A method for preparing aryl carboxylic acids by reacting aryl thioonium salts with carbon dioxide catalyzed by copper compounds.

Abstract

This invention discloses a method for preparing aryl carboxylic acids by reacting aryl thioonium salts with carbon dioxide using a copper compound as a catalyst and diethylzinc as a reducing agent. The aryl thioonium salt substrate is reacted with an organic solvent at room temperature under a carbon dioxide atmosphere at one atmosphere. The product is then acidified and purified to obtain the aryl carboxylic acid. This method uses readily available raw materials, is simple to operate, operates under mild conditions, and exhibits good functional group tolerance and substrate versatility. This method can not only synthesize various simply substituted aryl carboxylic acids but can also be used for the late-stage carboxylation modification of complex drug molecules. The practicality of this method has also been verified on a gram-scale, demonstrating promising prospects for industrial application.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and in particular relates to a method for preparing aryl carboxylic acids by reacting aryl thioonium salts with carbon dioxide catalyzed by copper compounds. Background Technology

[0002] Carbon dioxide, as a major greenhouse gas, is the primary culprit behind numerous climate, ecological, and environmental problems due to its excessive emissions. On the other hand, carbon dioxide is also an important non-toxic, inexpensive, and renewable C1 resource. Therefore, the chemical conversion of carbon dioxide into high-value-added chemicals is both in line with the principles of green chemistry and economically viable. The carboxyl group, as an important organic functional group, is widely found in various active natural products, pharmaceuticals, pesticides, daily chemical products, and functional materials. Catalytic carboxylation reactions using carbon dioxide with organic molecules are the simplest and atom-economical synthetic route for preparing carboxylic acids and their derivatives.

[0003] Due to the significant challenges posed by the kinetic inertness and thermodynamic stability of carbon dioxide, traditional carboxylation methods often directly react highly reactive organometallic reagents with carbon dioxide, resulting in harsh conditions and severely limited substrate scope. In recent years, chemists have successively achieved direct carboxylation reactions of aryl carbon-halogen bonds, carbon-oxygen bonds, and carbon-nitrogen bonds with carbon dioxide under transition metal catalysis, photocatalysis, or electrocatalysis. These transformations are milder than traditional reactions, expanding the substrate scope and functional group compatibility. However, the introduction of carbon heterobonds during the synthesis of these substrates faces numerous limitations, such as the inertia and selectivity of carbon-hydrogen bonds, making the carboxylation modification of many complex molecules difficult to achieve. Since 2019, Ritter et al. have reported that reagents based on thiaanthracene or dibenzothiophene can achieve highly site-selective C-H bond sulfidation of many complex molecules to obtain corresponding thioonium salts (Nature 2019, 567, 223-228; Angew. Chem. Int. Ed. 2020, 59, 1956-1960). Further transformation of these thioonium salts can indirectly achieve highly site-selective C-H bond functionalization. Currently, there is still potential for further development of these thioonium salt transformation reactions, especially their carboxylation reaction with carbon dioxide. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for preparing aryl carboxylic acids by reacting copper-catalyzed aryl thioonium salts with carbon dioxide.

[0005] The technical solution adopted in this invention is: a method for preparing aryl carboxylic acid by reacting aryl thioonium salts with carbon dioxide catalyzed by copper compounds, wherein aryl thioonium salts, ligands and copper catalysts are mixed, and organic solvents and diethylzinc are added under a carbon dioxide atmosphere, and aryl carboxylic acid is obtained after the reaction.

[0006]

[0007] Preferably, the aryl group in the aryl thioonium salt is phenyl, fused-ring aryl, biphenyl aryl, or dibenzofuranyl;

[0008] Preferably, the aryl group has no substituents or has substituents, and when it has substituents, the substituents are one or more of halogen, alkyl, haloalkyl, alkyloxy, carboxyl, aryloxy, ester, and cyano.

[0009] Preferably, the ligand is one or a combination of N,N'-dibenzyloxalyldiamine, N1,N2-bis(2-thiophenemethyl)-oxalamide, N,N'-diphenyloxalyldiamine, N1-benzyl-N2-(naphth-1-yl)oxalyldiamine, N1,N2-di(naphth-1-yl)oxalyldiamine, N1,N2-di([1,1'-biphenyl]-2-yl)oxalyldiamine, N,N,N',N'-tetramethylethylenediamine, N1,N2-dimethylethane-1,2-diamine, L-valine, 4,7-diphenyl-1,10-phenanthroline and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene;

[0010] N,N'-dibenzyloxalyldiamine or N,N,N',N'-tetramethylethylenediamine are preferred.

[0011] Preferably, in N,N'-dibenzyloxalyldiamine, N,N'-diphenyloxalyldiamine, N1-benzyl-N2-(naphth-1-yl)oxalyldiamine, N1,N2-di(naphth-1-yl)oxalyldiamine, and N1,N2-di([1,1'-biphenyl]-2-yl)oxalyldiamine, the benzene ring and naphthyl ring skeleton may or may not contain the same or different substituents such as alkyl, alkoxy, and aryloxy groups.

[0012] Preferably, the copper catalyst is one or more of the following: inorganic salts of copper, carboxylates of copper, alkoxides of copper, and ketones of copper; more preferably, cuprous chloride, cuprous acetate, cuprous oxide, cuprous bromide, or cuprous iodide, and even more preferably, cuprous chloride.

[0013] Preferably, the anion in the aryl thioonium salt is one or a combination of tetrafluoroborate, trifluoromethanesulfonate, hexafluorophosphate, and hexafluoroantimonate.

[0014] Preferably, the solvent is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone; more preferably, it is N,N-dimethylformamide.

[0015] Preferably, the specific steps are as follows:

[0016] Step 1: Under ambient atmosphere, add aryl thioonium salt, copper catalyst and ligand to the container and mix well; the molar ratio of aryl thioonium salt, copper catalyst and ligand is 1:0.05~0.1:0.1~0.2;

[0017] Step 2: Change the reaction atmosphere in the container to carbon dioxide, add solvent and 1-2 mol / L diethylzinc solution under a carbon dioxide gas stream, and stir the reaction at room temperature;

[0018] Step 3: After the reaction is complete, add a solution of dioxane (concentration 1-4 mol / L) of hydrogen chloride for acidification, stir for 5 minutes, remove the solvent, and then separate by column chromatography to obtain aryl carboxylic acid.

[0019] Preferably, the aryl thioonium salt is synthesized by a highly site-selective C-H bond sulfidation reaction of an aromatic substrate.

[0020] Arylcarboxylic acids were prepared by reacting copper-catalyzed aryl thioonium salts with carbon dioxide.

[0021] An aryl carboxylic acid compound, as shown in Formula 25 or Formula 27;

[0022]

[0023] The advantages and positive effects of this invention are as follows: It discloses a novel method for synthesizing aryl carboxylic acid compounds by reacting aryl thioonium salt substrates with carbon dioxide. This method uses carbon dioxide as a C1 resource, inexpensive copper salts as catalysts, and diethylzinc as a reducing agent to prepare aryl carboxylic acids in an organic solution at room temperature. The preparation process is mild, has good functional group tolerance, and a wide range of applicable substrates. It has good functional group tolerance and substrate universality. The reaction can prepare a series of conventional and even previously unreported carboxylic acid products in high yield. It has significant application value for the industrial synthesis of some conventional carboxylic acid compounds and has great application potential in the late-stage C-H bond carboxylation modification of complex drug molecules. Detailed Implementation

[0024] The embodiments of the present invention will be described below.

[0025] This invention discloses a novel method for preparing aryl carboxylic acids by reacting copper-catalyzed aryl thioonium salts with carbon dioxide, overcoming the limitations of traditional carbon dioxide-based carboxylation reactions, such as harsh conditions and narrow substrate range. The aryl thioonium salt, ligand, and copper catalyst are mixed, and an organic solvent and diethylzinc are added under a carbon dioxide atmosphere. The reaction yields aryl carboxylic acids.

[0026] Diethylzinc reacts with cuprous chloride to form ethyl copper. Ethyl copper undergoes β-H elimination and homolytic cleavage of the Cu-H bond, releasing ethylene and hydrogen, and generating the catalytically active species, zero-valent copper. Zero-valent copper then undergoes formal oxidative addition to the aryl thioonium salt substrate, breaking the carbon-sulfur bond to generate the divalent aryl copper intermediate ArCuXL and thiaanthracene or dibenzothiophene. The divalent aryl copper intermediate is reduced by diethylzinc to the monovalent aryl copper intermediate ArCuL, which then inserts carbon dioxide into the C-Cu bond to generate the monovalent aryl carboxylated copper intermediate ArCO2CuL. This intermediate reacts with diethylzinc to form the zinc carboxylate compound ArCO2ZnEt, while simultaneously regenerating ethyl copper for the next catalytic cycle. The aryl carboxylated zinc compound ArCO2ZnEt is acidified to yield the target product, aryl carboxylic acid. This method utilizes readily available substrates, operates under mild conditions, yields a wide range of aryl carboxylic acid products, and can prepare some previously unreported carboxylic acid products.

[0027] The specific preparation steps are as follows:

[0028] Step 1: Under an ambient atmosphere, the aryl thioonium salt substrate, copper compound catalyst, and ligand are mixed in a molar ratio of 1:0.05–0.1:0.1–0.2;

[0029] Step 2: Replace the reaction atmosphere in the container with carbon dioxide, add solvent and diethylzinc solution (concentration 1-2 mol / L) under a carbon dioxide atmosphere of 1 atm, stir the reaction at room temperature for 6-12 hours, and then acidify.

[0030] Step 3: After the reaction is complete, add a solution of dioxane (concentration 1-4 mol / L) of hydrogen chloride to acidify, stir for 5 minutes, remove the solvent, and then separate by column chromatography to obtain aryl carboxylic acid.

[0031]

[0032] In this context, Ar represents an aryl group. The aryl group in aryl thioonium salts can be phenyl, fused-ring aryl, biphenyl aryl, or dibenzofuranyl. The aryl group may or may not have substituents. When substituents are present, they can be one or more of the following: halogen, alkyl, haloalkyl, alkyloxy, carboxylalkyl, aryloxy, ester, and cyano. The anion X in aryl thioonium salts... - It is one or a combination of tetrafluoroborate, trifluoromethanesulfonate, hexafluorophosphate, and hexafluoroantimonate.

[0033] The ligands are one or more combinations of N,N'-dibenzyloxalyldiamine, N1,N2-bis(2-thiophenemethyl)-oxalamide, N,N'-diphenyloxalyldiamine, N1-benzyl-N2-(naphth-1-yl)oxalyldiamine, N1,N2-di(naphth-1-yl)oxalyldiamine, N1,N2-di([1,1'-biphenyl]-2-yl)oxalyldiamine, N,N,N',N'-tetramethylethylenediamine, N1,N2-dimethylethane-1,2-diamine, L-valine, 4,7-diphenyl-1,10-phenanthroline, and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene. N,N'-dibenzyloxalyldiamine, N,N'-diphenyloxalyldiamine, N1-benzyl-N2-(naphth-1-yl)oxalyldiamine, N1,N2-di(naphth-1-yl)oxalyldiamine, and N1,N2-di([1,1'-biphenyl]-2-yl)oxalyldiamine may or may not contain the same or different substituents such as alkyl, alkoxy, and aryloxy groups in the benzene ring and naphthyl ring skeleton. Preferably, N,N'-dibenzyloxalyldiamine or N,N,N',N'-tetramethylethylenediamine is preferred.

[0034] The copper catalyst is one or more of the following: inorganic salts of copper, carboxylates of copper, alkoxides of copper, and ketones of copper; such as cuprous chloride, cuprous acetate, cuprous oxide, cuprous bromide, or cuprous iodide, preferably cuprous chloride.

[0035] The solvent is one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone; preferably N,N-dimethylformamide.

[0036] In some embodiments of this invention, since aryl thioonium salt substrates are readily synthesized via highly site-selective C-H bond sulfidation reactions of aromatic substrates, this method provides a novel route for the indirect synthesis of aryl carboxylic acids from aromatic substrates and carbon dioxide with high site selectivity. Starting from readily available aromatics, this method, using inexpensive copper catalysis under mild conditions, offers highly site-selective preparation of aryl carboxylic acids. It can not only synthesize various simply substituted aryl carboxylic acids but also be used for the late-stage carboxylation modification of complex drug molecules. The practicality of this method has also been verified on a gram-scale, demonstrating promising prospects for industrial applications.

[0037] The present invention will now be described. Experimental methods that do not specify the operation steps are performed in accordance with the corresponding product manuals. Unless otherwise specified, the instruments, reagents and consumables used in the embodiments can be purchased from commercial companies.

[0038] Example 1:

[0039]

[0040] Preparation of 4-methylbenzoic acid (compound of formula 1):

[0041] In a 50 mL Schlenk flask, 0.3 mmol of p-4-methylphenylthiamane salt substrate (Formula 1a), 0.03 mmol of cuprous chloride, and N,N'-dibenzyloxalyldiamine were added sequentially. The reaction flask was then completely purged with carbon dioxide. Under a 1 atm carbon dioxide stream, 1 mL of N,N-dimethylformamide solvent and 0.75 mL of 2.0 mol / L diethylzinc toluene solution were added sequentially, followed by stirring at room temperature for 12 hours. After the reaction was complete, 5 mL of 4 mol / L dioxane chloride solution was added for thorough acidification. The mixture was concentrated by rotary evaporation, prepared by dry chromatography, and purified by column chromatography using petroleum ether, ethyl acetate, and trace amounts of acetic acid as the developing solvent to obtain the target product 4-methylbenzoic acid as shown in Formula 1, with a yield of 84%.

[0042] When using a dibenzothiophene thioonium salt (Formula 1a') as the substrate instead of a thiamthioonium salt, the procedure is the same as above, reacting at room temperature for 12 hours, followed by treatment and separation to obtain 4-methylbenzoic acid as shown in Formula 1, with a yield of 75%.

[0043] 1 H NMR (DMSO-d6, 400MHz): δ12.78 (s, 1H), 7.84 (d, J = 8.0Hz, 2H), 7.28 (d, J = 8.0Hz, 2H), 2.35 (s, 3H).

[0044] Example 2:

[0045]

[0046] Preparation of 4-ethylbenzoic acid (compound of formula 2):

[0047] The preparation process was the same as in Example 1, except that 4-ethylphenylthionium salt (compound of formula 1b) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-ethylbenzoic acid as shown in formula 2 was obtained after treatment, with a yield of 82%.

[0048] 1 H NMR (DMSO-d6, 400MHz): δ12.76 (s, 1H), 7.86 (d, J = 7.2Hz, 2H), 7.31 (d, J = 7.6Hz, 2H), 2.65 (q, J = 7.2Hz, 2H), 1.18 (t, J = 7.2Hz, 3H).

[0049] Example 3:

[0050]

[0051] Preparation of 4-isopropylbenzoic acid (compound of formula 3):

[0052] The preparation process was the same as in Example 1, except that 4-isopropylphenylthioonium salt (compound of formula 1c) was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-isopropylbenzoic acid as shown in formula 3 was obtained after treatment, with a yield of 73%.

[0053] 1 H NMR (DMSO-d6, 400MHz): δ12.80 (s, 1H), 7.87 (d, J = 8.0Hz, 2H), 7.34 (d, J = 8.4Hz, 2H), 3.00–2.90 (m, 1H), 1.20 (d, J = 7.2Hz, 3H).

[0054] Example 4:

[0055]

[0056] Preparation of 4-tert-butylbenzoic acid (compound of formula 4):

[0057] The preparation process was the same as in Example 1, except that 4-tert-butylphenylthioonium salt (compound of formula 1d) was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-tert-butylbenzoic acid, as shown in formula 4, was obtained after treatment with a yield of 78%.

[0058] 1 H NMR (DMSO-d6, 400MHz): δ12.76 (s, 1H), 7.87 (d, J = 8.0Hz, 2H), 7.49 (d, J = 8.0Hz, 2H), 1.28 (s, 9H).

[0059] Example 5:

[0060]

[0061] Preparation of 4-methoxybenzoic acid (compound of formula 5):

[0062] The preparation process was the same as in Example 1, except that 4-methoxyphenylthioonium salt (compound of formula 1e) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-methoxybenzoic acid as shown in formula 5 was obtained after treatment, with a yield of 84%.

[0063] 1 H NMR (DMSO-d6, 400MHz): δ12.63 (s, 1H), 7.89 (d, J = 8.8Hz, 2H), 7.01 (d, J = 8.8Hz, 2H), 3.81 (s, 3H).

[0064] Example 6:

[0065]

[0066] Preparation of 4-cyclopropylbenzoic acid (compound of formula 6):

[0067] The preparation process was the same as in Example 1, except that 4-cyclopropylphenylthioonium salt (compound of formula 1f) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-cyclopropylbenzoic acid as shown in formula 6 was obtained after treatment, with a yield of 85%.

[0068] 1 H NMR (DMSO-d6, 400MHz): δ12.73 (s, 1H), 7.81 (d, J = 8.0Hz, 2H), 7.15 (d, J = 8.4Hz, 2H), 2.00–1.93 (m, 1H), 1.03–0.98 (m, 2H), 0.75–0.71 (m, 2H).

[0069] Example 7:

[0070]

[0071] Preparation of 4-isopropoxybenzoic acid (compound of formula 7):

[0072] The preparation process was the same as in Example 1, except that 4-isopropoxyphenylthioonium salt (compound of formula 1g) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-isopropoxybenzoic acid as shown in formula 7 was obtained after treatment, with a yield of 84%.

[0073] 1 H NMR (DMSO-d6, 400MHz): δ12.57 (s, 1H), 7.86 (d, J = 8.8Hz, 2H), 6.97 (d, J = 8.8Hz, 2H), 4.72–4.66 (m, 1H), 1.27 (d, J = 6.0Hz, 6H).

[0074] Example 8:

[0075]

[0076] Preparation of 4-chlorobenzoic acid (compound of formula 8):

[0077] The preparation process was the same as in Example 1, except that 4-chlorophenylthionium salt (compound of formula 1h) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-chlorobenzoic acid, as shown in formula 8, was obtained after treatment, with a yield of 52%.

[0078] 1H NMR (DMSO-d6, 400MHz): δ13.18 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.56 (d, J = 8.4Hz, 2H).

[0079] Example 9:

[0080]

[0081] Preparation of 4-(3-chloropropyl)benzoic acid (compound of formula 9):

[0082] The preparation process was the same as in Example 1, except that 4-(3-chloropropyl)phenylthioium salt (compound of formula 1i) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-(3-chloropropyl)benzoic acid, as shown in formula 9, was obtained with a yield of 75%.

[0083] 1 H NMR (DMSO-d6, 400MHz): δ12.82 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.4Hz, 2H), 3.60 (t, J = 6.8Hz, 2H), 2.76 (t, J = 8.0Hz, 2H), 2.05–1.98 (m, 2H).

[0084] Example 10:

[0085]

[0086] Preparation of 3,4-dimethylbenzoic acid (compound of formula 10):

[0087] The preparation method was the same as in Example 1, except that the 3,4-dimethylphenylthiathaneonium salt substrate (compound of formula 1j, 0.3 mmol) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 3,4-dimethylbenzoic acid as shown in formula 10 was obtained after treatment, with a yield of 76%.

[0088] 1 H NMR (DMSO-d6, 400MHz): δ12.70 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.6Hz, 1H), 7.23 (d, J = 8.0Hz, 1H), 2.26 (s, 3H), 2.25 (s, 3H).

[0089] Example 11:

[0090]

[0091] Preparation of 2,5-dimethylbenzoic acid (compound of formula 11):

[0092] The preparation method was the same as in Example 1, except that 2,5-dimethylphenylthionium salt (compound of formula 1k) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2,5-dimethylbenzoic acid as shown in formula 11 was obtained after treatment, with a yield of 70%.

[0093] 1 H NMR (DMSO-d6, 400MHz): δ12.72 (s, 1H), 7.63 (s, 1H), 7.23 (d, J = 7.6Hz, 1H), 7.16 (d, J = 7.6Hz, 1H), 2.46 (s, 3H), 2.28 (s, 3H).

[0094] Example 12:

[0095]

[0096] Preparation of 3,4-dimethoxybenzoic acid (compound of formula 12):

[0097] The preparation method was the same as in Example 1, except that 3,4-dimethoxyphenylthioonium salt (compound of formula 11) was used instead of compound of formula 1j. The reaction was carried out at room temperature for 12 hours, and the target product 3,4-dimethoxybenzoic acid as shown in formula 12 was obtained after treatment, with a yield of 74%.

[0098] 1 H NMR (DMSO-d6, 400MHz): δ12.63 (s, 1H), 7.56 (dd, J1 = 8.4, J2 = 2.0Hz, 1H), 7.44 (d, J = 2.0Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H).

[0099] Example 13:

[0100]

[0101] Preparation of 3-fluoro-4-methoxybenzoic acid (compound of formula 13):

[0102] The preparation method was the same as in Example 1, except that the compound of formula 1a was replaced with the 3-fluoro-4-methoxyphenylthionium salt of formula 1m. The reaction was carried out at room temperature for 12 hours, and the target product 3-fluoro-4-methoxybenzoic acid of formula 13 was obtained after treatment, with a yield of 69%.

[0103] 1 H NMR (DMSO-d6, 400MHz): δ12.91 (s, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.65 (dd, J1 = 12.0, J2 = 2.0Hz, 1H), 7.26 (m, 1H), 3.90 (s, 1H).

[0104] Example 14:

[0105]

[0106] Preparation of 4-methoxy-3-(methoxycarbonyl)benzoic acid (compound of formula 14):

[0107] The preparation method was the same as in Example 1, except that 4-methoxy-3-(methoxycarbonyl)phenylthioonium salt (compound of formula 1n) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-methoxy-3-(methoxycarbonyl)benzoic acid, as shown in formula 14, was obtained with a yield of 52%.

[0108] 1 H NMR (DMSO-d6, 400MHz): δ12.79 (s, 1H), 8.22 (d, J = 2.0Hz, 1H), 8.08 (dd, J1 = 8.8, J2 = 2.4Hz, 1H), 7.24 (d, J = 8.8Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H).

[0109] Example 15:

[0110]

[0111] Preparation of 3-cyano-4-methoxybenzoic acid (compound of formula 15):

[0112] The preparation method is the same as in Example 1, except that 3-cyano-4-methoxyphenylthioonium salt (compound of formula 10) is used instead of compound of formula 1a. The reaction is carried out at room temperature for 12 hours, and the target product 3-cyano-4-methoxybenzoic acid as shown in formula 15 is obtained after treatment, with a yield of 55%.

[0113] 1 H NMR (DMSO-d6, 400MHz): δ13.13 (s, 1H), 8.20-8.18 (m, 2H), 7.35 (d, J = 9.6Hz, 1H), 3.99 (s, 3H).

[0114] Example 16:

[0115]

[0116] Preparation of 2,4,6-trimethylbenzoic acid (compound of formula 16):

[0117] In a 50 mL Schlenk flask, 0.03 mmol of 2,4,6-trimethylphenylthionium salt (formula 1p) and 0.03 mmol of cuprous chloride were added sequentially. The reaction flask was then completely purged with carbon dioxide. Under a 1 atm carbon dioxide stream, 1 mL of N,N-dimethylformamide solvent, 0.6 mmol of N,N,N',N'-tetramethylethylenediamine, and 0.75 mL of a 2.0 mol / L diethylzinc toluene solution were added sequentially, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 5 mL of a 4 mol / L dioxane chloride solution was added for thorough acidification. The mixture was then concentrated by rotary evaporation, prepared by dry method, and purified by column chromatography using petroleum ether, ethyl acetate, and trace amounts of acetic acid as the developing solvent to obtain the target product 2,4,6-trimethylbenzoic acid, as shown in Formula 16, in 40% yield.

[0118] 1 H NMR(DMSO-d6,400MHz): δ12.94(s,1H),6.87(s,2H),2.23(s,9H).

[0119] Example 17:

[0120]

[0121] Preparation of 4-bromo-2,5-dimethylbenzoic acid (compound of formula 17):

[0122] The preparation method was the same as in Example 1, except that the compound of formula 1a was replaced with the 4-bromo-2,5-dimethylphenylthionium salt of formula 1q. The reaction was carried out at room temperature for 12 hours, and the target product 4-bromo-2,5-dimethylbenzoic acid of formula 17 was obtained after treatment, with a yield of 70%.

[0123] 1 H NMR(DMSO-d6,400MHz): δ12.93(s,1H),7.75(s,1H),7.51(s,1H),2.45(s,3H),2.31(s,3H).

[0124] Example 18:

[0125]

[0126] Preparation of 5-(methoxycarbonyl)-2,4-dimethylbenzoic acid (compound of formula 18):

[0127] The preparation method was the same as in Example 16, except that 5-(methoxycarbonyl)-2,4-dimethylphenylthioonium salt (compound of formula 1r) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 5-(methoxycarbonyl)-2,4-dimethylbenzoic acid as shown in formula 18 was obtained with a yield of 68%.

[0128] 1 H NMR (DMSO-d6, 400MHz): δ12.97(s,1H),8.34(s,1H),7.25(s,1H),3.83(s,3H),2.54(s,3H),2.52(s,3H).

[0129] Example 19:

[0130]

[0131] Preparation of 4-phenoxybenzoic acid (compound of formula 19):

[0132] The preparation method was the same as in Example 1, except that 4-phenoxyphenylthioonium salt (compound of formula 1s) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-phenoxybenzoic acid of formula 19 was obtained after treatment, with a yield of 61%.

[0133] 1 H NMR (DMSO-d6, 400MHz): δ12.85 (s, 1H), 7.96 (d, J = 7.2Hz, 2H), 7.46 (t, J = 7.2Hz, 2H), 7.24 (m, 1H), 7.12 (d, J = 8.0Hz, 2H), 7.03 (d, J = 7.2Hz, 2H).

[0134] Example 20:

[0135]

[0136] Preparation of 4-(4-bromophenoxy)benzoic acid (compound of formula 20):

[0137] The preparation method was the same as in Example 1, except that 4-(4-bromophenoxy)phenylthioonium salt (compound of formula 1t) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-(4-bromophenoxy)benzoic acid, as shown in formula 20, was obtained with a yield of 76%.

[0138] 1 H NMR (DMSO-d6, 400MHz): δ12.83 (s, 1H), 7.95 (d, J = 8.8Hz, 2H), 7.60 (d, J = 8.8Hz, 2H), 7.08–7.04 (m, 4H).

[0139] Example 21:

[0140]

[0141] Preparation of 1,1'-biphenyl-4-carboxylic acid (compound of formula 21):

[0142] The preparation method was the same as in Example 1, except that 1,1'-biphenyl-4-thioonium salt (compound of formula 1u) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 1,1'-biphenyl-4-carboxylic acid, as shown in formula 21, was obtained with a yield of 80%.

[0143] 1 H NMR (DMSO-d6, 400MHz): δ12.97 (s, 1H), 8.03 (d, J = 8.4Hz, 2H), 7.79 (d, J = 8.4Hz, 2H), 7.72 (d, J = 7.2Hz, 2H), 7.43-7.40 (t, J = 7.6Hz, 2H), 7.41 (M, 1H).

[0144] Example 22:

[0145]

[0146] Preparation of 2'-fluoro-1,1'-biphenyl-4-carboxylic acid (compound of formula 22):

[0147] The preparation method was the same as in Example 1, except that 2'-fluoro-1,1'-biphenyl-4-thioonium salt (compound of formula 1v) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 2'-fluoro-1,1'-biphenyl-4-carboxylic acid, as shown in formula 22, was obtained with a yield of 72%.

[0148] 1 H NMR (DMSO-d6, 400MHz): δ13.03 (s, 1H), 8.04 (d, J = 7.6Hz, 1H), 7.68 (d, J = 7.2Hz, 2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 1H), 7.37-7.33 (m, 1H).

[0149] Example 23:

[0150]

[0151] Preparation of dibenzo[b,d]furan-2-carboxylic acid (compound of formula 23):

[0152] The preparation method was the same as in Example 1, except that dibenzo[b,d]furan-2-thioonium salt (compound of formula 1w) was used instead of compound of formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product dibenzo[b,d]furan-2-carboxylic acid, as shown in formula 23, was obtained with a yield of 77%.

[0153] 1H NMR (DMSO-d6, 400MHz): δ13.03 (s, 1H), 8.78 (s, 1H), 8.26 (t, J = 7.6Hz, 1H),8.12(dd,J1=8.4,J2=1.6Hz,1H),7.78-7.71(m,2H),7.56(t,J=7.6Hz,1H), 7.43(t,J=7.6Hz,1H).

[0154] Example 24:

[0155]

[0156] Preparation of 4-methoxy-1-naphthoic acid (compound of formula 24):

[0157] The preparation method was the same as in Example 1, except that 4-methoxy-1-naphthioonium salt (compound of formula 1x) was used instead of compound of formula 1j. The reaction was carried out at room temperature for 12 hours, and the target product 4-methoxy-1-naphthoic acid, as shown in formula 24, was obtained after treatment, with a yield of 47%.

[0158] 1 H NMR (DMSO-d6, 400MHz): δ12.70 (s, 1H), 9.03 (d, J = 8.8Hz, 1H), 8.24 (t, J = 7.6Hz, 2H), 7.65 (t, J = 7.6Hz, 1H), 7.56 (t, J = 7.6Hz, 1H), 7.05 (d, J = 8.4Hz, 1H),4.04(s,3H).

[0159] Example 25: Carboxylated pyridine

[0160]

[0161] Preparation of 4-(4-(2-(pyridin-2-acyloxy)propoxy)phenoxy)benzoic acid (compound of formula 25):

[0162] The preparation method was the same as in Example 16, except that the thioonium salt of Formula 1y was used instead of the compound of Formula 1j. The reaction was carried out at room temperature for 12 hours, and the target product 4-(4-(2-(pyridine-2-acyloxy)propoxy)phenoxy)benzoic acid of Formula 25 was obtained after treatment, with a yield of 45%.

[0163] 1H NMR (DMSO-d6, 400MHz): δ12.74(s,1H),8.17(d,J=3.2Hz,1H),7.92(d,J=8.8Hz,2H),7.70(t,J=6.8Hz,1H),7.08–6.93(m,7H),6.81(d,J=8.4Hz,1H), 5.52(m,1H),4.17(m,2H),1.39(d,J=6.0Hz,3H).

[0164] Example 26: Carboxylated estradiol

[0165]

[0166] Preparation of (8R,9S,13S,14S)-3-methoxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentanoic acid[a]phenanthrene-2-carboxylic acid (compound of formula 26):

[0167] The preparation method was the same as in Example 16, except that the thionium salt of Formula 1z was used instead of the compound of Formula 1j. The reaction was carried out at room temperature for 12 hours, and the target product (8R,9S,13S,14S)-3-methoxy-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentanoic acid[a]phenanthrene-2-carboxylic acid, as shown in Formula 26, was obtained in 38% yield.

[0168] 1 H NMR(DMSO-d6,400MHz): δ12.34(s,1H),7.58(s,1H),6.81(s,1H),3.77 (s,3H),2.9–2.86(m,2H),2.51-1.91(m,6H),1.76(d,J=8.0Hz,1H),1.51-1.32(m,6H),0.81(s,3H).

[0169] Example 27: Carboxylated etherephedrine

[0170]

[0171] Preparation of 2-ethoxy-5-(2-methyl-1-(3-phenoxybenzyl)oxy)prop-2-yl)benzoic acid (compound of formula 27):

[0172] The preparation method was the same as in Example 16, except that the thioonium salt of Formula 1aa was used instead of the compound of Formula 1j. The reaction was carried out at room temperature for 12 hours, and the target product 2-ethoxy-5-(2-methyl-1-(3-phenoxybenzyl)oxy)propyl-2-yl)benzoic acid of Formula 27 was obtained with a yield of 55%.

[0173] 1 H NMR (DMSO-d6, 400MHz): δ12.47(s,1H),7.61(d,J=1.6Hz,1H),7.41–7.38(m,3H),7.31(t,J=8.0Hz,1H),7.14(t,J=7.2Hz,1H),7.01–6.86(m,6H), 4.42(s,2H),4.04(q,J=6.8Hz,2H),3.39(s,2H),1.30(t,J=7.2Hz,3H),1.22(s,6H).

[0174] Example 28: Carboxylated gemfibrozil methyl ester

[0175]

[0176] Preparation of 4-(5-methoxy-4,4-dimethyl-5-oxopentyl)oxy)-2,5-dimethylbenzoic acid (compound of formula 28):

[0177] The preparation method was the same as in Example 16, except that the thionium salt of Formula 1ab was used instead of the compound of Formula 1j. The reaction was carried out at room temperature for 12 hours, and the target product 4-(5-methoxy-4,4-dimethyl-5-oxopentyl)oxy)-2,5-dimethylbenzoic acid, as shown in Formula 28, was obtained with a yield of 68%.

[0178] 1 H NMR(DMSO-d6,400MHz): δ12.35(s,1H),7.67(s,1H),6.77(s,1H),3.97(s,2H),3.58(s,3H),2.51(s,3H),2.12(s,3H),1.64(s,4H),1.15(s,6H).

[0179] Example 29: Preparation of compound of formula 1aa in Example 27

[0180] Using the bioactive molecule ethoxyphenoxyphenate as a raw material, carbon-hydrogen bond sulfidation is achieved with high selectivity at the ortho position of the ethoxy group in complex molecules. The preparation method can be based on existing technology (Nature 2019, 567, 223-228).

[0181]

[0182] The yield was 83%. The product obtained can be used in Example 27 to prepare the aryl carboxylic acid shown in Formula 27.

[0183] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the patent coverage of the present invention.

Claims

1. A method for preparing aryl carboxylic acids by reacting a copper compound-catalyzed aryl thioonium salt with carbon dioxide, characterized in that: Arylthioonium salt, ligand and copper catalyst were mixed, and an organic solvent and diethylzinc were added under a carbon dioxide atmosphere to obtain arylcarboxylic acid after reaction; ； Wherein, the aryl thioonium salt has an aryl Ar group that is phenyl, biphenyl aryl, or dibenzofuranyl; the aryl group may or may not have a substituent, and when it has a substituent, the substituent may be one or more of halogen, alkyl, haloalkyl, alkyloxy, carboxylalkyl, aryloxy, ester, and cyano. The negative ion X in the aryl thioonium salt - It is one or a combination of tetrafluoroborate, trifluoromethanesulfonate, hexafluorophosphate and hexafluoroantimonate. The ligand is N,N' -Dibenzyloxalidyldiamine, N 1, N 2-Bis(2-thienmethyl)-glyoxalamide, N,N' -Diphenyloxalidyldiamine, N 1-Benzyl- N 2-(naphth-1-yl)oxalyldiamine, N 1 ，N 2-Di(naphthyl-1-yl)oxalyldiamine, N 1, N 2-Di([1,1'-biphenyl]-2-yl)oxalyldiamine, N , N , N ', N '-Tetramethylethylenediamine, N 1, N 2-Dimethylethane-1,2-diamine L One or more combinations of valine, 4,7-diphenyl-1,10-phenanthroline and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; The copper catalyst is cuprous chloride, cuprous acetate, cuprous oxide, cuprous bromide, or cuprous iodide.

2. The method for preparing aryl carboxylic acids by reacting copper-catalyzed aryl thioonium salts with carbon dioxide according to claim 1, characterized in that: The ligand is N , N '-Dibenzyloxalyldiamine or N , N , N ', N '-Tetramethylethylenediamine.

3. The method for preparing aryl carboxylic acids by reacting copper-catalyzed aryl thioonium salts with carbon dioxide according to claim 1, characterized in that: The solvent is N , N -Dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide and N A combination of one or more methylpyrrolidones.

4. The method for preparing aryl carboxylic acids by reacting copper-catalyzed aryl thioonium salts with carbon dioxide according to any one of claims 1-3, characterized in that: The specific steps are as follows: Step 1: Under ambient atmosphere, add aryl thioonium salt, copper catalyst and ligand to the container and mix well; the molar ratio of aryl thioonium salt, copper catalyst and ligand is 1:0.05~0.1:0.1~0.2; Step 2: Change the reaction atmosphere in the container to carbon dioxide, add solvent and 1~2 mol / L diethylzinc solution under carbon dioxide gas flow, and stir the reaction at room temperature; Step 3: After the reaction is complete, add a 1-4 mol / L solution of dioxane with hydrogen chloride for acidification, stir for 5 minutes, remove the solvent, and then separate by column chromatography to obtain aryl carboxylic acid.

5. The method for preparing aryl carboxylic acids by reacting copper-catalyzed aryl thioonium salts with carbon dioxide according to any one of claims 1-3, characterized in that: The aryl thioonium salt is synthesized by a highly site-selective carbon-hydrogen bond sulfidation reaction of an aromatic substrate.

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