Electrochemical synthesis method of phthalide and its derivatives based on oxidative dehydrogenation

Abstract

The invention discloses an electrochemical synthesis method for synthesizing phthalide and its derivatives based on oxidative dehydrogenation, and relates to the technical field of chemical synthesis. First, o-methylbenzoic acid or its derivative (I) is added to a reaction container, and then an electrolyte and a solvent are added respectively, and then the mixed solution is subjected to a constant current electrolysis reaction at room temperature to obtain phthalide or its derivative (II). The invention does not require the use of a catalyst and a chemical oxidant, and has the significant advantage of low reaction cost; directly using cheap and readily available o-methylbenzoic acid or its derivative as a starting material, eliminating the substrate pre-activation step, and compared with the previous synthesis method, it has significant atomic economy and step economy; using clean electric current as a "traceless" oxidant to replace flammable, explosive, toxic and harmful chemical strong oxidizing agents, greatly improving the safety of the process, reducing the "three wastes" emissions of the process, and meeting the era background of green synthesis and safe production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to an electrochemical synthesis method for synthesizing phthalide and its derivatives based on oxidative dehydrogenation. Background Art

[0002] Phthalide and its derivatives are important intermediates in organic synthesis and fine chemical synthesis, and have a wide range of synthetic uses. In addition, phthalide is also an important structural unit of some drug molecules. Among the numerous phthalide synthesis methods, the synthesis of phthalide by intramolecular oxidative esterification of o-methylbenzoic acid (I) has received special attention, mainly because this type of method does not require pre-activation of the methyl group and has good step economy and atom economy. At present, the commonly used oxidants in this type of method are the following: NaBrO3, high-valent iodine reagents, or persulfates. Although these chemical oxidants can well promote the formation of phthalide and its analogs, the disadvantages are also obvious: first, the use of chemically equivalent toxic and harmful chemical oxidants will inevitably lead to a large amount of "three wastes" emissions, which is not in line with the era of green synthesis; second, high-valent iodine reagents are expensive, and the explosive properties of chemical strong oxidants increase the unsafe factors of the process.

[0003] From a theoretical analysis, using clean electric current as a "traceless" oxidant to replace flammable, explosive, toxic and harmful chemical strong oxidants will significantly reduce the emission of "three wastes" in the process and improve the safety factor of the process. Literature search found that there is currently only one patent technology involving electrochemical synthesis of phthalide derivatives (CN201710968083.7), but this technology can only obtain phthalide with a substituent at the C3 position and cannot directly synthesize phthalide.

[0004] In view of the important uses of phthalide in organic synthesis and medicinal chemistry, as well as the era of green synthesis, the efficient synthesis of phthalide and its derivatives by dehydrogenation and oxidation of o-toluic acid or its derivatives using electric current as a "traceless" oxidant without the participation of external redox reagents has important research significance and application value. However, there are currently no corresponding reports on this type of technology. Summary of the invention

[0005] The present invention aims to provide an electrochemical synthesis method for synthesizing phthalide and its derivatives based on oxidative dehydrogenation, and achieves the purpose of preparing phthalide and its derivatives efficiently and greenly without adding external chemical redox reagents by utilizing constant current electrolysis as a key technology.

[0006] In order to solve the above technical problems, the present invention is achieved through the following technical solutions:

[0007] The present invention is an electrochemical synthesis method for synthesizing phthalide and its derivatives based on oxidative dehydrogenation, comprising the following steps:

[0008] (1) adding o-toluic acid or its derivative (I) into a reaction container, and then adding an electrolyte and an organic solvent respectively, and stirring to obtain a mixed solution A;

[0009] (2) placing the mixed solution A in an electrolysis device for electrolysis reaction, maintaining constant current electrolysis for 6 hours, continuously stirring the mixed solution A during the electrolysis reaction, and controlling the temperature of the reaction system at 25° C., and obtaining a mixed solution B after the electrolysis reaction is completed;

[0010] (3) The mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction;

[0011] (4) The solution obtained by extraction is dried and distilled under reduced pressure to remove the remaining organic solvent, and finally separated and purified by column chromatography to obtain phthalide or its derivative product (II).

[0012] As a preferred technical solution of the present invention, the group R in the o-toluic acid or its derivative (I) can be selected from any one of hydrogen, methyl, ethyl, butyl, fluorine, chlorine, bromine and trifluoromethyl; the position of the group R in the o-toluic acid or its derivative (I) on the benzene ring can be selected from any one of the ortho position, meta position and para position of the carboxylic acid.

[0013] As a preferred technical solution of the present invention, the organic solvent is a mixed solution of 1,2-dichloroethane and hexafluoroisopropanol, and the volume ratio of 1,2-dichloroethane to hexafluoroisopropanol in the mixed solution is 1:1-7:1, preferably 3:1; the amount of 1,2-dichloroethane and hexafluoroisopropanol in the mixed solution A is such that the molar concentration of o-toluic acid or its derivative (I) in the organic solvent is 0.05-0.2 mol / L, preferably 0.075 mol / L.

[0014] As a preferred technical solution of the present invention, the electrolyte is selected from any one of tetraethylammonium perchlorate (Et4NClO4) and tetrabutylammonium perchlorate (n-Bu4NClO4), preferably tetraethylammonium perchlorate.

[0015] As a preferred technical solution of the present invention, the current density during the electrolysis reaction is 3-6 mA / cm2, preferably 4 mA / cm 2 .

[0016] As a preferred technical solution of the present invention, the anode material of the electrolysis device is graphite, and the cathode material is foamed nickel.

[0017] As a preferred technical solution of the present invention, the molar ratio of o-toluic acid or its derivative (I) to the electrolyte in the mixed solution A is 1:0.5-2, preferably 1:1.

[0018] The present invention has the following beneficial effects:

[0019] 1. The present invention does not require the use of catalysts and chemical oxidants when synthesizing phthalide and its derivatives, and has the significant advantage of low reaction cost.

[0020] 2. The synthesis method of phthalide and its derivatives in the present invention directly uses cheap and readily available o-toluic acid as a starting material, eliminating the substrate pre-activation step. Compared with the previous synthesis method, it has significant atom economy and step economy.

[0021] 3. The synthesis method of phthalide and its derivatives in the present invention uses clean electric current as a "traceless" oxidant to replace flammable, explosive, toxic and harmful chemical strong oxidizing agents, thereby improving the safety of the process and minimizing the emission of "three wastes", which is in line with the era background of green synthesis and safe production.

[0022] Of course, any product implementing the present invention does not necessarily need to achieve all of the advantages described above at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0024] Figure 1 The figure is a reaction flow chart of the electrochemical synthesis method of phthalide and its derivatives based on oxidative dehydrogenation. DETAILED DESCRIPTION

[0025] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments 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 creative work are within the scope of protection of the present invention.

[0026] Example 1: Electrochemical synthesis of II-1

[0027] The raw materials 2-methylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container and stirred to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally phthalide (II) was separated and purified by column chromatography. The target product can be named II-1, and its yield is 67%.

[0028]

[0029] Example 2: Electrochemical synthesis of II-1 (changing current density)

[0030] The raw materials 2-methylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container and stirred to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 6 mA / cm 2 After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally phthalide (II) was separated and purified by column chromatography. The target product can be named II-1, and its yield is 51%.

[0031]

[0032] Example 3: Electrochemical synthesis of II-1 (changing current density)

[0033] The raw materials 2-methylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 3 mA / cm 2After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally phthalide (II) was separated and purified by column chromatography. The target product can be named II-1, and its yield is 55%.

[0034]

[0035] Example 4: Electrochemical synthesis of II-1 (changing the ratio of mixed solvent)

[0036] The raw materials 2-methylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (2 mL) and hexafluoroisopropanol (2 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally phthalide (II) was separated and purified by column chromatography. The target product can be named II-1, and its yield is 32%.

[0037]

[0038] Example 5: Electrochemical synthesis of II-1 (changing the ratio of mixed solvent)

[0039] The raw materials 2-methylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3.5 mL) and hexafluoroisopropanol (0.5 mL) were added to the reaction container and stirred to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally phthalide (II) was separated and purified by column chromatography. The target product can be named II-1, and its yield is 41%.

[0040]

[0041] Example 6: Electrochemical synthesis of II-1 (changing the electrolyte)

[0042] The raw materials 2-methylbenzoic acid (0.3 mmol), n-Bu4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 ° C and the current density was 4 mA / cm 2 After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally phthalide (II) was separated and purified by column chromatography. The target product can be named II-1, and its yield is 61%.

[0043]

[0044] Example 7: Electrochemical synthesis of II-2

[0045] The raw materials 2,3-dimethylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis, a mixed solution B was obtained. Subsequently, the mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction. The extracted solution was dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-2, and its yield is 37%.

[0046]

[0047] Example 8: Electrochemical synthesis of II-3

[0048] The raw materials 2,4-dimethylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-3, and its yield is 66%.

[0049]

[0050] Example 9: Electrochemical Synthesis of II-4

[0051] The raw materials 2-methyl-4-fluorobenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-4, and its yield is 65%.

[0052]

[0053] Example 10: Electrochemical synthesis of II-5

[0054] The raw materials 2-methyl-4-chlorobenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-5, and its yield is 63%.

[0055]

[0056] Example 11: Electrochemical synthesis of II-6

[0057] The raw materials 2-methyl-4-bromobenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-6, and its yield is 63%.

[0058]

[0059] Example 12: Electrochemical synthesis of II-7

[0060] The raw materials 2-methyl-4-ethylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container respectively, and stirred evenly to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-7, and its yield is 59%.

[0061]

[0062] Example 13: Electrochemical synthesis of II-8

[0063] The raw materials 2-methyl-4-butylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container and stirred to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-8, and its yield is 54%.

[0064]

[0065] Example 14: Electrochemical Synthesis of II-9

[0066] The raw materials 2-methyl-5-trifluoromethylbenzoic acid (0.3 mmol), Et4NClO4 (0.3 mmol), 1,2-dichloroethane (3 mL) and hexafluoroisopropanol (1 mL) were added to the reaction container and stirred to obtain a mixed solution A. Then, the mixed solution A was electrolyzed in a constant current mode for 6 hours, with graphite as the anode and nickel foam as the cathode, and the reaction system temperature was controlled at 25 °C and the current density was 4 mA / cm 2 After the electrolysis is completed, a mixed solution B is obtained. Subsequently, the mixed solution B is transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution is added and stirred evenly, and then 60 mL of dichloromethane is added for extraction. The extracted solution is dried and distilled under reduced pressure to remove the remaining dichloromethane, and finally separated and purified by column chromatography to obtain a phthalide derivative (II). The target product can be named II-9, and its yield is 40%.

[0067]

[0068] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0069] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. An electrochemical synthesis method for synthesizing phthalide and its derivatives based on oxidative dehydrogenation, characterized in that: The steps include: (1) adding o-toluic acid or its derivative (I) into a reaction container, and then adding an electrolyte and an organic solvent respectively, and stirring to obtain a mixed solution A; (2) placing the mixed solution A in an electrolysis device for electrolysis reaction, maintaining constant current electrolysis for 6 h, continuously stirring the mixed solution A during the electrolysis reaction, and controlling the temperature of the reaction system at 25 o C, after the electrolysis reaction is completed, a mixed solution B is obtained; (3) The mixed solution B was transferred to a separatory funnel, 20 mL of sodium chloride aqueous solution was added and stirred evenly, and then 60 mL of dichloromethane was added for extraction; (4) drying the solution obtained by extraction and distilling under reduced pressure to remove the remaining organic solvent, and finally separating and purifying by column chromatography to obtain phthalide or its derivative product (II); The structural formula of the o-toluic acid or its derivative (I) is , wherein the group R is selected from any one of hydrogen, methyl, ethyl, butyl, fluorine, chlorine, bromine and trifluoromethyl; the position of the group R on the benzene ring is selected from any one of the ortho position, meta position and para position of the carboxylic acid; The organic solvent is a mixed solution of 1,2-dichloroethane and hexafluoroisopropanol, wherein the volume ratio of 1,2-dichloroethane to hexafluoroisopropanol in the mixed solution is 1:1-7:1; The electrolyte is selected from tetraethylammonium perchlorate and tetrabutylammonium perchlorate; the current density during the electrolysis reaction is 3-6 mA / cm 2 ; The molar ratio of o-toluic acid or its derivative (I) to electrolyte in the mixed solution A is 1:0.5-2; the amount of 1,2-dichloroethane and hexafluoroisopropanol in the mixed solution A is such that the molar concentration of o-toluic acid or its derivative (I) in the organic solvent is 0.05-0.2 mol / L.

2. The electrochemical synthesis method for synthesizing phthalide and its derivatives based on oxidative dehydrogenation according to claim 1, characterized in that: The anode material of the electrolysis device is graphite, and the cathode material is nickel foam.

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