A method for electrochemically preparing alpha-hydroxy ketones using methanol as an oxygen source

Abstract

The present application mixes ketone compounds and electrolyte, under the action of direct current electrolysis, halogen negative ions are oxidized into halogen radicals by anodic oxidation, as active substance, hydrogen atom transfer occurs in alpha position of ketone compounds, then reacts with another molecule of halogen, alpha-halogenated ketone compound intermediates are generated, meanwhile, methanol is hydrogenated at cathode to obtain methoxy negative ions with strong nucleophilicity, the alpha-halogenated ketone compound intermediates are subjected to nucleophilic attack, finally, the target compound is obtained by removing methyl under the action of protons. The present application adopts electrochemical method, avoiding the use of toxic cyanide, oxidant and transition metal catalyst. Meanwhile, when deuterated methanol is used as reaction solvent, alpha-deuterated hydroxy ketone compounds can be selectively generated. The operation is simple, the reaction is controllable, and most importantly, the method can better realize reaction amplification under the condition of increasing current, and has potential application value.

Description

Technical Field

[0001] The present 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, present in numerous biologically active compounds and synthetic drugs, and serve as key intermediates in the synthesis of numerous important molecules. Furthermore, they have a wide range of applications in luminescent materials. Although the earliest method for synthesizing these compounds was the benzoin condensation reaction, this reaction inevitably requires the use of highly toxic cyanide as a catalyst, raising safety concerns. Consequently, efforts have been underway to find simpler and safer methods for synthesizing α-hydroxyketones.

[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 increasingly mature. In these reactions, expensive metal catalysts, oxidants and reducing agents 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 garnered significant attention in organic synthesis due to its simple reaction conditions and the absence of additional oxidants and reducing agents. Recently, Qiu et al. achieved the dihydroxylation of activated alkenes using electrochemical oxidation with water as the oxygen source. Xu et al. reported the electrochemical C-H hydroxylation of aromatic groups in a continuous flow process. However, to our knowledge, the electrochemical α-hydroxylation of ketones without the involvement of oxidants and reducing agents has not yet been reported. Methanol, as an inexpensive, commodity chemical, is ubiquitous in chemical synthesis. Its most common use is as a reaction solvent. With the rise of green chemistry in recent years, methanol has been widely used as an excellent C1 source in organic synthesis. However, research on methanol as an independent oxygen source for the hydroxylation of compounds has remained largely unexplored. Therefore, the electrochemical α-hydroxylation of ketones using methanol as an oxygen source holds great promise. Based on this, this patent report addresses the selective synthesis of α-hydroxyketones and α-deuterated hydroxyketones, boasting a range of advantages, including broad substrate compatibility, short reaction times, simple, green reaction conditions, and ease of scale-up. Summary of the Invention

[0005] To this end, the present invention provides a method for electrochemically preparing α-hydroxy ketones using methanol as an oxygen source. Aromatic ketones containing different substituents, an electrolyte, and a base are added to a reaction tube, and electrodes are inserted. The reaction is evacuated more than twice under a nitrogen atmosphere. Finally, the 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 an α-hydroxy ketone compound.

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

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

[0008] Furthermore, the electrode materials use carbon rods and platinum sheets as anodes, and nickel sheets and platinum sheets as cathodes.

[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 with a volume ratio of petroleum ether: ethyl acetate = 5:1 is used as an eluent for elution.

[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 present invention has the beneficial effects of utilizing an electrochemical method, avoiding the use of expensive metal catalysts and redox agents, and achieving product formation with a relatively short reaction time. Furthermore, in the presence of deuterated methanol, α-deuterated hydroxyketone compounds can be selectively generated. The method is simple to operate, the reaction is controllable, and most importantly, it can be scaled up even with increased current, demonstrating its potential for application. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This 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 radicals, which undergo a hydrogen atom transfer reaction with substrate 1a to produce intermediate I and a molecule of hydrogen bromide. Intermediate I further reacts with bromine radicals to produce intermediate 3a. Simultaneously, methanol is reduced at the cathode, releasing hydrogen and forming a methoxyl anion (MeO-). Subsequently, the methoxyl anion acts as a nucleophile to attack intermediate 3a to produce intermediate 3b. Intermediate 3b then undergoes a demethylation reaction in the presence of hydrogen bromide, resulting in the removal of methyl bromide to produce 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 with reference to the embodiments.

[0023] Example 1

[0024] synthesis

[0025]

[0026] (1) 1-(p-Tolyl)propan-1-one (0.3 mmol, 44.4 mg), 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.

[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 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), 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.

[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 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), 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.

[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 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-PhenyIbutan-1-one (0.3 mmol, 44.4 mg), 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.

[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 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), 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.

[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 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), 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.

[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), 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.

[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), 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.

[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 solutions provided by the present invention are described in detail above. For those skilled in the art, according to the ideas of the embodiments of the present invention, there may be changes in the specific implementation methods and application scopes. In summary, the contents 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: A ketone compound and an electrolyte are mixed, and then methanol provides an oxygen source under the action of direct current electrolysis to synthesize an α-hydroxy ketone compound. Specifically, an aromatic ketone containing different substituents, an electrolyte, and a base are added to a reaction tube, and an electrode is inserted. The gas is evacuated more than twice under a nitrogen atmosphere, and finally, methanol as a reaction solvent 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 an α-hydroxy ketone compound. The electrolyte is a mixture of one or both of tetrabutylammonium bromide and tetraethylammonium bromide in any proportion; the other solvent is a mixture of one or both of N,N-dimethylformamide and acetonitrile in any proportion; and the electrolysis current is 10 to 80 mA.

2. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1, characterized in that: The methanol is replaced by deuterated methanol.

3. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1 or 2, characterized in that: The base is sodium carbonate.

4. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1 or 2, characterized in that: The electrode materials use carbon rods and platinum sheets as anodes, and nickel sheets and platinum sheets as cathodes.

5. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1 or 2, characterized in that: The electrolysis time is more than 2 h.

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

5.

7. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1 or 2, characterized in that: The post-treatment comprises the following steps: adding pure water to the reaction system to quench the reaction, followed by extraction with ethyl acetate, concentrating the organic layer, performing column chromatography, and using a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1 as an eluent for elution.

8. The method for electrochemically preparing α-hydroxyketone using methanol as an oxygen source according to claim 1 or 2, 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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