A method for late-stage carboxylation modification of C-H bond of aromatic hydrocarbon or pyridine by iron compound catalysis

Abstract

The application discloses a method for late-stage carboxylation modification of C-H bond of aromatic hydrocarbon or pyridine after catalysis by iron compound. The method comprises the following steps: using iron compound as a catalyst, using arylthianthrenium salt or pyridine quaternary phosphonium salt prepared from aromatic hydrocarbon or pyridine as a substrate, using diethyl zinc as a reducing agent, and performing reaction under the condition of room temperature and one standard atmosphere of carbon dioxide atmosphere, and then performing acidification and purification treatment to obtain a corresponding carboxylic acid product. The method uses a transition metal iron compound which is good in biological compatibility, high in yield and low in price as the catalyst, has simple and mild conditions, is convenient to operate, has excellent functional group tolerance, can be used for synthesizing various high-value-added aryl or pyridyl carboxylic acids and late-stage site-selective carboxylation modification of complex drug molecules containing benzene rings or pyridine rings, and has significant application potential in the fields of new drug development and industrial production of carboxylic acid compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and in particular relates to a method and application of carboxylation modification of aryl compounds using iron compounds as catalysts. Background Technology

[0002] In recent years, transition metal-catalyzed organic synthesis reactions have developed rapidly and made significant progress. Among them, 3d transition metals, especially copper, nickel, and cobalt, have attracted widespread attention due to their abundant yield, low price, low biotoxicity, and good catalytic activity. New organic reactions catalyzed by 3d transition metals have emerged continuously in recent years, demonstrating significant application potential. Regarding carboxylation reactions using carbon dioxide as the carboxyl source, the carboxylation reactions of haloaromatic hydrocarbons and their derivatives with carbon dioxide catalyzed by transition metals such as palladium, cobalt, nickel, and copper have been widely developed, and these reactions have become important means for the synthesis of aromatic carboxylic acids. Notably, the developed copper-catalyzed carboxylation reactions of aryl thioonium salts and pyridine quaternary phosphonium salts with carbon dioxide have for the first time achieved the synthesis of complex aromatic carboxylic acids and novel isonicotinic acid compounds involving carbon dioxide (Angew. Chem. Int. Ed. 2022, 61, e202212975; Angew. Chem. Int. Ed. 2024, 63, e202318572).

[0003] Compared to transition metals commonly used in catalysts such as palladium, cobalt, nickel, and copper, iron is the most abundant metal in the Earth's crust, even far exceeding the total abundance of other transition metals. Iron has become the most common and inexpensive metal in daily life. Furthermore, iron is a green and biocompatible transition metal. However, to date, iron-catalyzed organic reactions remain very limited (Chem. Rev. 2015, 115, 3170-3387), with the most common being coupling reactions involving Grignard reagents, far fewer in variety than those involving palladium, cobalt, nickel, and copper. In particular, iron-catalyzed carboxylation of aromatic halides and their analogues with carbon dioxide has not yet been achieved. Therefore, iron-catalyzed direct carboxylation of aryl carbon heterobonds with carbon dioxide has significant development potential, especially for the carboxylation of complex drug molecular skeletons. The use of non-toxic iron catalysts is of great importance for drug synthesis. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for the late-stage carboxylation modification of aromatic or pyridine CH bonds using iron compounds.

[0005] The technical solution adopted in this invention is: a method for carboxylating aromatic compounds using iron compounds, wherein an iron compound catalyzes the carboxylation reaction of aryl CS bonds or CP bonds with carbon dioxide, an aromatic compound substrate containing CS bonds or CP bonds, an iron catalyst and ligands are mixed, an organic solvent and diethylzinc are added, and the reaction is carried out under a normal pressure carbon dioxide atmosphere to obtain aryl carboxylic acids.

[0006] Preferably, the iron catalyst is one or more of the following: an inorganic salt of iron, an alkoxide of iron, and a carboxylate of iron; more preferably, it is ferrous chloride, ferric chloride, ferrous bromide, ferrous acetate, or ferrous acetylacetone, and even more preferably, ferrous chloride.

[0007] Preferably, the aryl CS bond is the CS bond in the aryl thiathanethium salt substrate; preferably, the aryl group is phenyl, fused-ring aryl, biphenyl aryl, or heterocyclic aryl, and the aryl group has no substituents or has substituents; when it has substituents, the substituents are one or more of alkyl, ester, alkoxy, halogen, haloalkyl, and cyano groups;

[0008] Alternatively, the aryl CP bond is the CP bond in the pyridine quaternary phosphonium salt substrate, preferably, the pyridine has one or more of aryl, alkyl, halogen and cyano groups;

[0009] Preferably, the aryl group is phenyl, fused-ring aryl, biphenyl aryl, or heterocyclic aryl, and the aryl group may or may not have substituents; when it has substituents, the substituents may be one or more of alkyl, alkoxy, alkenyl, alkynyl, ester, and cyano groups.

[0010] Preferably, the anion in the aryl thioonium salt and / or pyridine quaternary phosphonium salt is one or more of trifluoromethanesulfonate, tetrafluoroborate and hexafluorophosphate.

[0011] Preferably, the ligand is one or more selected from N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-o-phenanthroline, 2,9-dimethyl-1,10-o-phenanthroline, 1,10-o-phenanthroline-4,7-diol, and 4,7-diphenyl-1,10-o-phenanthroline;

[0012] Preferably, when using p-arylthianthaneonium salt as a substrate, the ligand is 4,7-diphenyl-1,10-o-phenanthroline;

[0013] When using p-pyridine quaternary phosphonium salt as a substrate, the ligand is N,N,N',N'-tetramethylethylenediamine.

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

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

[0016] Step 1: Under an inert atmosphere, add the substrate, iron compound, and ligand to the reaction vessel. Add the solvent and 1-2 mol / L diethylzinc solution under a carbon dioxide gas stream and stir the reaction at room temperature. When the ligand is solid, add it simultaneously with the substrate; when the ligand is liquid, add it simultaneously with the solvent.

[0017] Step 2: After the reaction is complete, add a solution of dioxane containing hydrogen chloride to acidify the product. After stirring, extract with water and ethyl acetate. After concentrating the ethyl acetate phase to remove the solvent, the carboxylated product is obtained.

[0018] Preferably, when the substrate is an arylthianthaneonium salt, it also includes lithium chloride, and the molar ratio of the arylthianthaneonium salt, iron compound, ligand and lithium chloride is 1:0.02-0.1:0.04-0.2:1-3; the concentration of the dioxane solution of hydrogen chloride is 1-4 mol / L.

[0019] When the substrate is a pyridine quaternary phosphonium salt, the molar ratio of the pyridine quaternary phosphonium salt substrate, the iron compound, and the ligand is 1:0.1–0.2:0.2–1, and the concentration of the dioxane solution of hydrogen chloride is 1–2 mol / L.

[0020] 7. The method for carboxylating aromatic compounds catalyzed by iron compounds according to claim 6, characterized in that: when the substrate is a pyridine quaternary phosphonium salt, it further includes the following steps;

[0021] Step 3: The crude product containing the carboxylation product is esterified by adding TMSCHN2 dropwise to methanol and diethyl ether solvent to generate the corresponding carboxylic acid methyl ester. The mixing ratio of methanol and diethyl ether is 1:2 to 4. TMSCHN2 is a hexane solution of trimethylsilyldiazomethane with a concentration of 1 to 4 mol / L.

[0022] Preferably, the specific steps for carboxylation of the aryl CS bond are as follows:

[0023] Step 1: Under an inert atmosphere, add the arylthiathaneonium salt substrate, iron compound, ligand, and lithium chloride to the reaction vessel; the molar ratio of arylthiathaneonium salt, iron compound, ligand, and lithium chloride is 1:0.02-0.1:0.04-0.2:1-3; evacuate the reaction vessel to a carbon dioxide atmosphere, and add the solvent and 1-2 mol / L diethylzinc solution using a syringe under a carbon dioxide gas flow, and stir the reaction at room temperature.

[0024] Step 2: After the reaction is complete, acidify with a solution of dioxane containing hydrogen chloride at a concentration of 1-4 mol / L, stir for 5 minutes, extract with water and ethyl acetate, concentrate the ethyl acetate phase to remove the solvent, and then separate by column chromatography to obtain the carboxylated product.

[0025] The specific steps of aryl CP bond carboxylation are as follows:

[0026] Step 1: Add pyridine quaternary phosphonium salt substrate, iron compound, and ligand to the reaction vessel. The molar ratio of pyridine quaternary phosphonium salt substrate, iron compound, and ligand is 1:0.1-0.2:0.2-1. Add solvent and 1-2 mol / L diethylzinc solution, and stir the reaction at room temperature under a carbon dioxide atmosphere. When the ligand is solid, add it simultaneously with the substrate; when the ligand is liquid, add it simultaneously with the solvent. After the reaction is complete, acidify with a 1-2 mol / L solution of dioxane chloride. After stirring, extract with water and ethyl acetate. Concentrate the ethyl acetate phase to remove the solvent and obtain the crude carboxylic acid product.

[0027] Step 2: The crude product is esterified by adding TMSCHN2 dropwise in methanol and diethyl ether solvent to generate the corresponding carboxylic acid methyl ester. The ratio of methanol to diethyl ether is 1:2 to 4, and the TMSCHN2 used is a hexane solution of trimethylsilyldiazomethane with a concentration of 1 to 4 mol / L.

[0028] A method for late-stage carboxylation modification of aromatic hydrocarbons or pyridines using iron compounds as catalysts, wherein the aromatic compounds are aromatic hydrocarbons or pyridines; selective thiaanthrylation of the aromatic hydrocarbon CH bonds to obtain arylthiaanthrium salts, or selective phosphonylation of the pyridine C4-H bonds to obtain pyridine quaternary phosphonium salts, and further modification by carboxylation modification of aromatic compounds using iron compounds as catalysts.

[0029] Application of iron-catalyzed carboxylation modification methods for aromatic compounds, or iron-catalyzed late-stage carboxylation modification methods for aromatic hydrocarbons or pyridines, in the carboxylation modification of drug molecule skeletons.

[0030] The application of iron-catalyzed carboxylation modification methods for aromatic compounds, or iron-catalyzed late-stage carboxylation modification methods for aromatic or pyridine CH bonds, in the synthesis of carboxylic acid compounds.

[0031] The advantages and positive effects of this invention are: the modification method uses an iron catalyst, which is a green, non-toxic, inexpensive, and high-yield catalyst with good biocompatibility and can be applied to drug synthesis processes;

[0032] Furthermore, this method uses non-toxic and readily available carbon dioxide as the carboxyl source and diethylzinc as the reducing agent, and the reaction is carried out at room temperature and one standard atmosphere. The conditions are simple, mild, and easy to operate. It has excellent functional group tolerance and can be used to synthesize a variety of high-value aryl or pyridyl carboxylic acids as well as for the late-stage site-selective carboxylation modification of complex drug molecules containing benzene or pyridine rings. It shows significant application potential in new drug development and the industrial production of carboxylic acid compounds. Detailed Implementation

[0033] The following description is based on embodiments of the present invention.

[0034] This invention relates to a method and application for carboxylation modification of aromatic compounds. It achieves carboxylation modification of aryl compounds by directly carboxylating aryl CS or CP bonds with carbon dioxide using iron compounds as catalysts. This invention represents the first successful application of iron-catalyzed reactions to prepare aromatic carboxylic acids using carbon dioxide as the carboxyl source, thus expanding the types of iron-catalyzed reactions.

[0035] Arylthiathaneonium salt or pyridine quaternary phosphonium salt is mixed with iron catalyst and ligands, and additives may be added if necessary; organic solvent and diethylzinc are added under carbon dioxide atmosphere, and the reaction is carried out at room temperature. After acidification and quenching, the carboxylic acid product is obtained.

[0036]

[0037] In the reaction process, diethylzinc first reacts with ferrous chloride to generate diethylferric chloride. Diethylferric chloride undergoes β-H elimination and reductive elimination, releasing ethane and ethylene, generating a catalytically active zero-valent iron species. The zero-valent iron species and the substrate break the CS or CP bond of the substrate through single-electron transfer, generating aryl radicals and monovalent iron salts. Then, the aryl radicals combine with the monovalent iron salts to generate divalent aryl iron intermediates. Carbon dioxide inserts into the divalent aryl C-Fe(II) bond to generate aryl carboxylic acid iron intermediates. This intermediate exchanges with diethylzinc ligands to regenerate the diethylferric species, realizing a catalytic cycle. Simultaneously, the generated aryl carboxylic acid zinc species is protonated to obtain the carboxylic acid product.

[0038] The specific preparation steps are as follows:

[0039] Iron compounds catalyze the direct carboxylation of aryl CS bonds with carbon dioxide, using p-arylthianthaneonium salts as substrates. The reflux process is as follows:

[0040]

[0041] Step 1: Under an inert atmosphere, add arylthianthaneonium salt substrate, iron compound, ligand and lithium chloride to the reaction vessel; wherein the molar ratio of arylthianthaneonium salt, iron compound, ligand and lithium chloride is 1:0.02~0.1:0.04~0.2:1~3;

[0042] Step 2: Vacuum the reaction vessel to a carbon dioxide atmosphere, add solvent and 1-2 mol / L diethylzinc solution using a syringe under a carbon dioxide gas flow, and stir the reaction at room temperature;

[0043] Step 3: After the reaction is complete, acidify with a dioxane solution of hydrogen chloride at a concentration of 1-4 mol / L, stir for 5 minutes, extract with water and ethyl acetate, concentrate the ethyl acetate phase to remove the solvent, and then separate by column chromatography to obtain the carboxylated product.

[0044] Iron compounds catalyze the direct carboxylation of aryl CP bonds with carbon dioxide, using p-pyridine quaternary phosphonium salts as substrates. The reflux process is as follows:

[0045]

[0046] Step 1: Under an inert atmosphere, add the pyridine quaternary phosphonium salt substrate, iron compound, and ligand (the ligand is solid) to the reaction vessel. The molar ratio of the pyridine quaternary phosphonium salt substrate, iron compound, and ligand is 1:0.1–0.2:0.2–1.

[0047] Step 2: Vacuum the reaction vessel to a carbon dioxide atmosphere, and add the solvent, 1-2 mol / L diethylzinc solution and ligand (liquid ligand) using a syringe under a carbon dioxide gas flow. Stir the reaction at room temperature.

[0048] Step 3: After the reaction is complete, add a solution of dioxane containing hydrogen chloride (1-2 mol / L) to acidify the product. Stir for 10 minutes, extract with water and ethyl acetate, concentrate the ethyl acetate phase to remove the solvent, and then obtain the carboxylated product.

[0049] The crude carboxylic acid product obtained in the above steps can be directly converted into the corresponding methyl carboxylic acid ester product without separation, following the steps below:

[0050] Step 4: The crude carboxylic acid product was esterified by adding TMSCHN2 dropwise to methanol and diethyl ether solvent. The reaction was carried out at room temperature for 10 minutes. After the reaction was completed, the solvent was removed by concentration, and the product was separated by column chromatography to obtain the methyl carboxylic acid ester product. The ratio of methanol to diethyl ether was 1:2 to 4. The TMSCHN2 used was a hexane solution of trimethylsilyldiazomethane with a concentration of 1 to 4 mol / L.

[0051] In some embodiments of the present invention, the iron compound is one or more of the following: an inorganic salt of iron, an alkoxide of iron, and a carboxylate of iron; preferably one or more of ferrous chloride, ferrous bromide, ferrous acetate, and ferrous acetylacetone, and more preferably ferrous chloride.

[0052] In arylthianthracene salts, the aryl group is phenyl, fused-ring aryl, biphenyl-based aryl, or heterocyclic aryl, and may or may not have substituents. When substituents are present, they are one or more of alkyl, ester, alkyloxy, halogen, haloalkyl, and cyano. In pyridine quaternary phosphonium salts, the pyridine group has one or more of aryl, alkyl, halogen, and cyano groups. When an aryl group is attached to the pyridine, it is phenyl, fused-ring aryl, biphenyl-based aryl, or heterocyclic aryl, and may or may not have substituents. When substituents are present, they are one or more of alkyl, alkyloxy, alkenyl, alkynyl, ester, and cyano groups. The anions in arylthianthracene salts and pyridine quaternary phosphonium salts are one or more combinations of trifluoromethanesulfonate, tetrafluoroborate, and hexafluorophosphate.

[0053] The ligand is one or more selected from N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-o-phenanthroline, 2,9-dimethyl-1,10-o-phenanthroline, 1,10-o-phenanthroline-4,7-diol, and 4,7-diphenyl-1,10-o-phenanthroline. The ligand used for arylthianonium salt substrates is preferably 4,7-diphenyl-1,10-o-phenanthroline; the ligand used for p-pyridine quaternary phosphonium salt substrates is preferably N,N,N',N'-tetramethylethylenediamine. The solvent is one or more combinations of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide; preferably N,N-dimethylacetamide.

[0054] This method involves simple substrate preparation, mild conditions, convenient operation, good functional group compatibility, and yields complex carboxylic acid products with high added value. Iron catalysts are inexpensive, readily available, and biocompatible, making them suitable for structure-activity relationship studies and new drug development.

[0055] The arylthianthaneonium salt substrates and pyridine quaternary phosphonium salt substrates in this invention are synthesized by highly selective CH bond sulfonation and phosphonation of the corresponding aromatic hydrocarbons or pyridine derivatives. The preparation conditions are simple, mild, and highly selective.

[0056] Selective CH bond sulfonation of aromatics:

[0057]

[0058] Selective C4-H bond phosphonation of pyridine:

[0059]

[0060] This method indirectly achieves the selective CH bond carboxylation reaction of aromatics and pyridine with carbon dioxide. This strategy is suitable for late-stage carboxylation modification of complex molecules, especially structurally complex drug molecules. Iron catalysts are the lowest-cost, most biocompatible, and most practically valuable catalysts. Therefore, the carboxylation modification method disclosed in this invention has promising applications in industrial production and drug development.

[0061] The following description is based on the present invention. 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.

[0062] Example 1:

[0063]

[0064] Preparation of p-Toluic Acid (Compound of Formula 1):

[0065] In a 50 mL Schlenk tube, p-methylphenylthiazine salt (Formula 1a, 0.3 mmol), ferrous chloride (0.03 mmol), 4,7-diphenyl-1,10-o-phenanthroline (0.06 mmol), and lithium chloride (0.6 mmol) were added sequentially. The tube was then purged to a carbon dioxide atmosphere. Under a 1 atm carbon dioxide flow, 1 mL of N,N-dimethylacetamide and 0.6 mL of 2.0 mol / L diethylzinc toluene solution were added sequentially using a syringe. The reaction tube was then closed, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 3 mL of dioxane chloride solution (4 mol / L) was added for acidification. The mixture was extracted with water and ethyl acetate, and the ethyl acetate phase was concentrated by evaporation. The sample was prepared by dry chromatography and purified by column chromatography using petroleum ether, ethyl acetate, and trace amounts of acetic acid as the developing solvent, yielding p-methylbenzoic acid as shown in Formula 1, in 82% yield.

[0066] 1 H NMR (DMSO-d6, 400MHz): δ12.81 (s, 1H), 7.84 (d, J = 8.0Hz, 2H), 7.28 (d, J = 7.6Hz, 2H), 2.35 (s, 3H).

[0067] Example 2:

[0068]

[0069] Preparation of p-methoxybenzoic acid (compound of formula 2):

[0070] The preparation process was the same as in Example 1, except that p-methoxyphenylthiathranilium 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 product p-methoxybenzoic acid shown in formula 2 was obtained after treatment, with a yield of 65%.

[0071] 1 H NMR (DMSO-d6, 600MHz): δ12.59 (s, 1H), 7.89 (d, J = 8.4Hz, 2H), 7.00 (d, J = 7.8Hz, 2H), 3.81 (s, 3H).

[0072] Example 3:

[0073]

[0074] Preparation of p-iodobenzoic acid (compound of formula 3):

[0075] The preparation process was the same as in Example 1, except that p-iodophenylthiathranilium salt (compound of formula 1c) was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the product p-iodobenzoic acid shown in formula 3 was obtained after treatment, with a yield of 66%.

[0076] 1 H NMR (DMSO-d6, 600MHz): δ13.12 (s, 1H), 7.86 (d, J = 8.4Hz, 2H), 7.68 (d, J = 8.4Hz, 2H).

[0077] Example 4:

[0078]

[0079] Preparation of 4-(3-chloropropyl)benzoic acid (compound of formula 4):

[0080] The preparation process was the same as in Example 1, except that 4-(3-chloropropyl)phenylthioonium salt (compound of formula 1d) was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the product 4-(3-chloropropyl)benzoic acid, as shown in formula 4, was obtained after treatment, with a yield of 66%.

[0081] 1 H NMR (DMSO-d6, 600MHz): δ12.80 (s, 1H), 7.87 (d, J = 7.8Hz, 2H), 7.34 (d, J = 7.8Hz, 2H), 3.62 (t, J = 6.0Hz, 2H), 2.77 (t, J = 7.2Hz, 2H), 2.05-2.01 (m, 2H).

[0082] Example 5:

[0083]

[0084] Preparation of 4-bromo-2,5-dimethylbenzoic acid (compound of formula 5):

[0085] The preparation method was the same as in Example 1, except that 4-bromo-2,5-dimethylphenylthiathanemonium 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 product 4-bromo-2,5-dimethylbenzoic acid, shown in formula 5, was obtained after treatment, with a yield of 73%.

[0086] 1 H NMR (DMSO-d6, 600MHz): δ12.93(s,1H),7.76(s,1H),7.52(s,1H),2.45(s,3H),2.32(s,3H).

[0087] Example 6:

[0088]

[0089] Preparation of 4'-((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-4-carboxylic acid (compound of formula 6):

[0090] The preparation process was the same as in Example 1, except that the thiaanthraium salt of Formula 1f was used instead of the compound of Formula 1a. The reaction was carried out at room temperature for 12 hours, and the product 4'-((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-4-carboxylic acid, as shown in Formula 6, was obtained with a yield of 73%.

[0091] 1 H NMR (DMSO-d6, 600MHz): δ13.11 (s, 1H), 8.04 (d, J = 7.2Hz, 2H), 7.91 (d, J = 7.8Hz, 2H), 7.82 (d, J = 7.8Hz, 2H), 7.61 (d, J = 8.4Hz, 2H).

[0092] Example 7:

[0093]

[0094] Preparation of 4-(4-bromophenoxy)benzoic acid (compound of formula 7):

[0095] The preparation method was the same as in Example 1, except that the thiaanthraium salt of Formula 1g was used instead of the compound of Formula 1a. The reaction was carried out at room temperature for 12 hours, and the target product 4-(4-bromophenoxy)benzoic acid of Formula 7 was obtained after treatment, with a yield of 75%.

[0096] 1H NMR (DMSO-d6, 600MHz): δ12.85 (s, 1H), 7.96 (d, J = 8.4Hz, 2H), 7.60 (d, J = 8.4Hz, 2H), 7.08-7.05 (m, 4H).

[0097] Example 8:

[0098]

[0099] Preparation of 4-(4-iodophenoxy)benzoic acid (compound of formula 8):

[0100] The preparation method was the same as in Example 1, except that the thiaanthraium salt of Formula 1h was used instead of the compound of Formula 1a. The reaction was carried out at room temperature for 12 hours, and the product 4-(4-bromophenoxy)benzoic acid of Formula 8 was obtained after treatment, with a yield of 64%.

[0101] 1 H NMR (DMSO-d6, 600MHz): δ12.86 (s, 1H), 7.95 (d, J = 7.8Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.06 (d, J = 8.4Hz, 2H), 6.94 (d, J = 7.8Hz, 2H).

[0102] Example 9:

[0103]

[0104] Preparation of 4-(3-cyano-2-fluorophenoxy)benzoic acid (compound of formula 9):

[0105] The preparation method was the same as in Example 1, except that the thiaanthraium salt of Formula 1i was used instead of the compound of Formula 1a. The reaction was carried out at room temperature for 12 hours, and the product 4-(3-cyano-2-fluorophenoxy)benzoic acid of Formula 9 was obtained after treatment, with a yield of 55%.

[0106] 1 H NMR (DMSO-d6, 600MHz): δ13.02 (s, 1H), 8.03 (d, J = 8.4Hz, 2H), 7.76 (q, J = 7.8Hz, 1H), 7.33 (t, J = 9.0Hz, 1H), 7.28 (d, J = 8.4Hz, 2H), 6.96 (d, J = 8.4Hz, 1H).

[0107] Example 10:

[0108]

[0109] Preparation of 2'-fluoro-4'-(1-methoxy-1-oxopropyl-2-yl)-[1,1'-biphenyl]-4-carboxylic acid (compound of formula 10):

[0110] The preparation process was the same as in Example 1, except that the thiaanthraium salt shown in 1j was used instead of compound 1a. The reaction was carried out at room temperature for 12 hours, and the product 2'-fluoro-4'-(1-methoxy-1-oxopropyl-2-yl)-[1,1'-biphenyl]-4-carboxylic acid, as shown in Formula 10, was obtained with a yield of 58%.

[0111] 1 H NMR (DMSO-d6, 600MHz): δ13.04(s,1H),8.03(d,J=7.8Hz,2H),7.67(d,J=7.2Hz,2H),7.54( t,J=7.8Hz,1H),7.29-7.24(m,2H),3.93-3.90(m,1H),3.62(s,3H),1.43(d,J=6.6Hz,3H).

[0112] Example 11:

[0113]

[0114] Preparation of methyl 2-phenylisonicotinic acid (compound of formula 11):

[0115] In a 50 mL Schlenk tube, p-pyridine quaternary phosphonium salt substrate (Formula 1k, 0.3 mmol) and ferrous chloride (0.03 mmol) were added sequentially. The tube was then purged to a carbon dioxide atmosphere. Under a 1 atm carbon dioxide stream, 1 mL of N,N-dimethylacetamide, 0.3 mmol of N,N,N',N'-tetramethylethylenediamine, and 0.6 mL of diethylzinc solution (2.0 mol / L toluene solution) were added sequentially. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the solution was acidified with 2 mL of 1 mol / L dioxane hydrochloride solution, stirred for 10 minutes, and then extracted with ethyl acetate. The ethyl acetate phase was evaporated and concentrated to obtain crude 2-phenylisonicotinic acid. Add 4 mL of diethyl ether and 1 mL of methanol to the crude product, and slowly add 2 mL of trimethylsilyldiazomethane solution (2.0 mol / L n-hexane solution) while stirring until the carboxylic acid esterification is complete. Concentrate by rotary evaporation, prepare the sample by dry method, and separate and purify by column chromatography with petroleum ether / ethyl acetate as the developing solvent to obtain the product methyl 2-phenylisonicotinic acid shown in Formula 11, with a yield of 81%.

[0116] 1 H NMR (CDCl3, 600MHz): δ8.84(d,J=4.8Hz,1H),8.30(s,1H),8.06(d,J=7.8Hz,2H),7.77(d,J=4.2Hz,1H),7.51-7.44(m,3H),3.99(s,3H).

[0117] Example 12:

[0118]

[0119] Preparation of methyl 2-propylisonicotinic acid (compound 112):

[0120] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonium salt of Formula 11 was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the target product methyl 2-propyl isonicotinic acid of Formula 12 was obtained after treatment, with a yield of 68%.

[0121] 1 H NMR (CDCl3, 600MHz): δ8.62(d,J=4.8Hz,1H),7.65(s,1H),7.59(d,J=4.2Hz,1H), 3.89(s,3H),2.79(t,J=7.2Hz,2H),1.73(q,J=7.2Hz,2H),0.92(t,J=7.2Hz,3H).

[0122] Example 13:

[0123]

[0124] Preparation of methyl 2-cyanoisonicotinic acid (compound of formula 13):

[0125] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonium salt of Formula 1m was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the target product methyl 2-cyanoisonicotinic acid of Formula 13 was obtained after treatment, with a yield of 51%.

[0126] 1 H NMR (CDCl3, 600MHz): δ8.88 (d, J = 4.2 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 3.99 (s, 3H).

[0127] Example 14:

[0128]

[0129] Preparation of methyl 2-(4-bromophenyl)isonicotinic acid (compound of formula 14):

[0130] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonium salt of Formula 1n was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the target product methyl 2-(4-bromophenyl)isonicotinic acid of Formula 14 was obtained after treatment, with a yield of 82%.

[0131] 1H NMR (CDCl3, 600MHz): δ8.82 (d, J = 4.2 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 4.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 3.99 (s, 3H).

[0132] Example 15:

[0133]

[0134] Preparation of methyl 2-(4-vinylphenyl)isonicotinic acid (compound of formula 1o):

[0135] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonate of Formula 10 was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the product 2-(4-vinylphenyl)isonicotinic acid methyl ester of Formula 15 was obtained after treatment, with a yield of 64%.

[0136] 1 H NMR (CDCl3, 600MHz): δ8.83(d,J=4.8Hz,1H),8.30(s,1H),8.04(d,J=7.8Hz,2H),7.76(d,J=4.2Hz,1H),7.54 (d,J=8.4Hz,2H),6.78(dd,J=17.4,10.8Hz,1H),5.85(d,J=18.0Hz,1H),5.33(d,J=10.8Hz,1H),3.99(s,3H).

[0137] Example 16:

[0138]

[0139] Preparation of methyl 2-(3-(phenylethynyl)phenyl)isonicotinic acid (compound of formula 1o):

[0140] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonium salt of Formula 1p was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the product 2-(3-(phenylethynyl)phenyl)isonicotinic acid methyl ester of Formula 16 was obtained after treatment, with a yield of 61%.

[0141] 1H NMR (CDCl3, 600MHz): δ8.85(d,J=4.8Hz,1H),8.33(s,1H),8.25(s,1H),8.04(d,J=7.8Hz,1H),7.81(d,J=4.8H z,1H),7.61(d,J=7.2Hz,1H),7.57(d,J=6.0Hz,2H),7.49(t,J=7.8Hz,1H),7.36(d,J=7.2Hz,3H),4.00(s,3H).

[0142] Example 17:

[0143]

[0144] Preparation of methyl 2-(benzofuran-2-yl)isonicotinic acid (compound of formula 1q):

[0145] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonium salt of Formula 1q was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the product 2-(3-(phenylethynyl)phenyl)isonicotinic acid methyl ester of Formula 17 was obtained after treatment, with a yield of 86%.

[0146] 1 H NMR (CDCl3, 600MHz): δ8.81 (s, 1H), 8.42 (s, 1H), 7.77 (s, 1H), 7.66 (d, J = 7.8Hz, 1H), 7. 59(d,J=8.4Hz,1H),7.49(s,1H),7.36(t,J=7.2Hz,1H),7.28-7.26(m,1H),4.00(s,3H).

[0147] Example 18:

[0148]

[0149] Preparation of (4-(methoxycarbonyl)pyridin-2-yl)methylene)bis(4,1-phenylene)diacetate (compound of formula 18, carboxylated-bisacodyl):

[0150] The preparation process was the same as in Example 11, except that the pyridine quaternary phosphonium salt of Formula 1r was used instead of the compound of Formula 1k. The reaction was carried out at room temperature for 24 hours, and the product carboxylated bisacodyl of Formula 18 was obtained after treatment, with a yield of 43%.

[0151] 1 H NMR (CDCl3, 600MHz): δ8.75 (s, 1H), 7.72 (s, 2H), 7.19 (d, J = 7.8Hz, 4H), 7.03 (d, J = 8.4Hz, 4H), 5.72 (s, 1H), 3.91 (s, 3H), 2.28 (s, 6H).

[0152] Example 19: Preparation of compound of formula 1a

[0153] The aryl thiathracene salt substrate was prepared by late-stage selective CH bond sulfonation of aromatic hydrocarbons. Taking compound 1a as an example, the preparation method can be based on existing technology (Nature 2019, 567, 223-228); the yield was 83%. The prepared thiathracene salt substrate can be used to prepare p-toluic acid as shown in Formula 1 in Example 1.

[0154]

[0155] Example 20: Preparation of compound of formula 1k

[0156] The pyridine quaternary phosphonium salt substrate was prepared by selective C4-H phosphonation of pyridine. Taking compound 1k as an example, the preparation method can be based on existing technology (J. Am. Chem. Soc. 2016, 138, 13806–13809); the yield was 85%. The prepared pyridine quaternary phosphonium salt substrate could be used in Example 11 to prepare methyl 2-phenylisonicotinic acid as shown in Formula 11.

[0157]

[0158] 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 carboxylating aromatic compounds using iron compounds as catalysts, characterized in that: Aryl carboxylic acids are obtained by catalyzing the carboxylation of aryl CS or CP bonds with carbon dioxide using iron compounds. An aromatic compound substrate containing CS or CP bonds, an iron catalyst, and ligands are mixed, and an organic solvent and diethylzinc are added. The reaction is carried out under a normal pressure carbon dioxide atmosphere.

2. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to claim 1, characterized in that: The iron catalyst is one or more of the following: inorganic salts of iron, alkoxides of iron, and carboxylates of iron; preferably ferrous chloride, ferric chloride, ferrous bromide, ferrous acetate, or ferrous acetylacetone, and more preferably ferrous chloride.

3. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to claim 1, characterized in that: The aryl CS bond is the CS bond in the aryl thiathanethium salt substrate; preferably, the aryl group is phenyl, fused-ring aryl, biphenyl aryl, or heterocyclic aryl, and the aryl group has no substituents or has substituents; when it has substituents, the substituents are one or more of alkyl, ester, alkoxy, halogen, haloalkyl, and cyano; or, the aryl CP bond is the CP bond in the pyridine quaternary phosphonium salt substrate, preferably, the pyridine has one or more of aryl, alkyl, halogen, and cyano groups; Preferably, the aryl group is phenyl, fused-ring aryl, biphenyl aryl, or heterocyclic aryl, and the aryl group may or may not have substituents; when it has substituents, the substituents may be one or more of alkyl, alkoxy, alkenyl, alkynyl, ester, and cyano groups. Preferably, the anion in the aryl thioonium salt and / or pyridine quaternary phosphonium salt is one or more of trifluoromethanesulfonate, tetrafluoroborate and hexafluorophosphate.

4. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to claim 1, characterized in that: The ligand is one or more of N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-o-phenanthroline, 2,9-dimethyl-1,10-o-phenanthroline, 1,10-o-phenanthroline-4,7-diol and 4,7-diphenyl-1,10-o-phenanthroline; Preferably, when using p-arylthianthaneonium salt as a substrate, the ligand is 4,7-diphenyl-1,10-o-phenanthroline; When using p-pyridine quaternary phosphonium salt as a substrate, the ligand is N,N,N',N'-tetramethylethylenediamine.

5. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to claim 1, characterized in that: The solvent is one or more combinations of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide; preferably N,N-dimethylacetamide.

6. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to any one of claims 1-5, characterized in that: The specific steps are as follows: Step 1: Under an inert atmosphere, add the substrate, iron compound, and ligand to the reaction vessel. Add the solvent and 1-2 mol / L diethylzinc solution under a carbon dioxide gas stream and stir the reaction at room temperature. When the ligand is solid, add it simultaneously with the substrate; when the ligand is liquid, add it simultaneously with the solvent. Step 2: After the reaction is complete, add a solution of dioxane containing hydrogen chloride to acidify the product. After stirring, extract with water and ethyl acetate. After concentrating the ethyl acetate phase to remove the solvent, the carboxylated product is obtained. Preferably, when the substrate is an arylthianthaneonium salt, it also includes lithium chloride, and the molar ratio of the arylthianthaneonium salt, iron compound, ligand and lithium chloride is 1:0.02-0.1:0.04-0.2:1-3; the concentration of the dioxane solution of hydrogen chloride is 1-4 mol / L. When the substrate is a pyridine quaternary phosphonium salt, the molar ratio of the pyridine quaternary phosphonium salt substrate, the iron compound, and the ligand is 1:0.1–0.2:0.2–1, and the concentration of the dioxane solution of hydrogen chloride is 1–2 mol / L.

7. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to claim 6, characterized in that: When the substrate is a pyridine quaternary phosphonium salt, the following steps are also included; Step 3: The crude product containing the carboxylation product is esterified by adding TMSCHN2 dropwise to methanol and diethyl ether solvent to generate the corresponding carboxylic acid methyl ester. The mixing ratio of methanol and diethyl ether is 1:2 to 4. TMSCHN2 is a hexane solution of trimethylsilyldiazomethane with a concentration of 1 to 4 mol / L.

8. A method for late-stage carboxylation modification of aromatic or pyridine bonds catalyzed by iron compounds, characterized in that: The aromatic compound is an aromatic hydrocarbon or pyridine; the selective thiaanthrylation of the CH bond of the aromatic hydrocarbon yields an aryl thiaanthrene salt, or the selective phosphonylation of the C4-H bond of pyridine yields a pyridine quaternary phosphonium salt, which is then further modified by the carboxylation modification method of the aromatic compound catalyzed by any one of claims 1-7.

9. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to any one of claims 1-7, or the method for late-stage carboxylation modification of aromatic hydrocarbons or pyridine CH bonds catalyzed by iron compounds according to claim 8, is used in the carboxylation modification of drug molecule skeletons.

10. The method for carboxylation modification of aromatic compounds catalyzed by iron compounds according to any one of claims 1-7, or the method for late-stage carboxylation modification of aromatic or pyridine CH bonds catalyzed by iron compounds according to claim 8, in the synthesis of carboxylic acid compounds.

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