Method for electrochemically preparing alpha-hydroxy ketone by using methanol as oxygen source

Abstract

The preparation method comprises the following steps: mixing a ketone compound with an electrolyte, oxidizing halogen anions into halogen free radicals by virtue of anodic oxidation under the action of direct-current electrolysis, carrying out hydrogen atom transfer on the halogen free radicals serving as an active substance and an alpha site of the ketone compound, and then carrying out free reaction with another molecule of halogen to generate an alpha-halogenated ketone compound intermediate; meanwhile, methoxyl anions with strong nucleophilicity are obtained from methanol under the action of cathodic hydrogen evolution, nucleophilic attack is carried out on the alpha-haloketone compound intermediate, finally, methyl is removed under the action of protons, and a target compound is obtained. According to the invention, an electrochemical method is adopted, so that the use of highly toxic cyanide, oxidant and transition metal catalyst is avoided. Meanwhile, when the deuterated methanol is used as a reaction solvent, the alpha-deuterated hydroxy ketone compound can be selectively generated. The method is simple in operation and controllable in reaction, most importantly, the method can better realize reaction amplification under the condition of increasing current, and the method has potential application value.

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, and in particular to a method for electrochemically preparing alpha-hydroxy ketone using methanol as an oxygen source. Background Art

[0002] α-Hydroxyketones are important building blocks in organic synthesis. They are present in many biologically active compounds and synthetic drugs and are key intermediates in the synthesis of many important molecules. In addition, they are also widely used in luminescent materials. Although the earliest method for synthesizing these compounds was the benzoin condensation reaction, the reaction inevitably uses highly toxic cyanide as a catalyst, which raises safety concerns. Therefore, people have been committed to finding simpler and safer methods for synthesizing α-hydroxyketone compounds.

[0003] In recent years, with the continuous development of synthesis technology, the synthesis technology of α-hydroxyketone compounds using transition metal catalysis and photochemistry has become more mature. In these reactions, expensive metal catalysts, oxidants and reductants are often required, and the reaction time is long, which greatly limits the development of reaction types, such as Figure 1 shown.

[0004] In recent years, electrochemistry has attracted extensive attention in the field of organic synthesis because of its simple reaction conditions and the absence of additional oxidants and reductants. Recently, Qiu and colleagues used electrochemical oxidation with water as the oxygen source to achieve the dihydroxylation of activated olefins. Xu and colleagues reported the electrochemical aryl CH hydroxylation reaction in a continuous flow. However, to the best of our knowledge, the α-hydroxylation of ketones under electrochemical conditions without the involvement of oxidants and reductants has not been reported so far. Methanol, as a cheap bulk chemical, is ubiquitous in chemical synthesis. Its most common use is as a reaction solvent. In recent years, with the rise of the concept of green chemistry, methanol has been widely used as an excellent C1 source in organic synthesis. However, research on methanol as an independent oxygen source to participate in the hydroxylation reaction of compounds has not been carried out. Therefore, the use of methanol as an oxygen source to achieve the α-hydroxylation of ketones under electrochemical conditions is undoubtedly very promising. Based on this, this patent report solves the problem of selectively achieving the synthesis of α-hydroxyketones and α-deuterated hydroxyketone compounds, with a series of characteristics such as strong substrate applicability, short reaction time, simple and green reaction conditions, and easy scale-up. Summary of the invention

[0005] To this end, the present invention provides a method for electrochemically preparing α-hydroxy ketone using methanol as an oxygen source, wherein aromatic ketones containing different substituents, an electrolyte and a base are added to a reaction tube, and electrodes are inserted, and the reaction is evacuated more than twice under a nitrogen atmosphere, and finally, a reaction solvent methanol and other solvents are added to the reaction tube for electrolysis, and the reaction is quenched with water after the reaction is completed, and the product is post-treated to obtain an α-hydroxy ketone compound.

[0006] Furthermore, the methanol is replaced by deuterated methanol.

[0007] Furthermore, the electrolyte is a mixture of any proportion of one or two of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride or tetraethylammonium bromide. The electrolyte used is relatively cheap and also acts as a reaction medium in the reaction process, activating the substrate ketone compound, and generating a strongly nucleophilic methoxyl anion under the action of cathode hydrogen evolution, and then synthesizing multiple types of α-hydroxy ketone compounds through a series of subsequent reactions, avoiding the use of expensive metal catalysts and redox agents.

[0008] Furthermore, the electrode material uses a carbon rod and a platinum sheet as an anode, and a nickel sheet and a platinum sheet as a cathode.

[0009] Furthermore, the other solvent is N,N-dimethylformamide or acetonitrile, or a mixture of the two in any proportion.

[0010] Furthermore, the electrolysis current is 10-80 mA, and the electrolysis time is more than 2 hours.

[0011] Furthermore, the molar ratio of the electrolyte to the aryl ketone is aryl ketone:electrolyte=1.0:1.5.

[0012] Furthermore, the post-treatment is as follows: pure water is added to the reaction system to quench the reaction, followed by extraction with ethyl acetate, the organic layer is concentrated and subjected to column chromatography, and a mixed solution of petroleum ether and ethyl acetate in a volume ratio of petroleum ether:ethyl acetate = 5:1 is used as an eluent for elution treatment.

[0013] Furthermore, the base is sodium carbonate.

[0014] Furthermore, the molar ratio of the aryl ketone, the electrolyte and the base is aryl ketone:electrolyte:base=0.3:0.45:0.36.

[0015] The beneficial effects of the present invention are: the present invention adopts an electrochemical method, avoids the use of expensive metal catalysts and redox agents, and can achieve the generation of products in a short reaction time. At the same time, in the presence of deuterated methanol, α-deuterated hydroxyketone compounds can be selectively generated. The operation is simple, the reaction is controllable, and most importantly, this method can better achieve the amplification of the reaction under the condition of increasing the current, and has potential application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 It is a method for synthesizing α-hydroxyketone compounds in the prior art;

[0017] Figure 2 The diagram is a mechanism diagram of the reaction described in the present invention. DETAILED DESCRIPTION

[0018] The mechanism of the present invention is as follows:

[0019] Bromine anions are oxidized at the anode to form bromine free radicals, which react with substrate 1a to form intermediate I and a molecule of hydrogen bromide. Intermediate I further reacts with bromine free radicals to form intermediate 3a. At the same time, methanol is reduced at the cathode, releasing hydrogen and forming methoxy anions (MeO-). Subsequently, methoxy anions attack intermediate 3a as nucleophiles to form intermediate 3b, which then undergoes a demethylation reaction in the presence of hydrogen bromide, resulting in the removal of methyl bromide, thereby generating the final target product. The general reaction formula is as follows:

[0020]

[0021] Wherein: R represents various electron-rich and electron-deficient substituent groups, electrolyst represents tetrabutylammonium bromide, tetrabutylammonium chloride, tetraethylammonium bromide and tetrabutylammonium iodide, and solvent represents N,N-dimethylformamide or acetonitrile.

[0022] The present invention will be further described below in conjunction with the embodiments.

[0023] Example 1

[0024] synthesis

[0025]

[0026] (1) 1-(p-Tolyl)propan-1-one (0.3 mmol, 44.4 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was completed by monitoring with a TLC spot plate.

[0027] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 41 mg of the product with a yield of 83%.

[0028] 1 H NMR (400MHz, Chloroform-d) δ7.76(d,J=8.2Hz,2H),7.23(d,J=8.0Hz,2H),5.06(q,J=7.0Hz,1H),2.36(s,3H),1.37(d,J=7.0Hz,3H).

[0029] 13 C NMR (101MHz, Chloroform-d) δ202.0,145.1,130.8,129.7,128.9,69.3,22.6,21.9.

[0030] Example 2

[0031] synthesis

[0032]

[0033] (1) 1-(3-methoxyphenyl)propan-1-one (0.3 mmol, 49.2 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was monitored by TLC spot plate.

[0034] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 55.9 mg of the product with a yield of 89%.

[0035] 1H NMR(400MHz,Chloroform-d)δ7.42–7.37(m,2H),7.36–7.29(m,1H),7.11–7.06 (m,1H),5.06(q,J=7.0Hz,1H),3.79(s,3H),3.26(s,1H),1.37(d,J=7.0Hz,3H).

[0036] 13 C NMR (101MHz, Chloroform-d) δ202.4,160.0,134.7,129.9,121.2,120.4,113.1,69.5,55.6,22.5.

[0037] Example 3

[0038] synthesis

[0039]

[0040] (1) 1-(4-Fluorophenyl)propan-1-one (0.3 mmol, 45.6 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was completed by monitoring with a TLC spot plate.

[0041] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 48.3 mg of the product with a yield of 96%.

[0042] 1 H NMR (400MHz, Chloroform-d) δ7.91 (ddd, J=8.9, 5.2, 2.5Hz, 2H), 7.17–7.07 (m, 2H), 5.06 (q, J=7.0Hz, 1H), 1.38 (d, J=7.0Hz, 3H).

[0043] 13 C NMR (101MHz, Chloroform-d) δ200.9,167.6,165.0,131.5,131.5,129.8,129.8,116.4,116.2,69.3,22.4.

[0044] 19F NMR(376MHz,Chloroform-d)δ-103.1.

[0045] Example 4

[0046] synthesis

[0047]

[0048] (1) 1-Phenylbutan-1-one (0.3 mmol, 44.4 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was monitored by TLC spot plate.

[0049] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 37.8 mg of the product with a yield of 77%.

[0050] 1 H NMR(400MHz,Chloroform-d)δ7.94–7.68(m,2H),7.58–7.50(m,1H),7.42(t,J=7.7Hz,2H),4.99(dd,J=6.9,3. 8Hz, 1H), 3.25 (s, 1H), 1.88 (dqd, J=14.9, 7.5, 3.8Hz, 1H), 1.54 (dp, J=14.3, 7.2Hz, 1H), 0.87 (t, J=7.4Hz, 3H).

[0051] 13 C NMR (101MHz, Chloroform-d) δ202.2,134.0,133.9,129.0,128.6,74.1,28.9,9.0.

[0052] Example 5

[0053] synthesis

[0054]

[0055] (1) 1-Phenylundecan-1-one (0.3 mmol, 73.8 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was completed by monitoring with a TLC spot plate.

[0056] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 26.2 mg of the product with a yield of 34%.

[0057] 1 H NMR(400MHz,Chloroform-d)δ7.83(d,J=8.1Hz,2H),7.54(t,J=7.3Hz,1H),7.42(t,J=7.7Hz,2H),5.00(dd,J=7.0,3.2Hz,1H),3. 26(s,1H),1.78(tt,J=10.6,5.8Hz,1H),1.45(qq,J=10.1,6.9,5.2Hz,2H),1.21(dd,J=20.9,8.1Hz,13H),0.79(t,J=6.7Hz,3H).

[0058] 13 C NMR (101MHz, Chloroform-d) δ202.3,134.0,133.8,129.0,128.6,73.2,36.0,32.0,29.6,29.5,29.5,29.4,25.0,22.8,14.2.

[0059] Example 6

[0060] synthesis

[0061]

[0062] (1) 1-(p-Tolyl)propan-1-one (0.3 mmol, 44.4 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of deuterated methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was monitored by TLC spot plate.

[0063] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 35.9 mg of deuterated product with a yield of 72% and a deuteration rate of 89%.

[0064] 1 H NMR (400MHz, Chloroform-d) δ7.76 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 2.36 (s, 3H), 1.36 (s, 3H).

[0065] 13 C NMR(101MHz,Chloroform-d)δ201.9,145.1,130.7,129.6,128.8,22.4,21.8.HRMS(ESI)exact mass calculated for[C 10 H 11 DO2+H] + :166.0973, found 166.0983. Example 7

[0066] synthesis

[0067]

[0068] (1) 1,3-Diphenylpropan-1-one (0.3 mmol, 63.0 mg), electrolyte tetrabutylammonium bromide (0.45 mmol, 145.1 mg) and sodium carbonate (0.36 mmol, 38.2 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 2.0 mL of N,N-dimethylformamide, 2.0 mL of acetonitrile and 2.0 mL of deuterated methanol were added as reaction solvents. The reaction was carried out at a current of 10 mA for 2.5 h. The reaction was completed by monitoring with a TLC spot plate.

[0069] (2) After the reaction was completed, 5 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 41.5 mg of deuterated product with a yield of 61% and a deuteration rate of 94%.

[0070] 1H NMR(400MHz,Chloroform-d)δ7.88–7.80(m,2H),7.55(t,J=7.4Hz,1H),7.43(t,J=7.7Hz,2H ),7.20–7.12(m,3H),7.04(d,J=6.5Hz,2H),3.11(d,J=14.2Hz,1H),2.81(d,J=14.2Hz,1H).

[0071] 13 C NMR (101MHz, Chloroform-d) δ201.1,136.6,134.1,134.0,129.5,129.1,128.7,128.4,126.9,73.9,73.7,73.5,73.2,42.0.

[0072] HRMS(ESI)exact mass calculated for[C 15 H 11 DO2+K] + :226.0688,found226.0686.Example 8

[0073] Amplification Synthesis

[0074]

[0075] (1) 1-(p-Tolyl)propan-1-one (15 mmol, 2.22 g), electrolyte tetrabutylammonium bromide (22.5 mmol, 7.255 g) and sodium carbonate (18 mmol, 573 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times under a nitrogen atmosphere. Finally, 30 mL of N,N-dimethylformamide, 30 mL of acetonitrile and 30 mL of methanol were added as reaction solvents. The reaction was carried out at 80 mA for 15 h. The reaction was monitored by TLC spot plate.

[0076] (2) After the reaction was completed, 100 mL of pure water was added to quench the reaction, and then extracted three times with ethyl acetate. The reaction solution was concentrated and subjected to column chromatography to obtain 1.85 g of product with a yield of 83%.

[0077] 1 H NMR (400MHz, Chloroform-d) δ7.76(d,J=8.2Hz,2H),7.23(d,J=8.0Hz,2H),5.06(q,J=7.0Hz,1H),2.36(s,3H),1.37(d,J=7.0Hz,3H).

[0078] 13C NMR (101MHz, Chloroform-d) δ202.0,145.1,130.8,129.7,128.9,69.3,22.6,21.9.

[0079] The technical solution provided by the present invention is introduced in detail above. For those skilled in the art, according to the concept of the embodiments of the present invention, there may be changes in the specific implementation method and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source, characterized in that: The ketone compound and the electrolyte are mixed, and then under the action of direct current electrolysis, methanol provides an oxygen source to synthesize α-hydroxy ketone compounds.

2. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1, characterized in that: Aromatic ketones containing different substituents, electrolytes and bases are added to a reaction tube, and electrodes are inserted. The reaction tube is evacuated more than twice under a nitrogen atmosphere. Finally, reaction solvent methanol and other solvents are added to the reaction tube for electrolysis. After the reaction is completed, the reaction is quenched with water, and the product is post-treated to obtain α-hydroxyketone compounds.

3. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 2, characterized in that: The methanol is replaced by deuterated methanol.

4. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The electrolyte is one of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride or tetraethylammonium bromide or a mixture of two of them in any proportion; the base is sodium carbonate.

5. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The electrode materials use carbon rods and platinum sheets as anodes, and nickel sheets and platinum sheets as cathodes.

6. The method for electrochemically preparing α-hydroxy ketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The other solvent is N,N-dimethylformamide or acetonitrile, or a mixture of the two in any proportion.

7. The method for electrochemically preparing α-hydroxy ketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The electrolysis current is 10-80 mA, and the electrolysis time is more than 2 hours.

8. The method for electrochemically preparing α-hydroxy ketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The molar ratio of the electrolyte to the aryl ketone is aryl ketone:electrolyte=1.0:1.

5.

9. The method for electrochemically preparing α-hydroxy ketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The post-treatment is as follows: pure water is added to the reaction system to quench the reaction, followed by extraction with ethyl acetate, concentration of the organic layer, column chromatography, and washing with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of petroleum ether:ethyl acetate = 5:1 as an eluent.

10. The method for electrochemically preparing α-hydroxy ketone using methanol as an oxygen source according to claim 2 or 3, characterized in that: The molar ratio of the aryl ketone, the electrolyte and the base is aryl ketone:electrolyte:base=0.3:0.45:0.36.

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