A method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination

Abstract

The present invention discloses a method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination, wherein SP 3 The fluorinated compound on C is mixed with an electrolyte, and then defluorinated by the ability of cathode reduction under the action of direct current electrolysis, reducing to obtain a carbon anion, which is then attacked by carbon dioxide nucleophilically to synthesize various carboxylic acid compounds; or deuterated water is introduced while carbon dioxide nucleophilically attacks to synthesize deuterated carboxylic acid compounds. The present invention adopts a cathode electrochemical reduction method, avoiding the use of expensive photosensitizers and only requiring a short reaction time to achieve product generation. At the same time, in the presence of deuterated water, selective generation of carboxylic acid compounds substituted with different deuterium atoms can be achieved. The operation is simple, the reaction is controllable, and most importantly, this method can better achieve large-scale reaction amplification under the condition of increasing the current, with 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 synthesizing deuterated carboxylic acid compounds by electrochemical defluorination. Background Art

[0002] Since the Industrial Revolution, the burning of fossil fuels, deforestation, and other human activities have released large amounts of carbon dioxide into the atmosphere, causing serious societal problems. Consequently, scientists in various fields have proposed diverse solutions for consuming this carbon dioxide. While some might argue that CO₂ fixation in organic synthesis is unlikely to reduce atmospheric CO₂ concentrations, CO₂ is an inexpensive C₁ feedstock, significantly reducing the cost of its capture and recovery. However, due to the inherent inertness of CO₂, its introduction into organic molecules through carbon fixation presents challenges.

[0003] In recent years, with the continuous development of synthetic technology, the synthesis of carboxylic acid compounds by CO2 activation using transition metal catalysis and photochemical methods has become increasingly mature. In these reactions, expensive metal catalysts, oxidants, and reducing agents are often required. In addition, the difficulty of reducing CO2 itself greatly limits the development of reaction types.

[0004] Fluorine-containing compounds are widely present in nature. Due to the presence of fluorine, the physical and chemical properties of substances are greatly changed. In recent years, with the continuous development of synthetic methods, the synthesis and transformation of fluorine-containing compounds have received more and more attention from chemists. In the past, metal catalytic reactions were usually limited to SP 2 CX key, for SP 3 The CX key is relatively difficult, because the SP 3 The CX bond is less prone to oxidative addition and is more prone to a series of side reactions, including HX elimination to generate olefins and nucleophilic substitution reactions with nucleophiles in the presence of bases and / or nucleophiles. 3The carboxylation of CF bonds is even more difficult. It was not until 2021 that Yu Dagang's research group used the reducing property of formate radical anions to achieve the generation of a single defluorinated carboxylic acid product under light conditions. In 2023, Michael W. Meanwell's research group also used electrochemical reduction to achieve the synthesis of fluorocarboxylic acid compounds by selective single defluorination and reaction with carbon dioxide under low temperature conditions. However, the following problems still exist: the photoreaction takes a long time, is not easy to scale up, expensive photosensitizers are used, and the reaction conditions are relatively complicated. The product achieved by the electrical reaction is still the same as the product of the photoreaction, and there is no better way to convert other fluorine atoms. Based on this, this patent report solves the problem of selectively realizing the deuterated carboxylation transformation of polyfluorinated compounds, and has 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 synthesizing deuterated carboxylic acid compounds by electrochemical defluorination, wherein SP 3 The fluorinated compound on C is mixed with an electrolyte, and then defluorinated by the cathode reduction ability under the action of direct current electrolysis to obtain carbon anions, which are then attacked by carbon dioxide nucleophilically to synthesize various types of carboxylic acid compounds; or deuterated water is introduced while carbon dioxide attacks nucleophilically to synthesize deuterated carboxylic acid compounds.

[0006] Furthermore, the specific steps are: adding monofluorotoluene containing different substituents and an electrolyte into a reaction tube equipped with a stirrer, inserting an anode and a cathode, then inserting a carbon dioxide balloon to pump more than twice, and finally adding a reaction solvent into the reaction tube, electrolyzing, quenching the reaction with hydrochloric acid after the reaction is completed, and the product is post-treated to obtain a defluorocarboxylic acid compound.

[0007] Furthermore, the specific steps are: adding difluorotoluene containing different substituents or trifluorotoluene containing different substituents, and an electrolyte to a reaction tube equipped with a stirrer, inserting an anode and a cathode, and then inserting a carbon dioxide balloon to evacuate more than twice, and finally adding a reaction solvent and deuterated water to the reaction tube, electrolyzing, quenching the reaction with hydrochloric acid after the reaction is completed, and the product is post-treated to obtain a defluorinated deuterated carboxylic acid compound.

[0008] Furthermore, the electrolyte is tetrabutylammonium perchlorate, tetrabutylammonium acetate or a mixture of the two in any proportion.

[0009] Furthermore, the magnesium sheet serves as the anode and the nickel foam serves as the cathode; and the concentration of the hydrochloric acid is 2M.

[0010] Furthermore, the reaction solvent is one of N,N-dimethylacetamide or dimethyl sulfoxide.

[0011] Furthermore, the electrolysis current is 25-35 mA, and the electrolysis time is more than 2 hours.

[0012] Furthermore, the molar ratio of the electrolyte to the fluoride is fluoride:electrolyte=1.0:1.25.

[0013] Furthermore, the post-treatment is as follows: hydrochloric acid 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 = 3:1 is used as an eluent for elution.

[0014] The present invention has the beneficial effects of utilizing a cathodic electrochemical reduction method, avoiding the use of expensive photosensitizers and achieving product formation with a relatively short reaction time. Furthermore, in the presence of deuterated water, it can selectively generate carboxylic acid compounds substituted with different deuterium atoms. The operation is simple, the reaction is controllable, and most importantly, this method can achieve greater amplification of the reaction under conditions of increased current, demonstrating its potential application. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The diagram is a mechanism diagram of the reaction described in the present invention. DETAILED DESCRIPTION

[0016] The mechanism of the present invention is as follows:

[0017] At the cathode, the monofluorotoluene with different substituents obtains electrons and is reduced to free radical anions, and then the fluorine anions are removed to obtain benzylic carbon radicals, which are further reduced to carbon anions and attack carbon dioxide nucleophilically to obtain carboxylic acid anions. At the same time, the anode magnesium sheet loses electrons and becomes Mg 2+ ions. The carboxylate anions produced at the cathode are Mg 2+ The ion is stabilized and then quenched by the addition of 2 M hydrochloric acid to obtain a carboxylic acid compound. For difluoro and trifluorotoluene, multiple reductions are performed in the presence of deuterated water and carbon dioxide to obtain the deuterated carboxylic acid product.

[0018] The general reaction formula is as follows:

[0019]

[0020] Wherein: R represents various electron-rich and electron-deficient substituent groups, electrolyst represents tetrabutylammonium perchlorate, tetrabutylammonium acetate, tetraethylammonium iodide and tetraethylammonium bromide, and solvent represents N,N-dimethylacetamide or dimethyl sulfoxide.

[0021] The present invention will be further described below with reference to the embodiments.

[0022] Example 1

[0023] synthesis

[0024]

[0025] (1) In a clean 15 mL reaction tube equipped with a stirrer and an electrode, 2-(fluoromethyl)naphthalene (0.4 mmol, 64.0 mg) and tetrabutylammonium perchlorate (0.5 mmol, 171 mg) as electrolyte were added. The reaction tube was evacuated three times by inserting a balloon filled with carbon dioxide into the tube. Finally, 6.0 mL of N,N-dimethylacetamide was added as the reaction solvent. The reaction was carried out at 35 mA for 2.0 h. The reaction was monitored by TLC.

[0026] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 90%.

[0027] 1 H NMR (400 MHz, CDCl3) δ 7.88 (m, 3H), 7.79 (d, J = 3.5 Hz, 1H), 7.47(m, 3H), 3.77 (d, J = 3.6 Hz, 2H).

[0028] 13 C NMR (100 MHz, CDCl3) δ 172.9, 133.1, 132.9, 132.0, 128.1, 127.9,127.8, 127.6, 127.6, 126.3, 125.8, 41.0.

[0029] Example 2

[0030] synthesis

[0031]

[0032] (1) Ethyl 4-(fluoromethyl)benzoate (0.4 mmol, 72.8 mg) and tetrabutylammonium perchlorate (0.5 mmol, 171 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times by inserting a balloon filled with carbon dioxide. Finally, 6.0 mL of N,N-dimethylacetamide was added as the reaction solvent. The reaction was carried out at 35 mA for 2.0 h. The reaction was monitored by TLC.

[0033] (2) After the reaction, the reaction solution was concentrated and subjected to column chromatography to obtain the pure carboxylated product with a yield of 90%.

[0034] 1 H NMR (400 MHz, CDCl3) δ 7.96–7.90 (m, 2H), 7.46–7.40 (m, 2H), 4.32(q, J = 7.1 Hz, 2H), 3.70 (s, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0035] 13 C NMR (100 MHz, CDCl3) δ 172.4, 165.8, 140.8, 130.0, 129.3, 128.5,60.8, 40.8, 14.3.

[0036] Example 3

[0037] synthesis

[0038]

[0039] (1) In a clean 15 mL reaction tube equipped with a stirrer and an electrode, tert-butyl 4-(fluoromethyl)benzoate (0.4 mmol, 84.0 mg) and tetrabutylammonium perchlorate (0.5 mmol, 171 mg) as electrolyte were added. The reaction tube was evacuated three times by inserting a balloon filled with carbon dioxide into the tube. Finally, 6.0 mL of N,N-dimethylacetamide was added as the reaction solvent. The reaction was carried out at 35 mA for 2.0 h. The reaction was monitored by TLC.

[0040] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 94%.

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2Hz, 2H), 3.68 (s, 2H), 1.55 (s, 9H).

[0042] 13 C NMR (100 MHz, CDCl3) δ 172.3, 165.0, 140.4, 129.9, 129.8, 129.1,80.7, 40.7, 27.9.

[0043] Example 4

[0044] synthesis

[0045]

[0046] (1) In a clean 15 mL reaction tube equipped with a stirrer and an electrode, add 4-(fluoromethyl)benzonitrile (0.4 mmol, 54.0 mg) and the electrolyte tetrabutylammonium perchlorate (0.5 mmol, 171 mg). Insert a balloon filled with carbon dioxide into the reaction tube and evacuate it three times. Finally, add 6.0 mL of N,N-dimethylacetamide as the reaction solvent. The reaction is carried out at 35 mA for 2.0 h. The reaction is monitored by TLC.

[0047] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 87%.

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.82–7.73 (m, 2H), 7.52–7.43 (m, 2H), 3.72(s, 2H).

[0049] 13 C NMR (100 MHz, CDCl3) δ 172.1, 141.1, 132.3, 130.8, 119.1, 109.7,40.6.

[0050] Example 5

[0051] synthesis

[0052]

[0053] (1) 5-Chloro-2-(fluoromethyl)benzonitrile (0.4 mmol, 67.6 mg) and tetrabutylammonium perchlorate (0.5 mmol, 171 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The reaction tube was evacuated three times by inserting a balloon filled with carbon dioxide into the tube. Finally, 6.0 mL of N,N-dimethylacetamide was added as the reaction solvent. The reaction was carried out at 35 mA for 2.0 h. The reaction was monitored by TLC.

[0054] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 90%.

[0055] 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 2.3 Hz, 1H), 7.74 (dd, J = 8.3,2.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 3.86 (s, 2H).

[0056] 13 C NMR (100 MHz, CDCl3) δ 171.0, 138.1, 133.3, 133.1, 132.3, 132.1,116.6, 114.6, 38.8.

[0057] Example 6

[0058] synthesis

[0059]

[0060] (1) 4-(Difluoromethyl)-1,1'-biphenyl (0.4 mmol, 67.6 mg) and tetrabutylammonium perchlorate (0.5 mmol, 171 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The tube was then evacuated three times using a balloon filled with carbon dioxide. Finally, 6.0 mL of N,N-dimethylacetamide was added as the reaction solvent. The reaction was carried out at 25 mA for 2.0 h. The reaction was monitored by TLC.

[0061] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 44% and a deuteration rate of 66%.

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.6–7.5 (m, 4H), 7.4 (dd, J = 8.4, 6.8 Hz, 2H), 7.4–7.3 (m, 3H), 3.7 (s, 1H).

[0063] 13 C NMR (100 MHz, CDCl3) δ 177.4, 140.7, 140.4, 132.3, 132.3, 129.8,129.8, 128.8, 127.4, 127.3, 127.1, 40.6.

[0064] HRMS (ESI +): Calcd. For C 14 H 11 DO2 - [MH] - : 212.0827; found:212.0824

[0065] Example 7

[0066] synthesis

[0067]

[0068] (1) In a clean 15 mL reaction tube equipped with a stirrer and an electrode, methyl 4-trifluoromethylbenzoate (0.4 mmol, 81.6 mg) and tetrabutylammonium acetate (0.5 mmol, 150.8 mg) were added. The reaction tube was evacuated three times by inserting a balloon filled with carbon dioxide into the tube. Finally, 6.0 mL of dimethyl sulfoxide was added as the reaction solvent. The reaction was carried out at 30 mA for 2.0 h. The reaction was monitored by TLC.

[0069] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 56% and a deuterated rate of 90%.

[0070] 1 H NMR (400 MHz, CDCl3) δ 8.0–8.0 (m, 2H), 7.4–7.3 (m, 2H), 3.9 (s,3H).

[0071] 13 C NMR (100 MHz, CDCl3) δ 176.1, 166.9, 138.4, 129.9, 129.5, 129.3,52.2, 52.1, 29.7.

[0072] HRMS (ESI+): Calcd. For C 10 H7D2O4 - [MH] - : 195.0632; found:195.0632

[0073] Example 8

[0074] synthesis

[0075]

[0076] (1) Ethyl 4-trifluoromethylbenzoate (0.4 mmol, 87.2 mg) and tetrabutylammonium acetate (0.5 mmol, 150.8 mg) were added to a clean 15 mL reaction tube equipped with a stirrer and an electrode. The tube was then evacuated three times using a balloon filled with carbon dioxide. Finally, 6.0 mL of dimethyl sulfoxide was added as the reaction solvent. The reaction was carried out at 30 mA for 2.0 h. The reaction was monitored by TLC.

[0077] (2) After the reaction, 5 mL of 2 M hydrochloric acid 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 the pure carboxylated product with a yield of 49% and a deuteration rate of 66%.

[0078] 1 H NMR (400 MHz, CDCl3) δ 8.0–8.0 (m, 2H), 7.4–7.3 (m, 2H), 4.4 (q, J= 7.1 Hz, 2H), 1.4 (t, J = 7.1 Hz, 3H).

[0079] 13 C NMR (100 MHz, CDCl3) δ 176.56, 166.4, 138.3, 129.9, 129.6, 129.4,129.4, 129.4, 61.0, 40.9, 40.7, 40.5, 14.3.

[0080] HRMS (ESI+): Calcd. For C 11 H9D2O4 - [MH] - : 209.0788; found: 209.0784

[0081] 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 synthesizing deuterated carboxylic acid compounds by electrochemical defluorination, characterized in that: Will contain SP 3 The fluorinated compound on C is mixed with an electrolyte, and then defluorinated by the cathode reduction ability under the action of direct current electrolysis to obtain a carbon anion. Then, deuterated water is introduced while carbon dioxide attacks nucleophilically to synthesize a deuterated carboxylic acid compound. The specific steps are: adding difluorotoluene or trifluorotoluene containing different substituents and an electrolyte into a reaction tube equipped with a stirrer, inserting an anode and a cathode, with a magnesium sheet serving as the anode and nickel foam serving as the cathode; then inserting a carbon dioxide balloon to pump the mixture for more than two times; finally, adding a reaction solvent and deuterated water into the reaction tube, and performing electrolysis with an electrolysis current of 25 to 35 mA; quenching the reaction with hydrochloric acid after the reaction is completed, and obtaining a defluorinated deuterated carboxylic acid compound through post-treatment of the product.

2. The method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination according to claim 1, characterized in that: The electrolyte is tetrabutylammonium perchlorate or tetrabutylammonium acetate or a mixture of the two in any proportion.

3. The method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination according to claim 1, characterized in that: The concentration of the hydrochloric acid is 2M.

4. The method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination according to claim 1, characterized in that: The reaction solvent is one of N,N-dimethylacetamide and dimethyl sulfoxide.

5. The method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination according to claim 1, characterized in that: The electrolysis time is more than 2 hours.

6. The method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination according to claim 1, characterized in that: The molar ratio of the electrolyte to the fluoride is fluoride:electrolyte=1.0:1.

25.

7. The method for synthesizing deuterated carboxylic acid compounds by electrochemical defluorination according to claim 1, characterized in that: The post-treatment comprises the following steps: adding hydrochloric acid to the reaction system for quenching 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 petroleum ether to ethyl acetate = 3:1 as an eluent for elution.

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