Preparation method of 2-methyl biarene derivative

Abstract

The invention discloses a preparation method of a 2-methyl biaromatic hydrocarbon derivative, and relates to the technical field of organic synthesis, and the preparation method comprises the following steps: sequentially adding alkali, a cocatalyst, a palladium catalyst, a ligand, aryl iodide, aryl bromide, methylboronic acid and an organic solvent into a reaction container subjected to nitrogen purging, and reacting at 80-120 DEG C for 15-30 hours to obtain the 2-methyl biaromatic hydrocarbon derivative. According to the preparation method of the 2-methyl biaromatic hydrocarbon derivative provided by the invention, different 2-methyl substituted biaromatic hydrocarbon compounds can be obtained at the same time, and the 2-methyl biaromatic hydrocarbon derivative has good chemical selectivity and stereoselectivity and can be synthesized into 2-methyl biaromatic hydrocarbon which is not easy to obtain by other methods. Moreover, the preparation method of the 2-methyl biaromatic hydrocarbon derivative is high in yield, mild in reaction condition, simple in operation steps, wide in substrate range, simple and convenient in post-treatment and green.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for preparing 2-methylbiaryl derivatives. Background Art

[0002] Biaryl skeletons exist in many bioactive natural products, drugs, and functional material molecules. Porous organic polymers formed by covalent bonding of biaryl skeletons are commonly used porous aromatic framework materials, which have characteristics such as high specific surface area, good stability, adjustable pore channels, and rich π-bond systems, and have good application prospects in the fields of fluorescence sensing, energy storage, drug delivery, and pollutant degradation. Extensive research has shown that the introduction of a methyl group can regulate the solubility, hydrophilicity, and conformation of candidate drugs, thereby having a profound impact on their biological activity, pharmacokinetic characteristics, and physical properties, which is known as the "magic methyl effect" in medicinal chemistry. Therefore, combining the utility of preparing porous aromatic framework materials with biaryls and the magic effect of methyl, the development of an efficient construction method for methyl-substituted biaryl skeletons has attracted the attention of many synthetic chemists. Currently, the traditional methods for constructing 2-methyl-substituted biaryls are as follows: one is to carry out the Suzuki-Miyaura coupling reaction through transition metal catalysis using pre-methylated aromatic substrates; the other is to construct an o-methylbiphenyl skeleton by coupling a pre-methylated aromatic metal reagent with a haloarene. These methods often have limitations such as poor chemoselectivity, stereoselectivity, and cumbersome operation of pre-methylated aromatic metal reagents. Therefore, the development of an efficient, highly chemoselective, and stereoselective synthesis method for 2-methylbiaryls has received increasing attention in the fields of pharmaceutical research and development and functional materials. Summary of the Invention

[0003] Therefore, the technical problem to be solved by the present invention is to overcome the defects in the prior art, so as to provide a method for preparing 2-methylbiaryl compounds, which has a short reaction route, is easy to operate, and is suitable for large-scale production.

[0004] To this end, the present invention provides a method for preparing 2-methylbiaryl derivatives, comprising the following steps: Add an alkali, a cocatalyst, a palladium catalyst, a ligand, an iodoarene, a bromoarene, methylboronic acid, and an organic solvent to a reaction vessel purged with nitrogen in sequence, and react at 80-120 °C for 15-30 h to obtain a 2-methylbiaryl derivative.

[0005] Preferably, the structural formula of the iodoarene is wherein R1 is hydrogen, alkyl, alkoxy, acyl, carboxylic acid ester group, amide group, trifluoromethyl group, trifluoromethoxy group, aryl, substituted aryl, hydroxyl group, hydroxymethyl group, halogen, heterocycle, or steroid; The structural formula of the bromoarene is wherein R2 is hydrogen, alkyl, alkoxy, acyl, carboxylic acid ester group, amide group, trifluoromethylalkyl, trifluoromethoxy, aryl, substituted aryl, hydroxyl, hydroxymethyl, halogen, heterocycle or steroid; The structural formula of the methylboronic acid is

[0006] The structural formula of the cocatalyst is wherein R3 is hydrogen, alkyl, acyl, aryl, carboxylic acid group, ester group, amide group, sulfonyl or trifluoromethyl, and R4 is hydrogen, alkyl, aryl, acyl, carboxylic acid group, ester group, amide group, sulfonyl or trifluoromethyl; The palladium catalyst is palladium acetate, palladium trifluoroacetate, palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(acetonitrile)palladium dichloride, palladium acetylacetonate, bis(acetylacetonato)palladium, allyl palladium chloride dimer, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium or tris(dibenzylideneacetone)dipalladium; The ligand is triphenylphosphine, tris(2-furyl)phosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, tris(naphthyl)phosphine, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 2-bis(cyclohexylphosphino)-2',6'-dimethoxybiphenyl, tricyclohexylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene, tris(2-methoxyphenyl)phosphine, tris(4-methoxyphenyl)phosphine, pyridine, bipyridine, 2-hydroxy-3-trifluoromethylpyridine, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), 1,1'-bis(diphenylphosphino)ferrocene, 1,1'-bis(diphenylphosphino)methane, 1,1'-bis(diphenylphosphino)ethane, 1,1'-bis(diphenylphosphino)propane or 1,1'-bi-2-naphthol; The base is sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium phosphate, potassium carbonate, potassium phosphate, potassium dihydrogen phosphate, cesium carbonate, cesium acetate, cesium hydroxide or 1,8-diazabicycloundec-7-ene.

[0007] Preferably, the organic solvent is dimethyl sulfoxide, N , N -dimethylformamide, N , N -dimethylacetamide, N -methyl-2-pyrrolidone, hexafluoroisopropanol, 1,2-dichloroethane, toluene, 1,4-dioxane, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, polyethylene glycol dimethyl ether and ethylene glycol diethyl ether.

[0008] Preferably, the molar ratio of the iodoarene, bromoarene, methylboronic acid, cocatalyst, palladium catalyst, ligand and base is 0.8~1.2:1.0~2.5:1.0~2.5:1.0~2.5:0.08~0.12:0.18~0.22: 1.8~3.5.

[0009] Preferably, the palladium catalyst is palladium acetate, the ligand is 1,1'-bis(diphenylphosphino)methane, the base is cesium carbonate, and the organic solvent is 1,2-dichloroethane.

[0010] Preferably, the molar ratio of the iodoarene, bromoarene, methylboronic acid, cocatalyst, palladium catalyst, ligand and base is 1:2:2:2:0.1:0.2:3.

[0011] Preferably, the reaction temperature is 100 °C and the reaction time is 24 h.

[0012] The technical solution of the present invention has the following advantages: The preparation method of a 2-methylbiaryl derivative provided by the present invention can simultaneously obtain different 2-methyl-substituted biaryl compounds, and has good chemoselectivity and stereoselectivity, and can synthesize 2-methylbiaryls that are difficult to obtain by other methods. Moreover, the preparation method of the 2-methylbiaryl derivative of the present invention has a high yield, mild reaction conditions, simple operation steps, a wide substrate range, and simple and green post-treatment. Specific Embodiments

[0013] The following examples are provided to better understand the present invention further, and are not limited to the best embodiment, and do not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior art falls within the protection scope of the present invention.

[0014] For those not specifying specific experimental steps or conditions in the examples, the operations or conditions of the conventional experimental steps described in the literature in the art can be followed. For the reagents or instruments not specifying the manufacturer, they are all conventional reagent products that can be obtained through commercial purchase. Examples

[0015] Preparation of methyl 2-(1-methylnaphthalen-2-yl)benzoate

[0016] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 1-iodonaphthalene, 0.2 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 20.1 mg of the target product with a yield of 73%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J J = 8.4 Hz,1H), 8.00 (dd, J J = 7.8, 1.1 Hz, 1H), 7.87 (d, J J = 7.2 Hz, 1H), 7.71 (d, J J =8.4 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.51 - 7.43 (m, 2H), 7.32 - 7.24 (m, 2H),3.54 (s, 3H), 2.42 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 167.9, 143.5,138.3, 132.7, 132.6, 131.5, 131.4, 130.5, 130.5, 130.0, 128.5, 127.4, 127.1,126.0, 125.3, 125.3, 124.4, 51.9, 16.0. Example

[0017] Preparation of methyl 2',3'-dimethyl-[1,1'-biphenyl]-2-carboxylate

[0018] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2-methyl iodobenzene, 0.2 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 15.4 mg of the target product with a yield of 64%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.94 (dd, J J =7.8, 1.4 Hz, 1H), 7.50 – 7.55 (m, 1H), 7.43 – 7.39 (m, 1H), 7.23 (dd, J J =7.7, 1.3 Hz, 1H), 7.15 (d, J J = 7.0 Hz, 1H), 7.10 (t, J J = 7.4 Hz, 1H), 6.93(d, J J = 7.3 Hz, 1H), 3.62 (s, 3H), 2.33 (s, 3H), 1.97 (s, 3H); 13 C NMR (101MHz, Chloroform- d ) δ 167.8, 143.5, 141.4, 136.3, 133.9, 131.4, 131.1, 130.4,129.8, 128.8, 126.9, 126.4, 124.8, 51.9, 20.5, 16.7. Example

[0019] Preparation of methyl 3'-methoxy-2'-methyl-[1,1'-biphenyl]-2-carboxylate

[0020] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2-methoxyphenyl iodide, 0.2 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen repeatedly 10 times and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 8.7 mg of the target product with a yield of 34%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.94 (dd, J J =7.8, 1.4 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.43 – 7.39 (m, 1H), 7.23 (dd, J J =7.6, 1.3 Hz, 1H), 7.17 (t, J J = 7.9 Hz, 1H), 6.85 (d, J J = 8.2 Hz, 1H), 6.72(d, J J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.63 (s, 3H), 1.94 (s, 3H); 13 C NMR (101MHz, Chloroform-d) δ 167.8, 157.3, 142.7, 142.6, 131.4, 131.0, 130.4, 129.8,127.0, 125.5, 124.2, 121.1, 108.8, 55.4, 51.9, 13.0. Example

[0021] Preparation of Dimethyl 2'-Methyl-[1,1'-biphenyl]-2,3'-dicarboxylate

[0022] Add 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of methyl 2-iodobenzoate, 0.1 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane to a 15 mL dry reaction tube. Fill it with nitrogen repeatedly for 10 times, place it in an oil bath at 100 °C, and react for 24 h; cool to room temperature, dilute the reaction solution with ethyl acetate, wash it three times with water, dry the organic phase with anhydrous Na2SO4, filter, concentrate, and purify by thin layer chromatography to obtain 28.4 mg of the target product with a yield of 100%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.00 (dd, J =7.9, 1.4 Hz, 1H), 7.85 (dd, J = 7.4, 2.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.31 – 7.17 (m, 3H), 3.90 (s, 3H), 3.61 (s, 3H), 2.26 (s, 3H); 13 C NMR (101 MHz, Chloroform- d ) δ 168.6, 167.4, 143.2, 142.5, 137.0, 132.0,131.8, 130.9, 130.3, 130.2, 130.1, 129.3, 127.4, 124.8, 51.9, 18.1. Example

[0023] Preparation of methyl 2',3',5'-trimethyl-[1,1'-biphenyl]-2-carboxylate

[0024] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2,4-dimethyl iodobenzene, 0.2 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 16 mg of the target product with a yield of 63%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.92 (d, J = 7.7Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.40 (t, J = 7.1 Hz, 1H), 7.23 (d, J = 7.4Hz, 1H), 3.63 (s, 3H), 2.29 (s, 5H), 1.92 (s, 2H); 13 C NMR (101 MHz,Chloroform- d ) δ 167.9, 143.7, 141.3, 136.0, 133.9, 131.4, 131.1, 130.8,130.4, 129.7, 129.7, 127.0, 126.8, 51.9, 20.9, 20.4, 16.2. Example

[0025] Preparation of methyl 3',5'-difluoro-2'-methyl-[1,1'-biphenyl]-2-carboxylate

[0026] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2,4-difluoroiodobenzene, 0.2 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for reaction for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 14.1 mg of the target product with a yield of 54%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.00 (d, J = 7.7Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6Hz, 1H), 6.81-6.76 (m, 1H), 6.66 (d, J = 8.7 Hz, 1H), 3.68 (s, 3H), 1.90 (s,3H); 13 C NMR (101 MHz, Chloroform- d ) δ 167.1, 161.6 (dd, J = 58.4, 12.9 Hz),159.2 (dd, J = 58.2, 12.8 Hz), 144.5 (dd, J = 9.4, 6.5 Hz), 140.7 (dd, J =3.1, 2.3 Hz), 131.2, 130.6, 130.3, 129.9, 127.9, 118.8 (dd, J = 17.2, 3.7Hz), 111.3 (dd, J = 21.5, 3.5 Hz), 102.2 (dd, J = 27.3, 24.8 Hz), 52.1, 11.4(d, J = 4.3 Hz); 1919F NMR (376 MHz, Chloroform- d ) δ -112.79 (d, J J = 6.7 Hz), -115.33 (d, J J = 6.7 Hz). Example

[0027] Preparation of Methyl 4-(1-Methylnaphthalen-2-yl)benzoate

[0028] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 1-iodonaphthalene, 0.2 mmol of methyl 4-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was flushed with nitrogen 10 times and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed three times with water, dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin layer chromatography to obtain 10.7 mg of the target product with a yield of 39%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, Chloroform- d ) δ 8.16 – 8.08 (m, 3H),7.89 (dd, J J = 7.7, 1.6 Hz, 1H), 7.77 (d, J J = 8.4 Hz, 1H), 7.61 – 7.57 (m,1H), 7.55 – 7.51 (m, 1H), 7.49 – 7.44 (m, 2H), 7.37 (d, J J = 8.4 Hz, 1H), 3.97(s, 3H), 2.60 (s, 3H); 13 13C NMR (101 MHz, Chloroform- d ) δ 167.1, 147.5, 137.9,132.7, 130.9, 129.9, 129.4, 128.5, 128.5, 127.7, 126.4, 126.1, 125.8, 124.6,113.5, 52.2, 16.3. Example

[0029] Preparation of Methyl 2-(10-methylphenanthren-9-yl)benzoate

[0030] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 9-iodophenanthrene, 0.2 mmol of methyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was purged with nitrogen 10 times and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed three times with water, dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 14.6 mg of the target product with a yield of 45%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.78 (dd, J J = 6.6, 2.8 Hz, 1H), 8.73 (d, J J = 8.1 Hz, 1H), 8.16 – 8.12 (m, 2H), 7.70 – 7.64 (m, 3H), 7.58 – 7.54 (m, 2H), 7.41 – 7.36 (m, 1H), 7.28 (d, J J = 6.5 Hz, 1H), 7.17 (d, J J = 8.2 Hz, 1H), 3.40 (s, 3H), 2.38 (s, 3H); 13 C NMR (101 MHz, Chloroform- d ) δ 167.2, 141.8, 136.3, 132.1, 132.0, 131.3, 130.4, 129.9, 129.1, 129.0, 127.5, 126.7, 126.6, 126.4, 126.0, 125.4, 124.9, 122.9, 122.4, 51.8, 17.2. Example

[0031] Preparation of Ethyl 2-(1-methylnaphthalen-2-yl)benzoate

[0032] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 1-iodonaphthalene, 0.2 mmol of ethyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for reaction for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 19.7 mg of the target product with a yield of 68%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.05 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 7.8, 1.2 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.50 – 7.44 (m, 2H), 7.31 – 7.24 (m, 2H), 4.01 – 3.91 (m, 2H), 2.41 (s, 3H), 0.76 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, Chloroform- d ) δ 167.7, 143.3, 138.6, 132.7, 132.5, 131.3, 131.2, 131.1, 130.6, 129.9, 128.5, 127.4, 127.1, 126.0, 125.3, 125.2, 124.3, 60.6, 16.0, 13.5. Example

[0033] Preparation of Ethyl 2',3'-Dimethyl-[1,1'-Biphenyl]-2-Carboxylate

[0034] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2-methyl iodobenzene, 0.2 mmol of ethyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin layer chromatography to obtain 18 mg of the target product with a yield of 71%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.94 (d, J = 7.7 Hz,1H), 7.52 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz,1H), 7.14 (d, J = 7.3 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 7.3 Hz,1H), 4.06 – 3.99 (m, 2H), 2.32 (s, 3H), 1.97 (s, 3H), 0.94 (t, J = 7.1 Hz,3H); 13 C NMR (101 MHz, Chloroform- d ) δ 167.8, 143.2, 141.7, 136.2, 133.9,131.3, 131.0, 130.9, 129.8, 128.7, 126.9, 126.4, 124.7, 60.6, 20.7, 16.7,13.5. Example

[0035] Preparation of Ethyl 3'-Methoxy-2'-Methyl-[1,1'-Biphenyl]-2-Carboxylate

[0036] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2-methoxyiodobenzene, 0.2 mmol of ethyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was flushed with nitrogen 10 times and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed three times with water, dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin layer chromatography to obtain 11.3 mg of the target product with a yield of 42%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.94 (dd, J J =7.8, 1.4 Hz, 1H), 7.53 – 7.49 (m, 1H), 7.43 – 7.39 (m, 1H), 7.23 (dd, J J =7.6, 1.3 Hz, 1H), 7.16 (t, J J = 7.9 Hz, 1H), 6.85 (d, J J = 8.2 Hz, 1H), 6.72(d, J J = 7.6 Hz, 1H), 4.07 – 4.00 (m, 2H), 3.86 (s, 3H), 1.94 (s, 3H), 0.97(t, J J = 7.1 Hz, 3H); 13 C NMR (101 MHz, Chloroform- d ) δ 167.7, 157.4, 142.8,142.5, 131.3, 130.9, 130.8, 129.8, 127.0, 125.5, 124.3, 121.2, 108.8, 60.6,55.5, 13.6, 12.9. Example

[0037] Preparation of Diethyl 2'-Methyl-[1,1'-biphenyl]-2,3'-dicarboxylate

[0038] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-en-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of ethyl 2-iodobenzoate, 0.2 mmol of ethyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin-layer chromatography to obtain 31.2 mg of the target product with a yield of 100%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 8.00 (dd, J =7.8, 1.4 Hz, 1H), 7.82 (dd, J = 7.3, 2.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.47-7.13 (m, 1H), 7.29 – 7.16 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 4.11 – 3.97 (m,2H), 2.26 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H); 13 C NMR(101 MHz, Chloroform- d ) δ 168.3, 167.3, 143.4, 142.2, 136.8, 131.9, 131.6,130.9, 130.8, 130.7, 130.2, 129.0, 127.4, 124.7, 60.8, 60.7, 18.1, 14.3,13.5. Example

[0039] Preparation of Ethyl 2',3',5'-Trimethyl-[1,1'-Biphenyl]-2-carboxylate

[0040] 0.3 mmol of cesium carbonate, 0.2 mmol of (1R,4R)-N-(p-tolyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide, 0.01 mmol of palladium acetate, 0.02 mmol of tris(2-furyl)phosphine, 0.1 mmol of 2,4-dimethyl iodobenzene, 0.2 mmol of ethyl 2-bromobenzoate, 0.2 mmol of methylboronic acid, and 1 mL of 1,2-dichloroethane were added to a 15 mL dry reaction tube. The tube was filled with nitrogen 10 times repeatedly and placed in an oil bath at 100 °C for 24 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by thin layer chromatography to obtain 20.4 mg of the target product with a yield of 76%. The NMR characterization of this compound is as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.92 (d, J =7.7 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.26 – 7.21(m, 1H), 6.97 (s, 1H), 6.76 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 2.28 (s, 6H),1.93 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, Chloroform- d ) δ167.9, 143.3, 141.5, 136.0, 133.9, 131.2, 131.1, 130.9, 130.8, 129.7, 129.5,127.1, 126.8, 60.7, 20.8, 20.4, 16.2, 13.5. Obviously, the above embodiments are merely examples given for clear illustration and are not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all the implementation manners here. And the obvious changes or modifications derived therefrom still fall within the protection scope of this invention.

Claims

1. A method for preparing a 2-methylbiaryl derivative, characterized in that: The method includes the following steps: Add an alkali, a cocatalyst, a palladium catalyst, a ligand, an iodoarene, a bromoarene, methylboronic acid and an organic solvent into a reaction vessel purged with nitrogen in sequence, and react at 80-120 °C for 15-30 h to obtain a 2-methylbiaryl derivative.

2. The preparation method of the 2-methylbiphenyl derivative according to claim 1, characterized in that, The structural formula of the iodoarene is , where R1 is hydrogen, alkyl, alkoxy, acyl, carboxylic acid ester group, amide group, trifluoromethyl group, trifluoromethoxy group, aryl, substituted aryl, hydroxyl group, hydroxymethyl group, halogen, heterocycle or steroid; The structure of the bromoarene , where R2 is hydrogen, alkyl, alkoxy, acyl, carboxylic acid ester group, amide group, trifluoromethyl group, trifluoromethoxy group, aryl, substituted aryl, hydroxyl group, hydroxymethyl group, halogen, heterocycle or steroid; The structural formula of the methylboronic acid is ; The structural formula of the cocatalyst is , where R3 is hydrogen, alkyl, acyl, aryl, carboxyl, ester, amide, sulfonyl or trifluoromethyl, and R4 is hydrogen, alkyl, aryl, acyl, carboxyl, ester, amide, sulfonyl or trifluoromethyl; The palladium catalyst is palladium acetate, palladium trifluoroacetate, palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(acetonitrile)palladium dichloride, palladium acetylacetonate, palladium diacetylacetonate, allyl palladium chloride dimer, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride or tris(dibenzylideneacetone)dipalladium; The ligand is triphenylphosphine, tris(2-furyl)phosphine, 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, tris(naphthyl)phosphine, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, 2-bis(cyclohexylphosphino)-2',6'-dimethoxybiphenyl, tricyclohexylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, tris(2-methoxyphenyl)phosphine, tris(4-methoxyphenyl)phosphine, pyridine, bipyridine, 2-hydroxy-3-trifluoromethylpyridine, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), 1,1'-bis(diphenylphosphino)ferrocene, 1,1'-bis(diphenylphosphino)methane, 1,1'-bis(diphenylphosphino)ethane, 1,1'-bis(diphenylphosphino)propane or 1,1'-bi-2-naphthol; The alkali is sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium phosphate, potassium carbonate, potassium phosphate, potassium dihydrogen phosphate, cesium carbonate, cesium acetate, cesium hydroxide or 1,8-diazabicyclo[5.4.0]undec-7-ene; 3. The preparation method of the 2-methylbiphenyl derivative according to claim 1, wherein The organic solvent is dimethyl sulfoxide, N , N -dimethylformamide, N , N -dimethylacetamide, N -methyl-2-pyrrolidone, hexafluoroisopropanol, 1,2-dichloroethane, toluene, 1,4-dioxane, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, polyethylene glycol dimethyl ether, and ethylene glycol diethyl ether.

4. The method for preparing the 2-methylbiaryl derivative according to claim 1 or 2, characterized in that, The molar ratio of the iodoarene, the bromoarene, methylboronic acid, the cocatalyst, the palladium catalyst, the ligand and the alkali is 0.8-1.2:1.0-2.5:1.0-2.5:1.0-2.5:0.08-0.12:0.18-0.22:1.8-3.5; 5. The preparation method of the 2-methylbiphenyl aromatic hydrocarbon derivative according to claim 1, characterized in that, The palladium catalyst is palladium acetate, the ligand is 1,1'-bis(diphenylphosphino)methane, the alkali is cesium carbonate, and the organic solvent is 1,2-dichloroethane; 6. The preparation method of the 2-methylbiaryl derivative according to claim 1 or 2, characterized in that, The molar ratio of the iodoarene, the bromoarene, methylboronic acid, the cocatalyst, the palladium catalyst, the ligand and the alkali is 1:2:2:2:0.1:0.2:3; 7. The method for preparing the 2-methylbiaryl derivative according to claim 1, wherein The reaction temperature is 100 °C and the reaction time is 24 h.

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