Aromatic carboxylic acid meta-alkylation products and methods for their synthesis

Abstract

The application discloses an aromatic carboxylic acid meta-alkylation product which is composed of a ligand, an aromatic carboxylic acid, an alkyl halide, a ruthenium catalyst, an alkaline compound, an additive and an organic solvent, and a structural formula of the aromatic carboxylic acid meta-alkylation product is shown in the following formula, wherein R 9 comprises a C1-C5 linear or branched alkyl group, an aryl group or a natural product substituted group; R 10 and R 11 respectively comprise a C1-C2 linear or cyclic alkyl group, fluorine or hydrogen. The application further discloses a synthesis method of the aromatic carboxylic acid meta-alkylation product. The method of the application takes the aromatic carboxylic acid and the alkyl halide as raw materials, takes the commercially available metal ruthenium as a catalyst, takes a nitrogen compound as a ligand, and the product has the characteristics of extremely high regioselectivity, wide substrate applicability, and the like, and the raw materials / catalyst are cheap and easy to obtain, the operation is simple, the atomic economy is high, and the yield is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a meta-alkylated product of aromatic carboxylic acids and its synthesis method. Background Technology

[0002] Alkylation of aromatic hydrocarbons is an important class of reactions in organic synthesis, especially for aromatic compounds containing difluoromethylene, which have important industrial applications in fields such as printing and dyeing, pharmaceuticals, detergents and life sciences.

[0003] Traditional methods use alkylating agents such as halogenated hydrocarbons, alkenes, and alcohols to react with aromatic hydrocarbons to obtain aromatic compounds containing alkane groups. However, the alkylation of aromatic hydrocarbons using traditional methods suffers from several major problems: 1) the use of highly corrosive and environmentally polluting catalysts, such as concentrated H₂SO₄ and anhydrous AlCl₃; 2) substrate limitation to electron-rich aromatic rings; 3) poor regioselectivity of alkylation products; and 4) the generation of byproducts such as over-alkylation and isomerization. Despite the good catalytic performance of traditional aromatic hydrocarbon alkylation reactions, the existence of these problems has sparked considerable interest in researching new synthetic methods.

[0004] With increasing environmental awareness, the use of simple and readily available raw materials for the alkylation of aromatics is attracting more and more attention. For example, the methylation of benzene rings can be prepared using simple benzene rings and methanol, with water as the only byproduct. However, this method also has some drawbacks, such as the need to prepare complex Lewis acid reagents, the limitation of substrates to simple alkyl alcohols, and various regioselectivity issues with aromatic alkylation products (ACS Catal. 2021, 11, 12186-12193; J. Am. Chem. Soc. 2023, 145, 3795-3801).

[0005] Therefore, developing a simple and efficient method for the site-directed alkylation of aromatics is crucial. Aromatic carboxylic acids are well-known for their abundance, structural diversity, ease of acquisition from readily available chemicals, and ability to be converted to various functional groups, making them highly valuable. To date, the alkylation of aromatic carboxylic acids has been limited to ortho-alkylation (JACS., 2007, 129, 3510; J.Am.Chem.Soc. 2016, 138, 10132; Angew.Chem.Int.Ed. 2009, 48, 6097-6100; ACS Catal. 2019, 9, 6738-6743). Meta-alkylation of aromatic carboxylic acids has not yet been reported. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, the present invention aims to provide a meta-alkylated product of aromatic carboxylic acids, which avoids the problems of poor regioselectivity and narrow substrate applicability of alkylated products.

[0007] The present invention also provides a method for synthesizing meta-alkylated products of aromatic carboxylic acids.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] A meta-alkylated product of an aromatic carboxylic acid, comprising a ligand, an aromatic carboxylic acid, an alkyl halide, a ruthenium catalyst, a basic compound, an additive, and an organic solvent, has the structural formula shown below.

[0010]

[0011] Among them, R 9 Including C1-C5 straight-chain or branched alkyl, aryl, or naturally substituted groups;

[0012] R 10 Includes C1-C2 straight-chain or cyclic alkyl groups, fluorine, or hydrogen;

[0013] R 11 Includes C1-C2 straight-chain or cyclic alkyl groups, fluorine, or hydrogen.

[0014] Preferably, the ligand comprises tri-cyclohexylphosphine, tri-methylphosphine, tri-butylphosphine, tri-octylphosphine, diphenylmethylphosphine, triphenylphosphine, tri(4-trifluorotolyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(pentafluorophenyl)phosphine, glycine, N-Boc-L-valine, L-tert-leucine, L-proline, diadamantyl-n-butylphosphine, di-cyclohexyl-phenylphosphine, [1,1'-biphenyl]-2-yldi-cyclohexylphosphine, tri(4-methoxyphenyl)phosphine, trifuranylphosphine, and piperazine. Pyridine-2-carboxylic acid, 5-(trifluoromethyl)pyridin-2-ol, bipyridine, 4,4-dimethoxybipyridine, 4,4-di-tert-butylbipyridine, 4,4-dimethylbipyridine, 4,4-ditrifluoromethylbipyridine, 4,4-dicyanobipyridine, 6,6'-dimethyl-2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, methyl 2,2'-bipyridine-4,4'-dicarboxylate, 5,5'-dibromo-2,2'-bipyridine, [2,2'-bipyridine]- 6,6'(1H,1'H)-dione, 5-bromo-2,2'-bipyridine, 2,2'-bipyridine, 4,4'-diamino-2,2'-bipyridine, 1,10-phenanthroline, 2-bromo-1,10-phenanthroline, 1,10-phenanthroline-5,6-dione, 2,9-dimethyl-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-diphenylphenanthroline, 4,7-dimethoxy-phenanthroline, (E)-N-benzyl-1-(pyridin-2-yl) One or more of the following: toluidine, (2E, 3E)-N2, N3-diphenylbutane-2,3-diimide, (2E, 3E)-N2, N3-diisopropylbutane-2,3-diimide, (2E, 3E)-N2, N3-bis(2,6-diisopropylphenyl)butane-2,3-diimide, N-benzylpyridine amide, N-(2-hydroxyethyl)pyridine amide, N,N'-(ethane-1,2-diacyl)diphenylsulfonamide, or [2,2'-bipyridine]-6,6'-diol.

[0015] Preferably, the ligand is 5,5'-dimethyl-2,2'-bipyridine.

[0016] Preferably, the protective atmosphere is nitrogen.

[0017] Preferably, the aromatic carboxylic acid is One or more of them;

[0018] Among them, R 1 Including methyl, ethyl, methoxy, fluorine, chlorine, or hydrogen;

[0019] R 2 With R 4 These include fluorine, chlorine, bromine, methoxy, or (2-methylallyl)oxy;

[0020] R 3 Including oxydifluoromethyl, oxytrifluoromethyl, methyl, methoxy, methylthio (CH3-S-), fluorine, chlorine, bromine or dimethyl nitrogen (N(Me)2);

[0021] Preferably, the alkyl halide includes One or more of them;

[0022] In each formula, X includes carbon, oxygen, sulfur, or nitrogen;

[0023] R 5 With R 6 Each includes a straight-chain or cyclic alkyl group (C1-C2), fluorine, or hydrogen;

[0024] R 5 With R 6 They are not both hydrogen;

[0025] R 7 Including C1-C5 straight-chain or branched alkyl, aryl, or naturally substituted groups;

[0026] R 8 Including C1-C4 straight-chain or branched alkyl, benzyl, ethyloxytert-butyl (CH2-OtBu), ethyl ester (CH2-COOMe) or hydrogen.

[0027] Preferably, the substituted groups of the natural product include L-menthol. Galactose lipid L(-)-Bornol Estrone West Coast Law Aminoluminate cholesterol or vitamin alcohol One or more of them.

[0028] Preferably, the ruthenium catalyst comprises one or more of the following: tris(triphenylphosphine) dichloride ruthenium(II), di(triphenylphosphine)cyclopentadienyl ruthenium(II), bis-(2-methylallyl)cyclooctyl-1,5-diene ruthenium, chloro(pentamethylcyclopentadienyl)(cyclooctadiene) ruthenium(II), ruthenium trichloride, diiodo(p-cymene) ruthenium(II) dimer, or dichloro(p-cymene) ruthenium(II) dimer.

[0029] Preferably, the ruthenium catalyst is a diiodo(p-cymene)ruthenium(II) dimer.

[0030] Preferably, the alkaline compound includes one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium acetate, sodium acetate, cesium acetate, or potassium acetate.

[0031] Preferably, the alkaline compound is potassium acetate.

[0032] Preferably, the additive includes one or more of bis(trifluoromethanesulfonylimide)silver, silver hexafluoroantimonate, silver trifluoromethanesulfonate, silver tetrafluoroborate, potassium chloride, sodium chloride, lithium chloride, lithium bromide, or lithium phosphate.

[0033] Preferably, the additive is lithium bromide.

[0034] Preferably, the organic solvent includes one or more of 1,4-dioxane, tetrahydrofuran, toluene, cyclohexane, 1,1,1,3,3,3-hexafluoro-2-propanol, trifluoroethanol, tert-butanol, acetonitrile, N-methylpyrrolidone, or N,N-dimethylformamide.

[0035] A method for synthesizing meta-alkylation of aromatic carboxylic acids, comprising the following steps: Under a protective atmosphere, an organic solvent, an aromatic carboxylic acid, an alkyl halide, a ruthenium catalyst, a ligand, a basic compound, and an additive are added sequentially to a reaction vessel. The reaction is carried out at 80–120 °C for 0–12 h to obtain a reaction solution. After subsequent processing, the meta-alkylated aromatic carboxylic acid product is obtained.

[0036] Preferably, the molar ratio of the aromatic carboxylic acid to the alkyl halide is 1.0 to 3.0:1.

[0037] Preferably, the molar ratio of the ruthenium catalyst to the aromatic carboxylic acid is 0.01 to 0.05:1.

[0038] Preferably, the molar ratio of the ruthenium catalyst to the aromatic carboxylic acid is 0.025 to 0.05:1.

[0039] Preferably, the molar ratio of the ligand to the aromatic carboxylic acid is 0.02 to 0.10:1.

[0040] Preferably, the molar ratio of the ligand to the aromatic carboxylic acid is 0.05 to 0.10:1.

[0041] Preferably, the subsequent processing includes one of a first subsequent processing and a second subsequent processing, and the specific steps of the first subsequent processing are as follows:

[0042] The reaction solution was sequentially cooled, pH adjusted, extracted, solvent removed from the organic phase, and purified.

[0043] The specific steps of the second subsequent processing are as follows:

[0044] The reaction solution was mixed with iodomethane and an alkaline compound and reacted at 60°C for 2-6 hours. Then, quenching reaction, extraction, removal of solvent from the organic phase and separation and purification were carried out in sequence.

[0045] Preferably, the specific steps for adjusting the pH value are as follows: adding dilute acid to adjust the pH value of the system to 0.5-1.5, and the extraction is performed using ethyl acetate.

[0046] Preferably, the quenching reaction refers to the addition of a saturated sodium bicarbonate solution to the reaction system.

[0047] Preferably, the removal of solvent from the organic phase refers to the removal of water and organic solvent from the organic phase.

[0048] Preferably, the removal of water from the organic phase refers to drying with a desiccant, namely anhydrous magnesium sulfate, followed by filtration; the removal of organic solvents from the organic phase refers to removing organic solvents by vacuum distillation.

[0049] Preferably, the separation and purification is performed using column chromatography, wherein the eluent for column chromatography includes a mixed solvent of petroleum ether and ethyl acetate, or a mixed solvent of petroleum ether, ethyl acetate and formic acid.

[0050] Preferably, the eluent comprises a mixed solvent of petroleum ether and ethyl acetate or a mixed solvent of petroleum ether, ethyl acetate and formic acid.

[0051] Preferably, the volume ratio of petroleum ether to ethyl acetate is 3-20:1, and the volume ratio of petroleum ether, ethyl acetate and formic acid is 50-80:20-50:1.

[0052] Preferably, the aromatic carboxylic acid used in the first follow-up treatment is as follows:

[0053]

[0054] The present invention has the following advantages and beneficial effects compared with the prior art:

[0055] (1) The method of the present invention uses aromatic carboxylic acids and alkyl halides as raw materials, commercially available ruthenium metal as catalyst, and nitrogen compounds as ligands. The product has the characteristics of extremely high regioselectivity, wide substrate applicability, cheap and readily available raw materials / catalysts, simple operation, high atom economy and high yield.

[0056] (2) The method of the present invention yields a meta-alkylated product of aromatic carboxylic acid, wherein the carboxylic acid is converted into a series of functional groups such as aldehyde, ketone, ester, amide, cyano and benzyl alcohol as a convertible functional group.

[0057] (3) The reaction solutions obtained in the synthesis of some aromatic carboxylic acid meta-alkylation products (e.g., Examples 3, 4, 5, 6, 14, 15) have high separation and purification efficiency when the first post-treatment method is used; other reaction solutions have low separation and purification efficiency when the first post-treatment method is used. In this case, the second post-treatment method is used to methylate them to improve the separation and purification efficiency. Attached Figure Description

[0058] Figure 1 The 1H NMR spectrum of the meta-alkylated aromatic carboxylic acid product obtained in Example 1;

[0059] Figure 2 The 1H NMR spectrum of the meta-alkylated aromatic carboxylic acid product obtained in Example 2;

[0060] Figure 3 The 1H NMR spectrum of the meta-alkylated aromatic carboxylic acid product obtained in Example 3;

[0061] Figure 4 The 1H NMR spectrum of the meta-alkylated aromatic carboxylic acid product obtained in Example 4;

[0062] Figure 5 The 1H NMR spectrum of the meta-alkylated aromatic carboxylic acid product obtained in Example 5;

[0063] Figure 6 The 1H NMR spectrum of the meta-alkylated aromatic carboxylic acid product obtained in Example 6;

[0064] Figure 7 Here are the chemical reaction equations for the synthesis method of this invention; Detailed Implementation

[0065] The invention's objective will be further described in detail below with reference to the accompanying drawings and specific embodiments. The embodiments cannot be described in detail here, but the implementation of the invention is not limited to the following embodiments.

[0066] Example 1

[0067] Under nitrogen protection, 0.6 mmol of benzoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 10:1 (v / v) mixture of petroleum ether and ethyl acetate, yielding 78%. The 1H NMR spectrum of the obtained meta-alkylated aromatic carboxylic acid product is shown below. Figure 1 As shown.

[0068] The structural characterization data of the obtained product are as follows:

[0069] 1 H NMR (500MHz, CDCl3) δ8.14(s,1H),7.99(d,J=7.7Hz,1H),7.63(d,J=7.8Hz,1H),7.47(t,J=7.8Hz,1H),7. 36(d,J=8.1Hz,2H),7.26(t,J=7.8Hz,2H),7.07(t,J=7.4Hz,1H),6.78(s,1H),3.93(s,3H),1.70(s,6H); 13 C NMR (125MHz, CDCl3) δ 174.8 (C q ),166.8(C q ),145.1(C q ),137.8(C q ),131.3(CH),130.8(CH),129.1(C q ),128.9(CH),128.6(CH),127.1(CH),124.3(CH),119.8(CH),52.3(CH3),48.0(C q ),27.0(CH3).

[0070] Based on the above data, the structure of the obtained product can be inferred as follows:

[0071]

[0072] Example 2

[0073] Under nitrogen protection, 0.6 mmol of 2-fluorobenzoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 10:1 (v / v) mixture of petroleum ether and ethyl acetate, with a yield of 90%. The 1H NMR spectrum of the obtained meta-alkylated aromatic carboxylic acid product is shown below. Figure 5 As shown.

[0074] The structural characterization data of the obtained product are as follows:

[0075] 1 H NMR(500MHz, CDCl3)δ7.84-7.80(m,1H),7.57(td,J=7.7,1.6Hz,1H),7.35(d,J=7.7Hz ,2H),7.23-7.18(m,3H),7.01(t,J=7.4Hz,1H),6.91(s,1H),3.82(s,3H),1.61(s,6H); 13 C NMR (125MHz, CDCl3) δ 174.1 (C q ),164.8(d,J C-F =3Hz,C q ),160.1(d,J C-F =263Hz,C q ),137.8(C q ),133.6(d,J C-F =14Hz,CH),131.7(d,J) C-F =5Hz,CH),131.5(CH),128.9(CH),124.3(CH),124.2(d,J C-F =4Hz,C q ),120.2(CH),119.7(d,J C-F =11Hz,C q), 52.4(CH3), 45.9(C q ),26.0(CH3).

[0076] Based on the above data, the structure of the product can be inferred.

[0077]

[0078] Example 3

[0079] Under nitrogen protection, 0.6 mmol of 2-chlorobenzoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH of the system to 0.5–1.5. Ethyl acetate was then added for extraction. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a mixed solvent of petroleum ether:ethyl acetate:formic acid (v / v), with a yield of 79%. The 1H NMR spectrum of the obtained meta-alkylated aromatic carboxylic acid product is shown below. Figure 6 As shown.

[0080] The structural characterization data of the obtained product are as follows:

[0081] 1 H NMR(500MHz,DMSO-d6)δ9.00(s,1H),7.72(d,J=7.6Hz,1H),7.55(dd,J=13.3,7.8Hz, 3H),7.47(t,J=7.7Hz,1H),7.27(t,J=7.8Hz,2H),7.03(t,J=7.3Hz,1H),1.62(s,6H); 13 C NMR(125MHz,DMSO-d6)δ174.7(C q ),168.4(C q ),143.9(C q ),139.8(C q ),135.5(CH),130.8(C q ),130.6(C q ),128.8(CH),128.3(CH),127.5(CH),123.8(CH),121.2(CH),48.3(Cq ),26.7(CH3).

[0082] Based on the above data, the structure of the product can be inferred.

[0083]

[0084] Example 4

[0085] Under nitrogen protection, 0.6 mmol of 3-((2-methylallyl)oxy)benzoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH of the system to 0.5-1.5. Then, ethyl acetate was added for extraction, and the organic phases were combined. The combined organic phases were dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether:ethyl acetate:formic acid with a volume ratio of 50:20:1, and the yield was 80%.

[0086] The structural characterization data of the obtained product are as follows:

[0087] 1 H NMR (400MHz, DMSO-d6) δ13.05(s,1H),9.16(s,1H),7.62-7.50(m,4H),7.37(dd,J=2.5,1.3Hz,1H),7.27(t,J=7.9H z,2H),7.18-7.15(m,1H),7.03(t,J=7.4Hz,1H),5.07(s,1H),4.95(s,1H),4.53(s,2H),1.77(s,3H),1.58(s,6H); 13 C NMR(125MHz,DMSO-d6)δ174.7(Cq),167.6(Cq),158.7(Cq),148.1(Cq),141.1(Cq),139.6(Cq),132.5(Cq),128.9(CH), 123.9(CH),120.8(CH),119.9(CH),118.3(CH),113.0(CH),112.9(CH2),71.6(CH2),47.8(Cq),27.1(CH3),19.7(CH3).

[0088] Based on the above data, the structure of the product can be inferred.

[0089]

[0090] Example 5

[0091] Under nitrogen protection, the following components were added sequentially to the reaction vessel: 0.6 mmol of 4-bromobenzoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol. The reaction was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH of the system to 0.5–1.5, followed by extraction with ethyl acetate.

[0092] The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The target product was then purified by column chromatography using a mixed solvent of petroleum ether:ethyl acetate:formic acid in a volume ratio of 50:20:1, with a yield of 49%.

[0093] The structural characterization data of the obtained product are as follows:

[0094] 1 H NMR(500MHz,DMSO-d6)δ13.28(s,1H),9.00(s,1H),8.16(d,J=2.0Hz,1H),7.79-7.70 (m,2H),7.54(d,J=8.4Hz,2H),7.28-7.21(m,2H),7.02(t,J=7.4Hz,1H),1.64(s,6H); 13 C NMR(125MHz,DMSO-d6)δ174.2(C q ),167.5(C q ),144.3(C q ),139.8(C q ),135.2(CH),130.7(CH),130.4(CH),129.7(C q ),129.0(C q ),128.7(CH),123.7(CH),121.1(CH),49.0(C q ),26.6(CH3).

[0095] Based on the above data, the structure of the obtained product can be inferred as follows:

[0096]

[0097] Example 6

[0098] Under nitrogen protection, 0.6 mmol of 2,5-di-methoxybenzoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH of the system to 0.5-1.5. Then, ethyl acetate was added for extraction, the organic phases were combined, dried with anhydrous magnesium sulfate, filtered, the solvent was removed by vacuum distillation, and the product was purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether:ethyl acetate:formic acid with a volume ratio of 50:20:1, and the yield was 80%.

[0099] The structural characterization data of the obtained product are as follows:

[0100] 1 H NMR(500MHz,DMSO-d6)δ8.84(s,1H),7.65(d,J=8.1Hz,2H),7.25(t,J=7.9Hz,2H),7.1 3(dd,J=6.8,3.0Hz,2H),7.00(t,J=7.4Hz,1H),3.81(s,3H),3.53(s,3H),1.52(s,6H); 13 C NMR(125MHz,DMSO-d6)δ175.5(C q ),168.2(C q ),154.2(C q ),152.2(C q ),141.1(C q ),140.1(CH),128.8(CH),125.5(CH),123.3(C q ),120.6(CH),118.2(CH),113.0(C q ), 61.6(CH3), 55.9(CH3), 46.2(C q ),26.8(CH3).

[0101] Based on the above data, the structure of the obtained product can be inferred as follows:

[0102]

[0103] Example 7

[0104] Under nitrogen protection, 0.6 mmol of 2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 72%.

[0105] The structural characterization data of the obtained product are as follows:

[0106] 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),7.62(s,1H),7.51(d,J=8.0Hz,2H),7.37(s,1H ),7.25(t,J=7.6Hz,2H),7.00(t,J=7.3Hz,1H),4.17(d,J=25.6Hz,4H),1.53(s,6H); 13 C NMR(125MHz,DMSO-d6)δ175.2(C q ),167.6(C q ),163.6(C q ),145.7(C q ),143.5(C q ),139.9(CH),134.5(CH),128.7(CH),123.5(C q ),123.4(CH),121.2(CH),121.1(C q ),117.5(CH),64.6(CH2),64.2(CH2),45.5(C q ),26.0(CH3).

[0107] Based on the above data, the structure of the obtained product can be inferred as follows:

[0108]

[0109] Example 8

[0110] Under nitrogen protection, 0.6 mmol of 1-methyl-1H-indole-5-carboxylic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 92%.

[0111] The structural characterization data of the obtained product are as follows:

[0112] 1 H NMR (400MHz, CDCl3) δ8.35(d,J=1.6Hz,1H),8.11(d,J=1.7Hz,1H),7.43-7.33(m,3H),7.30-7.22( m,2H),7.12-7.02(m,2H),6.66(d,J=3.2Hz,1H),3.89(s,3H),3.89(d,J=4.0Hz,3H),1.86(s,6H); 13 C NMR (100MHz, CDCl3) δ 176.4 (C q ),167.7(C q ),137.6(C q ),136.4(C q ),133.5(CH),131.3(CH),128.8(CH),127.6(C q ),124.5(CH),124.3(C q ),122.2(CH),121.1(C q ),119.8(CH),104.1(CH),51.8(CH3),47.4(C q), 37.8(CH3), 28.6(CH3).

[0113] Based on the above data, the structure of the obtained product can be inferred as follows:

[0114]

[0115] Example 9

[0116] Under nitrogen protection, 0.6 mmol of benzofuran-5-carboxylic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 54%.

[0117] The structural characterization data of the obtained product are as follows:

[0118] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=1.6Hz,1H),8.11(d,J=1.6Hz,1H),7.69(d,J=2.2Hz,1H),7.38-7. 31(m,2H),7.28-7.21(m,2H),7.10-7.01(m,2H),6.84(d,J=2.2Hz,1H),3.95(s,3H),1.83(s,6H); 13 C NMR (100MHz, CDCl3) δ 174.4 (C q ),167.1(C q ),155.1(C q ),146.5(CH),137.9(C q ),128.7(CH),128.2(CH),125.5(C q ),124.1(CH),123.5(CH),122.9(CH),120.0(C q), 107.0 (CH), 52.2 (CH3), 46.0 (C) q ),25.6(CH3).

[0119] Based on the above data, the structure of the obtained product can be inferred as follows:

[0120]

[0121] Example 10

[0122] Under nitrogen protection, 0.6 mmol of 2-methylbenzoic acid, 0.3 mmol of 3-bromo-3-methylbut-2-one, 0.0075 mmol of dichlororuthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1, and the yield was 29%.

[0123] The structural characterization data of the obtained product are as follows:

[0124] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=7.7Hz,1H),7.57(d,J=7.9Hz,1H),7.29(t,J=7.8Hz,1H),3.88(s,3H),2.31(s,3H),1.94(s,3H),1.49(s,6H); 13 CNMR (100MHz, CDCl3) δ 212.8 (C q ),169.1(C q ),144.2(C q ),136.8(C q ),133.1(CH),128.9(CH),128.6(C q ),126.0(CH),53.2(C q ),52.1(CH3),26.0(CH3),25.7(CH3),17.5(CH3).

[0125] Based on the above data, the structure of the obtained product can be inferred as follows:

[0126]

[0127] Example 11

[0128] Under nitrogen protection, 0.6 mmol of 2-methylbenzoic acid, 0.3 mmol of S-(2,6-dimethylphenyl)-2-bromo-2-methylpropanethiol, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1, and the yield was 67%.

[0129] The structural characterization data of the obtained product are as follows:

[0130] 1 H NMR(400MHz, CDCl3) δ7.78(dd,J=7.7,1.3Hz,1H),7.68(dd,J=8.0,1.4Hz,1H),7.33(t,J=7.8Hz,1H),7 .20(dd,J=8.4,6.5Hz,1H),7.12(d,J=7.5Hz,2H),3.91(s,3H),2.55(s,3H),2.32(s,6H),1.72(s,6H); 13 C NMR (100MHz, CDCl3) δ203.0 (C q ),168.9(C q ),143.0(C q ),142.6(C q ),138.6(C q ),132.8(C q ),129.9(CH),129.7(C q ),129.3(CH),128.2(CH),127.3(CH),125.7(CH),54.7(C q),52.0(CH3),27.7(CH3),21.6(CH3),19.3(CH3).

[0131] Based on the above data, the structure of the obtained product can be inferred as follows:

[0132]

[0133] Example 12

[0134] Under nitrogen protection, 0.3 mmol of 2-methylbenzoic acid, 1.2 mmol of methyl 2-bromopropionate, 0.0075 mmol of dichlororuthenium(II) dichloro(p-cymene)dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of sodium carbonate, 0.09 mmol of silver trifluoromethanesulfonate, and 2 mL of tert-butanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of petroleum ether and ethyl acetate, yielding 45%.

[0135] The structural characterization data of the obtained product are as follows:

[0136] 1 H NMR (500MHz, CDCl3) δ7.76-7.72(m,1H),7.43-7.40(m,1H),7.29-7.24(m,1H),5.31(q,J=7.1Hz,1H),4. 08(q,J=7.1Hz,1H),3.79(s,3H),3.66(s,3H),2.55(s,3H),1.61(d,J=7.1Hz,3H),1.48(d,J=7.1Hz,3H); 13 C NMR (125MHz, CDCl3) δ 174.9 (C q ),171.3(C q ),167.8(C q ),140.6(C q ),136.6(CH),131.1(C q ),130.3(CH),128.9(C q ),125.9(CH),69.0(CH),52.4(CH3),52.1(CH3),41.1(CH),18.0(CH3),16.9(CH3),16.1(CH3).

[0137] Based on the above data, the structure of the obtained product can be inferred as follows:

[0138]

[0139] Example 13

[0140] Under nitrogen protection, 0.6 mmol of 2-methylbenzoic acid, 0.3 mmol of 2-bromo-N,N-diethyl-2,2-difluoroacetamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of silver trifluoromethanesulfonate, and 2 mL of tert-butanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1, and the yield was 54%.

[0141] The structural characterization data of the obtained product are as follows:

[0142] 1 H NMR (500MHz, CDCl3) δ7.85(d,J=7.7Hz,1H),7.69(d,J=7.7Hz,1H),7.32(t,J=7.8Hz,1H),3.90(s,3H),3 .46-3.42(m,2H),3.39(q,J=7.9,7.0Hz,2H),2.52(s,3H),1.20(t,J=7.1Hz,3H),1.05(t,J=7.0Hz,3H); 13 C NMR (125MHz, CDCl3) δ 168.1 (C q ),162.4(t,J C-F =30Hz,C q ),138.0(t,J C-F =2.5Hz,C q ),134.3(t,J C-F =23.8Hz,C q ),132.9(CH),131.9(CH),128.6(t,J C-F =8.8Hz,C q ),125.5(CH),116.4(t,J C-F =251.3Hz,Cq ),52.1(CH3),42.1(t,J C-F =5.0Hz,CH2),41.8(CH2),17.0(CH3),13.7(CH3),12.2(CH3).

[0143] Based on the above data, the structure of the obtained product can be inferred as follows:

[0144]

[0145] Example 14

[0146] Under nitrogen protection, 0.6 mmol of 2-methylbenzoic acid, 0.3 mmol of (8R,9S,13S,14S)-14-methyl-15-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadiene[a]phenanthrene-3-yl-2-bromo-2-methylpropionate, and 0.0075 mmol of dichloro( A mixture of ruthenium(II) dimer (p-cymene), 0.015 mmol of 5,5'-dimethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol was stirred at 100 °C for 12 h. Heating and stirring were then stopped, and the mixture was cooled to room temperature. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH of the system to 0.5–1.5. Ethyl acetate was then added for extraction. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a mixed solvent of petroleum ether:ethyl acetate:formic acid in a volume ratio of 50:20:1, yielding 72%.

[0147] The structural characterization data of the obtained product are as follows:

[0148] 1 H NMR (400MHz, DMSO-d6) δ12.97 (s, 1H), 7.62 (d, J = 7.8Hz, 2H), 7.43-7.23 (m, 2H), 6 .88-6.67(m,2H),2.82(dd,J=9.3,4.3Hz,2H),2.54-2.49(m,1H),2.46(s,1H),2. 35-2.29(m,1H),2.23-2.15(m,1H),2.10-2.00(m,1H),1.97-1.87(m,2H),1.76(d ,J=10.1Hz,1H),1.66(s,6H),1.59-1.43(m,3H),1.42-1.27(m,3H),0.81(s,3H); 13C NMR(100MHz,DMSO-d6)δ176.7(C q ),170.4(C q ),148.8(C q ),143.8(C q ),138.4(C q ),137.8(C q ),135.6(C q ),134.6(C q ),128.6(CH),128.3(CH),126.9(CH),126.3(CH),121.5(CH),118.8(CH),50.0(C q ),47.7(C q ),46.9(CH),44.0(CH),37.9(CH),35.8(CH2),31.8(CH2),29.3(CH2),27.4(CH2),26.2(CH3),25.8(CH2),21.6(CH2),17.8(CH3),13.9(CH3).

[0149] Based on the above data, the structure of the obtained product can be inferred as follows:

[0150]

[0151] Example 15

[0152] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH of the system to 0.5-1.5. Then, ethyl acetate was added for extraction, the organic phases were combined, dried with anhydrous magnesium sulfate, filtered, the solvent was removed by vacuum distillation, and the product was purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether:ethyl acetate:formic acid with a volume ratio of 50:20:1, and the yield was 72%.

[0153] The structural characterization data of the obtained product are as follows:

[0154] 1H NMR (500MHz, DMSO-d6) δ8.94(s,1H),8.77(d,J=8.6Hz,1H),8.28(d,J=8.7Hz,1H),8.02(dd,J=7.2,1.1Hz,1H),7.80(d,J=7 .3Hz,1H),7.73-7.67(m,1H),7.56(dd,J=8.8,7.2Hz,1H),7.45(d,J=7.5Hz,2H),7.26-7.15(m,2H),6.99(t,J=7.4Hz,1H); 13 C NMR(125MHz,DMSO-d6)δ176.9(C q ),169.6(C q ),141.4(C q ),139.4(C q ),132.0(C q ),131.8(C q ),130.3(CH),128.8(CH),128.8(CH),128.7(CH),127.4(CH),125.6(C q ),125.5(CH),125.2(CH),124.0(CH),121.2(CH),47.8(C q ),28.2(CH3).

[0155] Based on the above data, the structure of the obtained product can be inferred as follows:

[0156]

[0157] Example 16

[0158] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of N-(2-bromo-2-methylpropionyl)-O-(tert-butyl)serine methyl ester, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, and 2 mL of 1,4-dioxane were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 35%.

[0159] The structural characterization data of the obtained product are as follows:

[0160] 1 H NMR (500MHz, CDCl3) δ8.81(d,J=8.7Hz,1H),8.16(d,J=8.7Hz,1H),8.08(dt,J=6.6,2.9Hz,1H) ,7.77-7.68(m,1H),7.60(ddd,J=8.6,6.8,4.1Hz,1H),7.48(ddt,J=11.2,6.4,2.8Hz,1H),5.90 (d,J=8.4Hz,1H),4.65(dt,J=8.9,3.1Hz,1H),3.99(dd,J=5.3,2.7Hz,3H),3.60(dd,J=4.7,2.5 Hz,3H),3.56(dt,J=8.8,3.3Hz,1H),3.18-2.97(m,1H),1.83(s,3H),1.74(s,3H),0.64(s,9H); 13 C NMR (125MHz, CDCl3) δ 177.7 (C q ),170.7(C q ),168.10(C q ),140.6(C q ),132.4(C q ),131.5(C q ),130.0(CH),129.0(CH),128.6(CH),126.8(C q ),125.9(CH),124.4(CH),124.2(CH),72.7(C q ),61.3(CH2),52.2(CH),52.1(CH3),52.0(CH3),47.0(C q ),28.2(CH3),27.3(CH3),26.5(CH3).

[0161] Based on the above data, the structure of the obtained product can be inferred as follows:

[0162]

[0163] Example 17

[0164] Under nitrogen protection, 0.6 mmol of 6-methoxy-1-naphthoic acid, 0.3 mmol of 2-bromo-2-methyl-N-phenylpropionamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1, and the yield was 65%.

[0165] The structural characterization data of the obtained product are as follows:

[0166] 1 H NMR (400MHz, CDCl3) δ8.88 (dd, J=9.6, 0.9Hz, 1H), 8.36-8.19 (m, 1H), 7.96 (dd, J=7.2, 1.0Hz, 1H), 7.51-7.38 (m,2H),7.25-7.18(m,4H),7.03(tt,J=4.9,3.5Hz,1H),6.83(s,1H),4.01(s,3H),3.96(s,3H),1.95(s,6H); 13 C NMR (100MHz, CDCl3) δ 178.2 (C q ),168.3(C q ),156.8(C q ),138.0(C q ),133.7(C q ),129.1(CH),128.7(CH),128.2(CH),127.8(CH),127.7(C q ),127.3(C q ),125.2(CH),124.1(CH),124.0(CH),120.0(CH),116.4(C q ), 56.5(CH3), 52.3(CH3), 48.8(C q ),28.6(CH3).

[0167] Based on the above data, the structure of the obtained product can be inferred as follows:

[0168]

[0169] Example 18

[0170] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2-bromo-2-methylpropionate, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 71%.

[0171] The structural characterization data of the obtained product are as follows:

[0172] 1 H NMR (400MHz, CDCl3) δ8.81 (d, J = 8.1Hz, 1H), 8.21-8.05 (m, 2H), 7.68-7.54 (m, 2H), 7.48 (d d,J=8.7,7.2Hz,1H),4.76(ddd,J=9.8,3.3,2.1Hz,1H),4.00(s,3H),2.31-2.19(m,1H),1 .79(d,J=1.7Hz,6H),1.51(t,J=4.5Hz,1H),1.48-1.39(m,1H),1.37-1.22(m,1H),1.11-0 .99(m,1H),0.91-0.83(m,1H),0.82(s,3H),0.72(s,3H),0.64-0.55(m,1H),0.46(s,3H); 13 C NMR (125MHz, CDCl3) δ 178.7 (C q ),168.3(C q ),141.3(C q ),132.1(C q ),131.5(C q),129.3(CH),128.9(CH),128.5(CH),126.9(C q ),125.0(CH),124.1(CH),123.1(CH),80.5(CH),52.2(CH3),48.4(C q ),47.4(C q ),46.6(C q ),44.6(CH),36.0(CH2),27.7(CH3),27.5(CH2),26.4(CH2),19.4(CH3),18.7(CH3),13.0(CH3).

[0173] Based on the above data, the structure of the obtained product can be inferred as follows:

[0174]

[0175] Example 19

[0176] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of 2-bromo-N-(1-(2,6-dimethylphenoxy)prop-2-yl)-2-methylpropionamide, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 52%.

[0177] The structural characterization data of the obtained product are as follows:

[0178] 1H NMR(500MHz, CDCl3)δ8.82(d,J=8.7Hz,1H),8.19(d,J=8.7Hz,1H),8.11-8.06(m,1H),7.68 (d,J=6.9Hz,1H),7.58(dd,J=8.5,7.4Hz,1H),7.49(dd,J=8.6,7.3Hz,1H),6.89-6.79(m,3 H),5.68(d,J=8.4Hz,1H),4.30(ddd,J=11.2,6.7,3.4Hz,1H),4.01(s,3H),3.51(dd,J=9.0 ,2.9Hz,1H),3.36(dd,J=9.0,3.7Hz,1H),1.77(s,3H),1.76(s,9H),1.15(d,J=6.8Hz,3H); 13 C NMR (125MHz, CDCl3) δ 177.6 (C q ),168.2(C q ),154.3(C q ),140.8(C q ),132.5(C q ),131.4(C q ),130.4(CH),130.0(C q ),129.3(CH),128.73(CH),128.66(CH),126.9(C q ),126.0(CH),124.4(CH),124.3(CH),123.9(CH),73.5(CH2),52.3(CH3),47.1(CH),45.4(C q ),28.1(CH3),27.9(CH3),17.3(CH3),15.6(CH3).

[0179] Based on the above data, the structure of the obtained product can be inferred as follows:

[0180]

[0181] Example 20

[0182] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of (8S,9R,13R,14R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadiene[a]phenanthrene-3-yl-2-bromo-2-methylpropionate, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of petroleum ether and ethyl acetate, with a yield of 76%.

[0183] The structural characterization data of the obtained product are as follows:

[0184] 1 H NMR (500MHz, CDCl3) δ8.80(d,J=8.6Hz,1H),8.27(d,J=8.7Hz,1H),8.12(d,J=7.2Hz,1H),7.67(d,J=7.2Hz, 1H),7.62-7.58(m,1H),7.57-7.53(m,1H),7.14(d,J=8.5Hz,1H),6.53(dd,J=8.5,2.2Hz,1H),6.49(d,J=1.9 Hz,1H),4.00(s,3H),2.83-2.76(m,2H),2.47(dd,J=19.1,8.7Hz,1H),2.20(d,J=10.2Hz,1H),2.15-2.06(m ,1H),2.04-1.93(m,2H),1.89(s,6H),1.63-1.51(m,2H),1.51-1.39(m,4H),1.39-1.26(m,2H),0.86(s,3H); 13 C NMR (125MHz, CDCl3) δ 177.6 (C q ),168.3(C q ),148.5(C q ),140.5(C q ),137.7(C q),137.2(C q ),132.2(C q ),131.5(C q ),128.9(CH),128.7(CH),127.0(CH),126.1(C q ),125.4(CH),124.5(CH),123.4(CH),121.1(CH),118.3(CH),52.2(CH3),50.3(C q ),47.8(C q ),46.6(C q ),43.9(C q ),37.8(C q ),35.7(CH2),31.4(CH2),29.2(CH2),27.6(CH3),26.2(CH2),25.6(CH2),21.4(CH2),13.7(CH3).

[0185] Based on the above data, the structure of the obtained product can be inferred as follows:

[0186]

[0187] Example 21

[0188] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of (3R, 8R, 9R, 10S, 13S, 14R, 17S)-10,13-dimethyl-17-((S)-6-methylheptane-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecane-1H-cyclopentadiene[a]phenanthrene-3-yl-2-bromo-2-methylpropionate, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, and 0.015 mmol of 4 4'-Ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol potassium acetate, 0.09 mmol lithium bromide, 1.8 mL tert-butanol, and 0.2 mL 1,1,1,3,3,3-hexafluoro-2-propanol were added and stirred at 100 °C for 12 h. Heating and stirring were then stopped, and the mixture was cooled to room temperature. 3.0 mmol methyl iodoform and 0.6 mmol potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of petroleum ether and ethyl acetate, yielding 45%.

[0189] The structural characterization data of the obtained product are as follows:

[0190] 1H NMR (500MHz, CDCl3) δ8.68(dd,J=7.1,2.3Hz,1H),8.00(dd,J=10.7,8.0Hz,2H),7.50(q,J=4.8Hz,2H),7.39(dd,J=8.6,7.3Hz,1H),5. 24-5.18(m,1H),4.60-4.49(m,1H),3.93(s,3H),2.02-1.97(m,1H),1.91-1.86(m,2H),1.86-1.80(m,1H),1.73(dd,J=8.5,4.7Hz,1H), 1.67(d,J=0.9Hz,6H),1.45(ddd,J=19.4,11.8,4.4Hz,4H),1.35(d,J=8.5Hz,1H),1.30-1.24(m,4H),1.14(dd,J=20.0,9.4Hz,4H),1. 13C NMR(125MHz, CDCl3)δ178.0(Cq),168.5(Cq),141.3(Cq),139.5(Cq),132.1(Cq),131.5(Cq),129.2(CH),128.9(CH),128.7(CH ),126.9(CH),125.1(Cq),124.1(CH),123.3(CH),122.5(CH),74.5(CH),56.6(CH),56.1(CH),52.3(CH3),49.9(CH),46.5(Cq), 42.2(Cq),39.7(CH2),39.5(CH2),37.6(CH2),36.8(CH2),36.5(Cq),36.1(Cq),35.7(CH),31.8(CH2),31.8(CH),28.2(CH2),28 .0(CH2),27.7(CH),27.2(CH2),24.2(CH2),23.8(CH2),22.8(CH3),22.5(CH3),20.9(CH2),19.2(CH3),18.7(CH3),11.8(CH3).

[0191] Based on the above data, the structure of the obtained product can be inferred as follows:

[0192]

[0193] Example 22

[0194] Under nitrogen protection, 0.6 mmol of 1-naphthoic acid, 0.3 mmol of (S)-2,5,7,8-tetramethyl-2-((4S,8S)-4,8,12-trimethyltetrazyl)chroman-6-yl-2-bromo-2-methylpropionate, 0.0075 mmol of dichloro(p-cymene)ruthenium(II) dimer, 0.015 mmol of 4,4'-ditrifluoromethyl-2,2'-bipyridine, 0.6 mmol of potassium acetate, 0.09 mmol of lithium bromide, 1.8 mL of tert-butanol, and 0.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 12 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography to obtain the target product. The column chromatography eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 20:1, and the yield was 51%.

[0195] The structural characterization data of the obtained product are as follows:

[0196] 1 H NMR (400MHz, CDCl3) δ8.90(d,J=8.6Hz,1H),8.54(d,J=8.7Hz,1H),8.17(d,J=7.2Hz,1H),7.79(d,J=7 .3Hz,1H),7.70-7.64(m,1H),7.57-7.49(m,1H),4.05(s,3H),2.50(t,J=6.4Hz,2H),2.04(s,9H),1.77 (td,J=13.4,6.9Hz,2H),1.64(s,3H),1.58(s,3H),1.57-1.51(m,2H),1.46-1.38(m,4H),1.34-1.27( m,6H),1.20(dd,J=17.7,10.1Hz,7H),1.14-1.04(m,4H),0.92(d,J=6.6Hz,6H),0.89(d,J=6.3Hz,6H); 13 C NMR (100MHz, CDCl3) δ 176.2 (C q ),168.3(C q ),149.2(C q ),140.3(C q ),140.2(C q),132.3(C q ),131.9(C q ),130.2(CH),129.1(CH),128.6(CH),127.1(C q ),126.8(C q ),125.6(C q ),125.0(C q ),124.3(CH),123.8(CH),122.9(CH),117.2(C q ),74.9(C q ), 52.2(CH3), 47.0(C q ),39.3(CH2),37.4(CH2),37.2(CH2),32.7(CH2),32.6(CH2),28.1(CH),27.9(CH2),24.7(CH3),24.4(CH), 22.7(CH3),22.6(CH2),20.9(CH3),20.5(CH2),19.7(CH3),19.6(CH2),12.8(CH3),11.9(CH3),11.7(CH3).

[0197] Based on the above data, the structure of the obtained product can be inferred as follows:

[0198]

[0199] The above-described specific embodiments are preferred embodiments of the present invention and are not intended to limit the present invention. Any other changes or equivalent substitutions made without departing from the technical solution of the present invention are included within the protection scope of the present invention.

Claims

1. A method for preparing a meta-alkylated product of an aromatic carboxylic acid, characterized in that, The specific steps are as follows: Under a protective atmosphere, an organic solvent, an alkyl halide, an aromatic carboxylic acid, a ruthenium catalyst, a ligand, a basic compound, and an additive are added sequentially to a reaction vessel. The reaction is carried out at 80-120°C for 0-12 hours to obtain a reaction solution. After subsequent processing, the meta-alkylated aromatic carboxylic acid product is obtained. The molar ratio of the alkyl halide to the aromatic carboxylic acid is 1.0~3.0:1; The molar ratio of the ruthenium catalyst to the aromatic carboxylic acid is 0.01~0.05:1; The molar ratio of the ligand to the aromatic carboxylic acid is 0.02~0.10:1; The ligand is 4,4-ditrifluoromethylbipyridine or 5,5'-dimethyl-2,2'-bipyridine; The ruthenium catalyst is a dichloro(p-cymene)ruthenium(II) dimer; The alkaline compound is one of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium acetate, sodium acetate, cesium acetate, or potassium acetate. The additive is one of the following: bis(trifluoromethanesulfonylimide)silver, silver hexafluoroantimonate, silver trifluoromethanesulfonate, silver tetrafluoroborate, potassium chloride, sodium chloride, lithium chloride, lithium bromide, or lithium phosphate. The subsequent processing includes one of a first subsequent processing and a second subsequent processing. The specific steps of the first subsequent processing are as follows: The reaction solution was sequentially cooled, pH adjusted, extracted, solvent removed from the organic phase, and purified. The specific steps of the second subsequent processing are as follows: The reaction solution was mixed with iodomethane and an alkaline compound and reacted at 60°C for 2-6 hours. Then, quenching reaction, extraction, removal of solvent from the organic phase and separation and purification were carried out in sequence. The alkyl halides are 2-bromo-2-methyl-N-phenylpropionamide, 3-bromo-3-methylbut-2-one, S-(2,6-dimethylphenyl)2-bromo-2-methylpropanethiol, methyl 2-bromopropionate, 2-bromo-N,N-diethyl-2,2-difluoroacetamide, (8R,9S,13S,14S)-14-methyl-15-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadiene[a]phenanthrene-3-yl-2-bromo-2-methylpropionate, 2-bromo-2-methyl-N-phenylpropionamide, N-(2-bromo-2-methylpropionyl)-O-(tert-butyl)serine methyl ester, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl-2 2-Bromo-2-methylpropionate, 2-Bromo-N-(1-(2,6-dimethylphenoxy)prop-2-yl)-2-methylpropionamide, (8S,9R,13R,14R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadiene[a]phenanthrene-3-yl-2-bromo-2-methylpropionate The ester, (3R, 8R, 9R, 10S, 13S, 14R, 17S)-10,13-dimethyl-17-((S)-6-methylheptane-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecylhydro-1H-cyclopentadiene[a]phenanthrene-3-yl-2-bromo-2-methylpropionate or (S)-2,5,7,8-tetramethyl-2-((4S,8S)-4,8,12-trimethyltetrazyl)chromium-6-yl-2-bromo-2-methylpropionate; The aromatic carboxylic acid is one of benzoic acid, 2-fluorobenzoic acid, 2-chlorobenzoic acid, 3-((2-methylallyl)oxy)benzoic acid, 4-bromobenzoic acid, 2,5-di-methoxybenzoic acid, 2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylic acid, 1-methyl-1H-indole-5-carboxylic acid, benzofuran-5-carboxylic acid, 2-methylbenzoic acid, 1-naphthoic acid, or 6-methoxy-1-naphthoic acid; The products of the first or second subsequent processing are respectively , , , , , , , , , , , , , , , , , , , , or One of them.

2. The method for preparing a meta-alkylated product of an aromatic carboxylic acid according to claim 1, characterized in that, The organic solvent is one of 1,4-dioxane, tetrahydrofuran, toluene, cyclohexane, 1,1,1,3,3,3-hexafluoro-2-propanol, trifluoroethanol, tert-butanol, acetonitrile, N-methylpyrrolidone, or N,N-dimethylformamide.

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