, 96%).1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 1.9 Hz, 2H), 7.82 (d, J = 9.2 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.25 (dd, J = 15.0, 2.5 Hz, 2H), 6.96 (d, J = 15.0 Hz, 2H), 4.14 - 4.25 (m, 4H), 3.97 - 4.07 (m, 4H), 3.43 - 3.67 (m, 8H), 3.39 (t, J = 6.7 Hz, 4H).

[0073] The reaction formula is:

[0074]

[0075] Example 7

[0076] (1) Triethylene glycol (5.00 g, 33.3 mmol) and triethylamine (9.26 mL, 66.6 mmol) were added to a 250 mL round-bottom flask containing 50 mL of dichloromethane. The temperature was lowered to 0 °C, and sulfuryl fluoride was introduced into the reaction solution and stirred at room temperature for 2 hours. When the content of glycol in the system was less than 0.3%, the introduction of sulfuryl fluoride gas was stopped, and after the reaction was completed, nitrogen was introduced into the reaction system to blow off the residual sulfuryl fluoride gas in the system, to obtain a triethylene glycol difluorosulfonate solution.

[0077]

[0078] (2) Under nitrogen protection, potassium hydroxide (56.1 mg, 1.0 mmol), tetrabutylammonium hydrogen sulfate (8.5 mg) were added into dimethylcatechol (69.1 mg, 0.5 mmol) in tetrahydrofuran solution 10 mL at 0℃ for 30 min. Subsequently, triethylene glycol difluorosulfonyl ester solution (1.0 mmol) was added, and the reaction was completed after refluxing for 3 h. The reaction solution was extracted with dichloromethane for three times, washed with saturated sodium chloride aqueous solution for three times, and dried over anhydrous sodium sulfate. After removing the organic solvent by rotary evaporation, the product was obtained as a white solid (123 mg, 97%). 1H NMR (500 MHz, Chloroform-d) δ 6.78 (s, 2H), 4.17-4.13 (m, 4H), 3.86-3.78 (m, 8H), 2.19 (s, 6H).

[0079] The reaction formula is:

[0080]

[0081] Example 8

[0082] Example 8 is basically the same as Example 1, except that the organic solvent in step (2) is different, as shown in Table 1 below:

[0083] Table 1

[0084] Solvent Yield (%) THF 93 MeCN 91 DCE 95 2-MeTHF 92 DCM 96 DMSO 55 DMF 72

[0085] As can be seen from Table 1, under the same reaction conditions, the target compound can be obtained in different organic solvents, and the yield is better in the organic solvents THF, MeCN, DCE, 2-MeTHF and DCM.

[0086] Example 9

[0087] Example 9 is basically the same as Example 1, except that the catalyst in step (2) is different, as shown in Table 2 below:

[0088] Table 2

[0089]

[0090]

[0091] As can be seen from Table 2, under the same reaction conditions, the catalytic efficiency of different catalysts is similar, and the yield is also similar.

[0092] The present application uses sulfuryl fluoride or chlorofluorosulfonyl, a commonly used and economical protective reagent, to carry out the reaction, and a variety of aryl crown ether compounds can be prepared by one-pot method. The product obtained by the synthesis method has the advantages of simple operation, low cost and high yield.

[0093] It should be noted that the above examples are only used to illustrate the technical solutions of the present application but not limit the present application. Although the present application is described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or equivalently replaced, without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. A method for one-pot preparation of aryl crown ether compounds, characterized by: Comprising, a polyglycol is reacted with thionyl fluoride or chlorosulfonic fluoride in the presence of a base A in an organic solvent A to obtain a polyglycol difluorosulfonate of formula I; wherein n = 1-5; a dihydroxy aryl compound is reacted with the polyglycol difluorosulfonate of formula I in the presence of a catalyst and a base B in an organic solvent B to obtain an aryl crown ether compound; the dihydroxy aryl compound is selected from one of the following compounds: the aryl crown ether compound is one of the following compounds: the base A is selected from one of triethylamine, cesium carbonate, diisopropylethylamine; the polyglycol is any one of diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol; the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride; the base B is selected from one of sodium hydroxide, sodium hydride, potassium carbonate.

2. The method of claim 1, wherein the aryl crown ether compound is prepared in one pot. The molar ratio of the polyglycol to the base A is 1:1-20.

3. The method of one-pot preparation of aryl crown ether compound according to claim 1 or 2, characterized in that: The organic solvent A is one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl pyrrolidone, methyl tert-butyl ether, and chloroform.

4. The method of claim 3, wherein the one-pot preparation of aryl crown ether compound is characterized by: The thionyl fluoride or chlorosulfonic fluoride is a gas, which is bubbled into a mixture of the polyglycol, the base A, and the organic solvent A, and the bubbling is stopped when the content of the glycol in the system is less than 0.3%.

5. The method of one-pot preparation of aryl crown ether compound as claimed in any one of claims 1, 2, 4, wherein: The molar ratio of the dihydroxy aryl compound to the polyglycol difluorosulfonate is 1:0.2-20.

6. The method of claim 5, wherein the one-pot preparation of aryl crown ether compound is characterized by: The amount of the catalyst added is 1-50 mol% of the dihydroxy aryl compound.

7. The method for preparing aryl crown ether compounds in a one-pot process according to any one of claims 1, 2, 4, and 6, characterized in that: The amount of the base B added is 100-2000 mol% of the polyglycol difluorosulfonate.

8. The method of claim 7, wherein the aryl crown ether compound is prepared in one pot. The organic solvent B is one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1,4-dioxane, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl pyrrolidone, methyl tert-butyl ether, and chloroform.

9. The one-pot method for preparing aryl crown ether compound according to any one of claims 1, 2, 4, 6, 8, characterized in that: The reaction is carried out at a temperature of -10-100°C for 1-24 hours.

10. The method of claim 9, wherein the one-pot preparation of aryl crown ether compound is characterized by: The reaction product, the aryl crown ether compound, is further purified.

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