Preparation method of phenylpropiolic acid and derivatives thereof

Abstract

The invention relates to a repeatable and environment-friendly process for preparing phenylpropiolic acid and derivatives thereof by a one-step method, in particular to a preparation method of phenylpropiolic acid and derivatives thereof. Specifically, the invention provides a method for preparing phenylpropiolic acid and derivatives thereof by taking CO2 as a carboxyl source under mild reaction conditions, the method has the advantages of greenness, high efficiency and good selectivity, the application range of a substrate is wide, the compatibility of functional groups of a product is good, raw materials are easy to obtain, the operation is simple and convenient, and the method has a potential synthesis application prospect.

Description

Technical Field

[0001] This invention discloses a method for preparing phenylpropynic acid and its derivatives. Under electrochemical conditions, phenylacetylene compounds are used as raw materials, and the corresponding phenylpropynic acid compounds are prepared by reacting at room temperature in a carbon dioxide atmosphere for 3 hours. Compared with previously reported preparation methods, this invention has advantages such as being green, efficient, selective, having a wide range of applicable substrates, good compatibility of product functional groups, readily available raw materials, and simple operation. Background Technology

[0002] Alkynes are widely used as a sustainable feedstock for the synthesis of fine chemicals, a process typically achieved through the hydrolysis of calcium carbide. Furthermore, calcium carbide (CaC2) is industrially produced using coal and lime in an electric arc furnace. Therefore, the functionalization of alkynes is a fundamental goal for chemists in both industry and academia, enabling the conversion of coal-derived feedstocks into high-value-added fine chemicals. Consequently, significant effort has been devoted to the functionalization of alkynes.

[0003] Over the past few decades, carbon dioxide fixation has garnered widespread attention due to the continuous increase in carbon dioxide concentration. Carbon dioxide is an abundant, non-toxic, and renewable carbon source, as well as an environmentally friendly C1 compound, and an attractive carboxyl source in organic synthesis. Utilizing carbon dioxide is more appealing than storing it, especially if it is converted into useful fine chemicals. While there is considerable research on carbon dioxide conversion technologies, the harsh reaction conditions are a major factor limiting its practical application. Therefore, developing efficient carbon dioxide conversion technologies under mild conditions is essential, particularly for practical applications.

[0004] From an ecological and economic perspective, the production of carboxylic acids using low-value starting materials (such as alkynes) with carbon dioxide is more attractive, especially the metal-catalyzed direct carboxylation of terminal alkynes with carbon dioxide to obtain 3-arylacrylic acid, which has been extensively studied. However, due to the inherent thermodynamic and kinetic stability of carbon dioxide itself, the process of converting this gas molecule into a highly selective value-added carboxylic acid remains challenging and its development is relatively low. Electrochemical synthesis, a sustainable and tunable chemical strategy, has become a key method in organic synthesis and can address the aforementioned activation problems by adjusting current and voltage. (R. Chinchilla, C. Nájera, Chem. Rev. 2013, 114, 1783-1826; B. Trofimov, E. Y. Schmidt, Acc. Chem. Res. 2018, 51, 1117-1130. P. Jiang, G. Zhao, H. Zhang, T. Ji, L. Mu, X. Lu, J. Zhu, Green Energy) Environ.2024,9,1068-1078.Y.Pan,N.Li,Y.Yan,S.Shi,Z.Yan,L.Shi,Q.Liu,Z.Liu,Chem. Eng.J.2023,461,142043.A.Corma,Chem.Rev.2014,114,1545-1546.C.Hu,J.Mena,IVAlabug in, Nat.Rev.Chem.2023,7,405-423; Chem.2022,66,703-724; Y.Zhang,X.Zhao,G.Qing,Chem.Synth.2024,4,2-29.R.Kortlever,J.Shen,KJPSchout en,F.Calle-Vallejo,MTMKoper,J.Phys.Chem.Lett.2015,6,4073-4082;A.Tortajada,F.Juliá-Hernández,M. T.Moragas,R.Martin,Angew.Chem.Int.Ed.2018,57,15948-15982.W.Wang,S.-S.Yan,Y.Liu,J.-S.Zhu,J.-W.Yang,J.-C.Xu,Y.-Y.Tao,J.-C.Li,L.S. g,J.-H.Ye,D.-G.Yu,J.Am.Chem.Soc.2025,147,23715-23723;W.Xiong,F.Shi,R.Cheng,B.Zhu,L.Wang,P.Chen,H.Lou,W.Wu,C.Qi,M.Leang,H.J. Catal.2020,10,7968-7978;Y.Sun,P.Yang,J.Liu,P.Liu,X.Wang,J.-S.Zhou,B.Tang,Angew.Chem.Int.Ed.2025,64,e2025 02920.Q.Wang,Y.Wang,M.Liu,G.Chu,Y.Qiu,Chin.J.Chem.2024,42,2249-2266;J.-H.Ye,T.Ju,H.Huang,L.-L.Liao,D.-G. Yu,Acc.Chem.Res.2021,54,2518-2531;IIFBoogaerts,SPNolan,Chem.Commun.2011,47,3021-3024;D.Yang,Y.Sun,N.Feng ,Y.Zhong,J.Zhou,F.Zhou,Angew.Chem.Int.Ed.2025,64,e202419702.S.Li,J.Sun,Z.Zhang,R.Xie,X.Fang,M.Zhou,Dalton Trans.2016,45,10577-10584;F.Manjolinho,M.Arndt,K.Gooβen,LJGooβen,ACSCatal.2012,2,2014-2021;R.Pradhan,KLGutman,A.Mas Udley,Wargallick,KEBHollic,Vallic,Vallic,O. 2023,42,362-371;W.-H.Wang,L.Jia,X.Feng,D.Fang,H.Guo,M.Bao,Asian J.Org.Chem.2019,8,1501-1505;Y.Wang,J.Zhang,S.Wang,Z.Tan,Y.Yang,Y.Zhao,B.Han,Q.Li,J.Xiang, ACS Catal. 2024, 14, 18397-18405; L. Zhang, EQ Gao, Coord. Chem. Rev. 2023, 486, 215138.). However, these synthetic methods are limited by the substrate range or require the addition of noble metal catalysts. We envision that an electrochemical organic synthesis method, using direct electrochemical carboxylation of phenylacetylene and carbon dioxide (CO2) to obtain carboxylic acids, would be an ideal route for obtaining phenylpropynic acid.

[0005] This invention proposes a highly efficient and environmentally friendly method for the electrochemical carboxylation synthesis of phenylpropynic acid compounds. The method employs mild reaction conditions and a simple reaction apparatus. The synthesized phenylpropynic acid 4 can be used as a precursor for the synthesis of phenyl-substituted coumarins with anti-tuberculosis activity (T. Kawate, N. Iwase, M. Shimizu, SAStanley, S. Wellington, E. Kazyanskaya, D. T. Hung, Bioorg., Med. Chem. Lett., 2013, 23, 6052-6059). Summary of the Invention

[0006] The purpose of this invention is to provide a simple and convenient method for preparing phenylpropynic acid compounds using electrochemical methods, which has the advantages of energy saving and environmental protection, readily available raw materials, mild and safe reaction conditions, and wide adaptability.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] Under electrochemical conditions and in a carbon dioxide atmosphere, phenylacetylene 2 was electrochemically carboxylated with carbon dioxide to synthesize phenylpropynyl acid compound 1. After the reaction, the product was separated and characterized using conventional separation and purification methods to obtain the corresponding product.

[0009]

[0010] The technical solution is characterized by:

[0011] 1. Using substituted phenylacetylene 2 as a raw material, its substituents are:

[0012] Where R 1 It is a substituted phenyl group (substituents include: methyl, methoxy, phenyl, tert-butyl, fluorine, chlorine, etc.), naphthyl, thiophene, and cyclopropyl.

[0013] 2. The reaction solvent is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; among which, N,N-dimethylformamide is preferred.

[0014] 3. The reaction electrolyte is tetrabutylphosphine bromide.

[0015] 4. The reaction anode material is one of magnesium, nickel, and aluminum; among them, magnesium is the best material.

[0016] 5. The reaction cathode material is one of graphite carbon, graphite felt, and platinum; among them, the best material is graphite carbon.

[0017] 6. The constant electrochemical reaction current is 6-10 mA. The optimal reaction current is 10 mA.

[0018] 7. The reaction temperature ranges from -10 to 40℃. The optimal reaction temperature is 25℃.

[0019] The reaction is carried out in a reaction vessel equipped with a cathode and an anode, which are positioned opposite each other at a distance of 8-12 mm. Part or all of the cathode and anode are immersed in the reaction liquid of the reaction system, and the surface area of ​​the anode and cathode in the reaction liquid is 80-100 mm². 2 The optimal size is 90-100mm. 2 A current is applied between the cathode and anode in the reaction system.

[0020] The present invention has the following advantages:

[0021] 1) High efficiency: The synthesis method has a short reaction time and high yield;

[0022] 2) Environmentally friendly: It adopts an electrochemical method, which does not require the use of toxic and harmful reagents and solvents, nor does it require the participation of precious metals;

[0023] 3) Mild conditions: The reaction conditions are mild and do not require harsh conditions such as high temperature and high pressure;

[0024] 4) Raw materials are readily available: The raw materials used are readily available and inexpensive;

[0025] 5) Easy to operate: It is easy to operate and can be easily implemented in laboratory and industrial production.

[0026] In summary, this method utilizes "electrons" as a cleaning agent, eliminating the need for any additional oxidizing or reducing agents. It operates under mild conditions, is energy-efficient and environmentally friendly, uses readily available and inexpensive raw materials, is easy to operate, safe and reliable, and is easy to scale up with a high product yield. Attached Figure Description

[0027] Figure 1 This is the NMR hydrogen-carbon spectrum of Example 1.

[0028] Figure 2 The image shows the NMR hydrogen-carbon spectrum of Example 7.

[0029] Figure 3 The image shows the NMR hydrogen-carbon spectrum of Example 15. Detailed Implementation

[0030] The following examples will help to further understand the present invention, but the scope of the present invention is not limited thereto.

[0031] Example 1

[0032] In a 10 mL reaction tube, tetrabutylphosphine bromide (33.9 mg, 0.1 mmol) was added sequentially. A magnetic stir bar was used. The reaction tube was equipped with a graphite carbon cathode (20 mm long × 10 mm wide × 2 mm thick) and a magnesium sheet anode (20 mm long × 10 mm wide × 1 mm thick). The anode and cathode were positioned opposite each other, 10 mm apart, and the surface area of ​​the anode and cathode facing each other in the reaction solution was 100 mm². 2 A current was applied between the cathode and anode in the reaction system. After sealing the reaction tube, it was purged and charged with carbon dioxide three times (purging-charging alternately). 3 mL of N,N-dimethylformamide and phenylacetylene (21.9 μL, 0.2 mmol) were added as solvent. The reaction tube was kept at room temperature (25 °C) and constant current (10 mA) for 3 h. After the reaction, hydrochloric acid solution (2 N, 2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated brine, dried with anhydrous Na2SO4, filtered, and the volatile components were removed under reduced pressure to obtain the crude product. Then, the crude product was separated by silica gel column chromatography (eluting buffer was petroleum ether (60-90 °C) / ethyl acetate / acetic acid, with a linear gradient of v / v / v = 10:1:1‰ to 1:1:1‰) to obtain the white solid target product 4 (24.83 mg, yield 85%). The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0033] 3-Phenylpropiolic acid (4), 85% yield (24.83mg), white solid, Mp=123.5~124.3℃. 1 H NMR (600MHz, CDCl3) δ10.81 (s, 1H), 7.62 (d, J = 7.2Hz, 2H), 7.49 (t, J = 7.5Hz, 1H), 7.40 (t, J = 7.7Hz, 2H). 13 C NMR (151MHz, CDCl3)δ

[0034] 158.82,133.45,131.32,128.82,119.21,89.31,80.17.

[0035] Example 2

[0036] In a 10 mL reaction tube, tetrabutylphosphine bromide (38.7 mg, 0.1 mmol) was added sequentially. A magnetic stir bar was used. The reaction tube was equipped with graphite carbon as both the cathode (20 mm long × 10 mm wide × 2 mm thick) and anode (20 mm long × 10 mm wide × 2 mm thick), with the anode and cathode facing each other at a distance of 10 mm. The combined surface area of ​​the anode and cathode in the reaction solution was 100 mm². 2 A current was applied between the cathode and anode in the reaction system. After sealing the reaction tube, it was purged and charged with carbon dioxide three times (purging-charging alternately). 3 mL of N-methylpyrrolidone was added as solvent and phenylacetylene (21.9 μL, 0.2 mmol). The reaction tube was kept at 0 °C and a constant current of 10 mA for 3 h. After the reaction, hydrochloric acid solution (2 N, 2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated brine, dried with anhydrous Na2SO4, filtered, and the volatile components were removed under reduced pressure to obtain the crude product. Then, the crude product was separated by silica gel column chromatography (eluting buffer was petroleum ether (60-90 °C) / ethyl acetate / acetic acid, with a linear gradient of v / v / v = 10:1:1‰ to 1:1:1‰) to obtain the white solid target product 4 (16.40 mg, yield 55%). The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0037] Example 3

[0038] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that the reaction electrolyte was tetrabutylammonium tribromide. The reaction was stopped, and post-treatment did not yield the target product 4. This indicates that the reaction cannot proceed with the tetrabutylammonium tribromide electrolyte.

[0039] Application Example 1

[0040] Product 4 obtained in Example 1 can be used to synthesize phenyl-substituted coumarins with anti-tuberculosis activity (T. Kawate, N. Iwase, M. Shimizu, SAStanley, S. Wellington, E. Kazyanskaya, D. T. Hung, Bioorg., Med. Chem. Lett., 2013, 23, 6052-6059.).

[0041]

[0042] Example 4

[0043] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that the reaction was carried out without electricity. The reaction was stopped, and post-treatment did not yield the target product 4. This indicates that the reaction cannot proceed without electricity.

[0044] Example 5

[0045] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that acetonitrile was used as the reaction solvent. The reaction was stopped, and the target product 4 (yield trace) was obtained after post-treatment. This indicates that using acetonitrile as a solvent is not conducive to the reaction.

[0046] Example 6

[0047] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that the reaction temperature was 0°C. The reaction was stopped, and after post-processing, the target product 4 (22.5 mg, yield 77%) was obtained. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry. This indicates that lowering the reaction temperature is detrimental to the reaction.

[0048] Example 7

[0049] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that tetrabutylammonium chloride (the same amount as tetrabutylphosphine bromide, replacing the amount of tetrabutylphosphine bromide) was added as the electrolyte. The reaction was stopped, and after post-processing, the target product 4 (21.6 mg, yield 54%) was obtained. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry. This indicates that tetrabutylammonium chloride is detrimental to the reaction.

[0050] Example 8

[0051]

[0052] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that the starting material added to the reaction system was p-methylphenylacetylene 9 (23.21 mg, 0.2 mmol), and the reaction solvent was N-methylpyrrolidone. The reaction was stopped, and after post-treatment, the target product 10 (28.17 mg, yield 88%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0053] Example 9

[0054]

[0055] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that m-methylphenylacetylene 11 (23.21 mg, 0.2 mmol) was added to the reaction system, and dimethyl sulfoxide was used as the reaction solvent. The reaction was stopped, and after post-treatment, the target product 12 (27.2 mg, yield 85%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0056] Example 10

[0057]

[0058] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that p-n-butylphenylacetylene 13 (31.6 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 14 (32.98 mg, yield 72%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0059] Example 11

[0060]

[0061] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that p-methoxyphenylacetylene 15 (26.4 mg, 0.2 mmol) was added to the reaction system, aluminum was used as the anode material, and nickel was used as the cathode material. The reaction was stopped, and after post-treatment, the target product 16 (27.5 mg, yield 78%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0062] Example 12

[0063]

[0064] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that m-phenylacetylene 17 (35.6 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 18 (21.32 mg, yield 48%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0065] Example 13

[0066]

[0067] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that p-fluorophenylacetylene 19 (24.0 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 20 (10.2 mg, yield 31%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0068] Example 14

[0069]

[0070] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that m-fluorophenylacetylene 21 (24.0 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 22 (10.8 mg, yield 33%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0071] Example 15

[0072]

[0073] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that p-chlorophenylacetylene 23 (27.2 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 24 (10.8 mg, yield 36%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0074] Example 16

[0075]

[0076] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that 2-ethynylnaphthalene 25 (30.4 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 26 (33.3 mg, 85% yield) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0077] Example 17

[0078]

[0079] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that 1-ethynylnaphthalene 27 (30.4 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 28 (25.5 mg, yield 65%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0080] Example 18

[0081]

[0082] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that 2-ethynylthiophene 29 (21.6 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 30 (14.9 mg, yield 49%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0083] Example 19

[0084]

[0085] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that 3-ethynylthiophene 31 (21.6 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 32 (11.6 mg, yield 38%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

[0086] Example 20

[0087]

[0088] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 4, except that cyclopropylacetylene 33 (13.2 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and after post-treatment, the target product 34 (15 mg, yield 71%) was obtained as a white solid. The target product was confirmed by 1H NMR, 1C NMR, and high-resolution mass spectrometry.

Claims

1. A method for synthesizing phenylpropynoic acid compounds by electrochemically synthesizing phenylpropynoic acid compounds from phenylacetylene and carbon dioxide, characterized by, The phenylpropynoic acid compound structure 1 is as follows: wherein R 1 is one or two or more of phenyl or substituted phenyl, naphthyl, thienyl, cyclopropyl, and the substituents on the substituted phenyl are one or two or more of methyl, methoxy, phenyl, tert-butyl, fluorine, and chlorine.

2. The synthesis method according to claim 1, characterized in that: The synthesis route is shown in the following reaction formula, taking substituted phenylacetylene 2 as raw material, reacting with carbon dioxide under electrocatalytic conditions to generate acetylenic acid compound 1; wherein the substituents R 1 are the same as in claim 1. 1 are the same as in claim 1.

3. The synthesis method according to claim 1, characterized in that: In the electrochemical reaction, the anode material is one or more of magnesium, aluminum, zinc, nickel, iron and graphite carbon, preferably one or more of magnesium, aluminum, zinc and graphite carbon, and the optimal anode material is magnesium; the cathode material is one or more of graphite carbon, nickel, platinum, copper and graphite felt, preferably one or more of graphite carbon and platinum, and the optimal cathode material is graphite carbon; The reaction solvent is one or more of N,N-dimethylformamide, dimethyl sulfoxide and N-methyl pyrrolidone, and the optimal solvent is N,N-dimethylformamide; The reaction electrolyte is tetrabutylphosphonium bromide; the electrochemical constant reaction current density is 6-10 mA, the reaction time is 3-4 hours; the reaction temperature is -10 to 40 degrees Celsius, and the reaction atmosphere is carbon dioxide atmosphere; after the reaction is completed, 0.004-0.010 mol of HCl is added for product separation and purification to obtain acetylenic acid compound 1.

4. The method of synthesis according to claim 3, wherein: When different phenyl-substituted acetylenic compounds 2 react with carbon dioxide to obtain acetylenic acid compound 1, the optimal reaction solvent is N,N-dimethylformamide, and the optional temperature range is -10 to room temperature in Celsius, and the optimal reaction temperature is room temperature; In the structure formula 1 of the acetylenic acid compound, R1 is one or more of phenyl or substituted phenyl, naphthyl, thiophenyl and cyclopropyl, and the substituents on the substituted phenyl are one or more of methyl, methoxy, phenyl, tert-butyl, fluorine and chlorine.

5. The method of synthesis according to any one of claims 2 to 4, characterized in that: The reaction is carried out in a reaction vessel provided with a cathode and an anode, the anode and the cathode are oppositely arranged with a distance of 8-12 mm, and part or all of the cathode and the anode are placed in the reaction liquid of the reaction system, and the area of the opposite surfaces of the anode and the cathode placed in the reaction liquid is 80-100 mm 2 , and most preferably 90-100 mm 2 ; and an electric current is applied between the cathode and the anode in the reaction system.

6. The method of synthesis according to any one of claims 2 to 4, characterized in that: The reaction current is 6-10 mA, and the optimal constant reaction current is 10 mA.

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