A method for electrochemically synthesizing methylene quinone compounds

Abstract

The present invention relates to a method for the electrochemical synthesis of methylene quinone compounds, comprising reacting an aldehyde-substituted ring A compound, a phenol derivative, and a secondary amine under electrolytic conditions. The present invention utilizes a one-pot electrochemical oxidation process to synthesize methylene quinone compounds, resulting in high yields, simple operation, low production costs, and an environmentally friendly synthesis route with potential for large-scale industrial production. In a preferred embodiment of the present invention, a piperidine derivative is used as the secondary amine catalyst, significantly reducing the catalyst dosage. When preparing methylene quinone compounds using the electrolytic method, the yield is significantly improved compared to conventional heating methods when ring A is a heteroaromatic ring.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing methylene quinone compounds, and in particular to a method for electrochemically synthesizing methylene quinone compounds. Background Art

[0002] Quinone methide compounds, due to their high activity, are widely used in organic synthesis. Quinone methide compounds belong to the third generation of polymerization inhibitors, characterized by low toxicity and environmental friendliness. Quinone methide compounds exhibit excellent antioxidant and polymerization inhibition properties and can be used to inhibit the polymerization of styrene and acrylic compounds. They are the main component of a new generation of green compound polymerization inhibitors.

[0003] Among the numerous methods for synthesizing methylene quinone compounds, the Mannich method is relatively the most practical. However, it also has some drawbacks. First, the catalysts are generally toxic and expensive, making them environmentally unfriendly. The exothermic reaction process results in energy loss, and the reactants volatilize and emit an unpleasant odor. Second, the reaction process is complex and requires strict control of reaction temperature and time. Therefore, it is particularly important to make the reaction process environmentally friendly and save manpower and material resources.

[0004] Certain progress has been made in the synthesis of new polymerization inhibitor quinone methylene compounds. However, traditional preparation methods mostly use the Mannich reaction with hot reflux, which causes raw material loss and energy and heat loss. In addition, a water-carrying agent is required to remove the water generated during the reaction. The process operation is complicated and requires strict control of reaction temperature and time.

[0005] CN116410073A discloses a method for preparing methylenequinone compounds by deamination using a Mannich base. The method involves reacting an amino acid with a Mannich base. The organic amine on the Mannich base reacts with the amino acid to form a water-soluble amide compound. Because the amino acid has a hydrophilic group, the resulting amide can be easily separated from the reaction system by washing with water. The reaction conditions are mild, and selectivity is good. Furthermore, the byproduct amide can be recovered and used as an organic synthesis intermediate. However, the recovery and treatment of the byproduct still introduces unnecessary steps into the reaction, significantly increasing production costs, especially during scale-up.

[0006] The inventors' previous patent CN114656348A discloses an improved method for preparing methylenequinone compounds. This involves reacting an aldehyde-substituted Ring A compound with a phenol derivative in the presence of a piperidine derivative. This method improves upon the conventional practice of using a large amount of a secondary amine catalyst. This patent successfully completes the reaction using only a catalytic amount of a piperidine derivative. However, the inventors discovered that the catalytic efficiency for heteroaromatic aldehyde compounds is low, resulting in low yields. Summary of the Invention

[0007] To address the high energy consumption and complex operations associated with existing preparations of methylene quinone compounds, the present invention provides a method for synthesizing methylene quinone compounds through electrochemical oxidation using a one-pot electrolysis process. By adjusting the reactant dosages, solvent selection, electrolyte selection, and electrolysis conditions, the reaction is simplified, energy loss is reduced, and environmental friendliness and yield are improved. Furthermore, the inventors unexpectedly discovered that the use of electrolysis can significantly improve the low yield of heteroaromatic ring-containing aldehyde compounds encountered in conventional heating methods.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0009] A method for electrochemically synthesizing methylene quinone compounds, comprising reacting an aldehyde-substituted ring A compound, a phenol derivative, and a secondary amine under electrolytic conditions. The synthesis route is as follows:

[0010]

[0011] Ring A is an aryl group or a heteroaryl group, and R1 is independently selected from a C1-6 alkyl group; the electrolysis is carried out in a mixed solution of an aqueous solution of an inorganic salt and an organic solvent miscible with water, with a current of 10-1000 mA and an electrolysis time of 5-20 h.

[0012] Furthermore, ring A is at least one of phenyl, naphthyl, anthracenyl, benzanthryl, phenanthryl, pyrenyl, peryl, biphenyl, spirobifluorenyl, thienyl, furyl, nitrophenyl, pyrimidinyl, benzofuranyl, indolyl, isoindolyl, carbazolyl, pyridinyl, quinolyl, isoquinolyl, pyrazolyl, indazolyl, benzopyrimidinyl, quinoxalinyl, pyrazinyl, phenazinyl, phenothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl.

[0013] Preferably, Ring A is a heteroaromatic ring, such as thiophene-2-carboxaldehyde or furfural. The inventors unexpectedly discovered that electrolysis can significantly improve the yield of methylene quinone compounds. Conventional heating methods, however, often yield lower yields when preparing products in which Ring A is a heteroaromatic ring.

[0014] The C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0015] Furthermore, the synthesis method includes the following steps: adding an aldehyde-substituted ring A compound, a phenol derivative, and a secondary amine to a mixed solution containing an aqueous solution of an inorganic salt and an organic solvent miscible with water, and electrolyzing the solution in an electrolytic cell to obtain a product, a methylene quinone compound.

[0016] Furthermore, the inorganic salt concentration in the aqueous solution of the inorganic salt is 0.01 mol / L, and the inorganic salt is selected from at least one of halogen salts, bicarbonates, nitrates, and sulfates; specifically includes at least one of ammonium chloride, sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate, sodium sulfate, and potassium sulfate; the organic solvent is selected from at least one of acetonitrile, ethanol, methanol, propylene glycol, ethylene glycol, dimethylformamide, and dimethyl sulfoxide.

[0017] Furthermore, in the mixed solution, the volume ratio of the aqueous solution of the inorganic salt to the organic solvent is 3-5:7-10.

[0018] Furthermore, the cathode of the electrolysis is selected from one of a zinc sheet, a platinum sheet, and an iron sheet; the anode is selected from one of a graphite sheet and a platinum sheet; the electrolysis current is 10-1000 mA, preferably 50-500 mA, more preferably 100-200 mA; and the electrolysis time is 10-20 hours. Preferably, the electrolysis conditions are such that the current increases linearly with the extension of the reaction time, or a stepwise reaction can be performed, first reacting at a low current condition (30-50 mA) for 4-6 hours, and then continuing the reaction at a high current condition (100-200 mA) for 10-15 hours. The purpose of increasing the current is to improve the reaction efficiency.

[0019] Furthermore, the molar ratio of the aldehyde-substituted ring A compound to the phenol derivative is 0.9-1.3:1, preferably 1-1.1:1. Furthermore, the mass volume ratio of the aldehyde-substituted ring A compound to the mixed solution is 5-10 g:100 mL.

[0020] Preferably, before electrolysis, a redox medium such as TEMPO, Fe 2+ 、Fe 3+ 、Co 2+ 、Co 3+ The amount of the redox mediator added is 1-10%, preferably 5-10%, of the molar amount of the phenol derivative. Adding a small amount of the redox mediator can further improve the yield.

[0021] Furthermore, the secondary amine is selected from at least one of diethylamine, dibutylamine, diisopropylamine, piperidine derivatives, pyrrolidine, and morpholine, preferably a piperidine derivative; the structural formula of the piperidine derivative is Wherein R3 is independently selected from at least one of H, C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-C6 ester, nitro, hydroxyl, halogen atom, and C1-4 alkoxy; provided that R3 cannot all be H.

[0022] Furthermore, the C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl; the C2-6 alkenyl group is selected from ethenyl, propenyl, and butenyl; the C2-6 alkynyl group is selected from ethynyl, propynyl, and butynyl; the C1-4 alkoxy group is selected from methoxy, ethoxy, propoxy, and butoxy; and the C2-C6 ester group is selected from methyl formate, methyl acetate, ethyl formate, and ethyl acetate. Preferably, the piperidine derivative is at least one of an alkyl-substituted piperidine, an alkoxy-substituted piperidine, and an ester-substituted piperidine, and examples thereof include at least one of 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, 2,3-dimethylpiperidine, 2,4-dimethylpiperidine, 3,5-dimethylpiperidine, methyl 3-piperidinecarboxylate, and ethyl 3-piperidinecarboxylate.

[0023] Furthermore, when the secondary amine is a piperidine derivative, the amount used is 5-10% of the molar amount of the phenol derivative; when the secondary amine is an amine other than a piperidine derivative, the amount used is 40-60%, such as 50%, of the molar amount of the phenol derivative. The inventors have found that when the secondary amine is a piperidine derivative, a satisfactory yield can be achieved by significantly reducing the amount of the piperidine derivative used.

[0024] The reaction mechanism of the present synthesis involves a phenol derivative serving as a model substrate, which is oxidized and deprotonated at the anode. Amines then undergo nucleophilic addition to the substrate, forming an iminium ion intermediate through dehydration and deprotonation. The iminium ion then acts as an electrophilic reagent to attack the aldehyde-substituted ring A of the compound containing an active hydrogen, resulting in the loss of a proton, thereby yielding the desired Mannich product. The present synthesis method does not require conventional heating conditions and is environmentally friendly. Furthermore, when ring A is a heteroaromatic ring, the yield is significantly improved.

[0025] Furthermore, in the preparation method of the methylene quinone compound, the reactants, catalyst, electrolyte and solvent are added together into a container, a potentiostat is connected, a suitable cathode and anode are selected, the potentiostat parameters are adjusted to a constant current of 30-50 mA, and after reacting for 4-6 hours, the parameters are adjusted to a constant current of 100-200 mA, and the reaction is continued for 10-15 hours. The solid and liquid phases are separated by filtration, and the liquid phase is extracted and then distilled under reduced pressure, and silica gel column chromatography is performed to obtain the product methylene quinone compound.

[0026] Compared with the prior art, the present invention has achieved at least the following beneficial technical effects:

[0027] 1. The present invention adopts a one-pot electrochemical oxidation method to synthesize methylene quinone compounds, which has a considerable yield, simple operation, low production cost, and is green and environmentally friendly. It is an environmentally friendly synthesis route and is expected to achieve large-scale industrial production.

[0028] 2. In the preferred technical solution of the present invention, piperidine derivatives are used as secondary amine catalysts, and the amount of catalyst used is significantly reduced.

[0029] 3. When preparing methylene quinone compounds by the electrolysis method of the present invention, when ring A is a heteroaromatic ring, the yield will be significantly improved compared with the traditional heating method. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The product obtained in Example 3 1 H-NMR spectrum.

[0031] Figure 2 The product obtained in Example 9 1 H-NMR spectrum.

[0032] Figure 3 The product obtained in Example 10 1 H-NMR spectrum.

[0033] Figure 4 The product obtained in Example 11 1 H-NMR spectrum. DETAILED DESCRIPTION

[0034] The present application will be further described below through examples.

[0035] Example 1

[0036]

[0037] 5.83g (0.055mol) of benzaldehyde, 9.90g (0.048mol) of 2,6-di-tert-butylphenol, 1.75g ​​(0.024mol) of diethylamine, 30ml of a 0.01mol / L KHCO3 solution, and 70ml of acetonitrile were added to a 150ml electrolytic reaction cell. A graphite anode and a zinc cathode were inserted. A potentiostat was connected and the current was adjusted to 50mA. The reaction was allowed to proceed for 4-6h, monitored by TLC. The current was then gradually increased to 100mA and the reaction continued for approximately 15h. The crude product was extracted with dichloromethane, distilled under reduced pressure, and chromatographed on a silica gel column to yield 10.26g of a yellow solid product with a purity of 97.3% and a yield of 81.4%.

[0038] Example 2

[0039] The other conditions were the same as those in Example 1. The difference was that diethylamine was replaced with an equimolar amount of dibutylamine. The product of Example 2 had a purity of 96.8% and a yield of 78.5%.

[0040] Example 3

[0041] The other conditions were the same as those in Example 1. The difference was that diethylamine was replaced with 2.4 mmol of 2-methylpiperidine. The purity of the product in Example 3 was 98.2% and the yield was 80.3%. 1 H-NMR (CDCl3) Figure 1 As shown, the structure of the obtained product is proved to be correct.

[0042] Example 4

[0043] The other conditions were the same as those in Example 1, except that diethylamine was replaced with an equal molar amount of morpholine. The product of Example 4 had a purity of 96.2% and a yield of 75.6%.

[0044] Example 5

[0045] The other conditions were the same as those in Example 1. The difference was that diethylamine was replaced with 2.4 mmol of methyl 3-piperidinate. The product of Example 5 had a purity of 98.4% and a yield of 81.5%.

[0046] Example 6

[0047] The other conditions were the same as those in Example 1. The difference was that the electrolysis was performed at 100 mA for 20 h. The purity of the product in Example 6 was 96.0% and the yield was 79.1%.

[0048] Example 7

[0049] Other conditions were the same as those in Example 1, except that 0.75 g of TEMPO (0.0048 mol) as a redox medium was added to the reaction system. The final product had a purity of 97.6% and a yield of 83.2%.

[0050] Example 8

[0051]

[0052] Other conditions were the same as those in Example 3, except that the ring A compound was terephthalaldehyde. The final product had a purity of 97.2% and a yield of 70.6%. 1 H-NMR spectrum Figure 2 As shown, the structure of the obtained product is proved to be correct.

[0053] Example 9

[0054]

[0055] Other conditions are the same as those in Example 3. The difference is that the ring A compound is p-methoxybenzaldehyde. The final product has a purity of 96.6% and a yield of 81.6%. 1 H-NMR (CDCl3) Figure 3 As shown, the structure of the obtained product is proved to be correct.

[0056] Example 10

[0057]

[0058] The other conditions were the same as those in Example 3. The difference was that the compound in ring A was thiophene-2-carboxaldehyde. The final product had a purity of 98.5% and a yield of 85.3%. 1 H-NMR (CDCl3) Figure 4 As shown, the structure of the obtained product is proved to be correct.

[0059] Example 11

[0060]

[0061] Other conditions were the same as in Example 3, except that the compound in Ring A was furfural. The final product had a purity of 97.4% and a yield of 88.2%.

[0062] Comparative Example 1

[0063] Other conditions were the same as those in Example 10, except that the reaction conditions were changed from electrolysis to heating. Specifically, the reactants, thiophene-2-carboxaldehyde and 2,6-di-tert-butylphenol, were added to the solvent benzene, and 2-methylpiperidine was slowly added dropwise over 2 hours. The temperature was raised to 120°C and the reaction was continued for 18 hours. The temperature was then raised to 150°C and the reaction was continued for 3 hours. The reaction was then distilled under reduced pressure. The crude product was purified by column chromatography and recrystallized from a mixed solvent of ethanol, petroleum ether, and acetonitrile in a volume ratio of 3:1:1. The product was washed to obtain the product with a purity of 98.2% and a yield of 65.3%.

[0064] Comparative Example 2

[0065] Other conditions were the same as in Example 1, except that the reaction conditions were changed from electrolysis to heating. Specifically, the reactants furfural and 2,6-di-tert-butylphenol were added to the solvent benzene, and 2-methylpiperidine was slowly added dropwise over 2 hours. The temperature was raised to 120°C and the reaction was allowed to proceed for 18 hours. The temperature was raised to 150°C and the reaction was continued for 3 hours. The crude product was then distilled under reduced pressure. After column chromatography, it was recrystallized from a mixed solvent of ethanol, petroleum ether, and acetonitrile in a volume ratio of 3:1:1 and washed to obtain the product. The product had a purity of 97.4% and a yield of 63.8%.

Claims

1. A method for electrochemically synthesizing methylene quinone compounds, characterized in that: The aldehyde-substituted ring A compound, a phenol derivative, and a secondary amine react under electrolytic conditions. The synthetic route is as follows: ； Ring A is an aryl group or a heteroaryl group, and R1 is independently selected from a C1-6 alkyl group; the electrolysis is carried out in a mixed solution of an inorganic salt aqueous solution and a water-miscible organic solvent, with a current of 10-1000 mA and an electrolysis time of 5-20 hours.

2. The method according to claim 1, characterized in that Ring A is at least one of phenyl, naphthyl, anthracenyl, benzanthryl, phenanthryl, pyrenyl, perylenyl, biphenyl, spirobifluorenyl, thienyl, furyl, nitrophenyl, pyrimidinyl, benzofuranyl, indolyl, isoindolyl, carbazolyl, pyridinyl, quinolyl, isoquinolyl, pyrazolyl, indazolyl, benzopyrimidinyl, quinoxalinyl, pyrazinyl, phenazinyl, phenothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl.

3. The method according to claim 1, characterized in that Ring A is a heteroaryl group.

4. The method according to claim 1, wherein The ring A compound is thiophene-2-carboxaldehyde or furfural.

5. The method according to claim 1, wherein The following steps are involved: The aldehyde-substituted ring A compound, phenol derivatives and secondary amine are added to a mixed solution containing an inorganic salt aqueous solution and an organic solvent miscible with water, and electrolyzed in an electrolytic cell to obtain a product, a methylene quinone compound.

6. The method according to claim 1, wherein The inorganic salt concentration in the aqueous solution of the inorganic salt is 0.01 mol / L, and the inorganic salt is selected from at least one of halogen salts, bicarbonates, nitrates, and sulfates; and the organic solvent is selected from at least one of acetonitrile, ethanol, methanol, propylene glycol, ethylene glycol, dimethylformamide, and dimethyl sulfoxide.

7. The method according to claim 6, characterized in that The inorganic salt is selected from at least one of ammonium chloride, sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate, sodium sulfate and potassium sulfate.

8. The method according to claim 1, characterized in that In the mixed solution, the volume ratio of the inorganic salt aqueous solution to the organic solvent is 3-5:7-10.

9. The method according to claim 1, characterized in that The cathode of electrolysis is selected from one of platinum sheet, iron sheet, zinc sheet and stainless steel sheet; the anode is selected from one of platinum sheet and graphite sheet; the electrolysis current is 10-1000mA, and the electrolysis time is 10-20h.

10. The method according to claim 9, characterized in that The current of electrolysis is 50-500mA.

11. The method according to claim 9, characterized in that The current of electrolysis is 100-200mA.

12. The method according to claim 9, characterized in that The electrolysis is first carried out under low current conditions of 30-50 mA for 4-6 hours, and then continued under high current conditions of 100-200 mA for 10-15 hours.

13. The method according to claim 1, wherein The molar ratio of the aldehyde-substituted ring A compound and the phenol derivative is 0.9-1.3:

1.

14. The method according to claim 13, characterized in that The mass volume ratio of the aldehyde-substituted ring A compound to the mixed solution is 5-10 g:100 mL.

15. The method according to claim 1, wherein Before electrolysis, a redox medium is added to the reaction system, and the amount of the redox medium added is 1-10% of the molar amount of the phenol derivative.

16. The method according to claim 15, characterized in that The redox mediator is selected from TEMPO, Fe 2+ 、Fe 3+ 、Co 2 + 、Co 3+ , CuBr2, CuI.

17. The method according to claim 15, characterized in that The amount of the redox mediator added is 5-10% of the molar amount of the phenol derivative.

18. The method according to claim 1, wherein The secondary amine is selected from at least one of diethylamine, dibutylamine, diisopropylamine, pyrrolidine and morpholine.

19. The method according to claim 1, wherein The secondary amine is a piperidine derivative; the structural formula of the piperidine derivative is ; Wherein R3 is independently selected from at least one of H, C1-C6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-C6 ester, nitro, hydroxyl, halogen atom, and C1-4 alkoxy; provided that R3 cannot all be H.

20. The method according to claim 19, characterized in that The C1-C6 alkyl group is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl; the C2-6 alkenyl group is selected from vinyl, propenyl, and butenyl; the C2-6 alkynyl group is selected from ethynyl, propynyl, and butynyl; the C1-4 alkoxy group is selected from methoxy, ethoxy, propoxy, and butoxy; the C2-C6 ester group is selected from methyl formate, methyl acetate, ethyl formate, and ethyl acetate.

21. The method according to claim 1, wherein The secondary amine is at least one of alkyl-substituted piperidine, alkoxy-substituted piperidine, and ester-substituted piperidine.

22. The method according to claim 1, wherein The secondary amine is selected from at least one of 2-methylpiperidine, 3-methylpiperidine, 4-methylpiperidine, 2,3-dimethylpiperidine, 2,4-dimethylpiperidine, 3,5-dimethylpiperidine, methyl 3-piperidinecarboxylate, and ethyl 3-piperidinecarboxylate.

23. The method according to claim 19, wherein The amount of the piperidine derivative is 5-10% of the molar amount of the phenol derivative.

24. The method according to claim 18, wherein The amount of the secondary amine used is 40-60% of the molar amount of the phenol derivative.

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