A low load palladium catalyzed Suzuki-miyaura coupling reaction with di-tert-butyl phenyl phosphine to synthesize biphenyls

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a Suzuki-Miyaura coupling reaction based on a low-loading palladium catalytic system and using di-tert-butyl phenyl phosphine as a key ligand, which can efficiently prepare substituted biphenyl compounds by using only 0.002% equivalent of palladium catalyst. The method uses aryl boron compounds and o-chloronitrobenzene as reaction substrates, and successfully realizes Suzuki-Miyaura cross coupling in green solvent water under the synergistic action of palladium acetate as a transition metal catalyst, di-tert-butyl phenyl phosphine as a ligand and sodium hydroxide as a base, and the target is converted into various biphenyl compounds. The application successfully develops a new process for one-pot synthesis of biphenyl compounds by precisely constructing a palladium catalytic system, which not only has the characteristics of mild reaction conditions and simple operation, but also shows significant technical advantages in economy, substrate universality and process expandability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for preparing substituted biphenyl compounds using the Suzuki-Miyaura reaction. The method uses water as the sole solvent and aryl chlorides and arylphenylboronic acids as reactants, and the reaction is carried out in the presence of a low-loaded palladium catalyst and a di-tert-butylphenylphosphine ligand. Background Technology

[0002] Biphenyls and their structural analogues constitute an important class of pharmacodynamic skeletons, playing a central role in pharmaceutical chemistry and natural products. Numerous studies have demonstrated that the diaryl skeleton possesses diverse biological activities across multiple therapeutic areas, including anti-inflammatory, antihypertensive, central nervous system modulation, antitumor, antifungal, and anti-HIV activities. These remarkable properties highlight their significant value and enormous potential in developing novel therapeutics. Examples include magnolol (A), diflunixin (B), fenbufen (C), flagellate amylopectin (D), GABA agonists (E), NPY-5 receptor antagonists (F), bisacodyl (G), bisaxifene (H), and fluopyram (I). Given the crucial role of the biphenyl skeleton in pharmaceuticals and natural products, numerous synthetic routes for these compounds have been developed over the past century. Among these synthetic strategies, transition metal-catalyzed cross-coupling reactions have become the primary method for biphenyl construction, particularly through the Negishi, Kumada, Hiyama, and Stille coupling reactions. Unlike these cross-coupling reactions, the Suzuki-Miyaura cross-coupling (SMCC) has significant advantages because it can be carried out under ambient aqueous conditions, utilizing water as a sustainable solvent, which aligns with the principles of green chemistry. Therefore, it is widely considered one of the most efficient and widely used methods for synthesizing biphenyl derivatives. Currently, this method faces two main challenges: first, the amount of palladium used in the catalyst remains relatively high, increasing cost pressure; second, organic solvents are commonly used industrially as reaction solvents, and ether solvents present problems such as volatility, explosiveness, and difficulty in recovery. Therefore, it is necessary to continue exploring advantageous routes for the synthesis of biphenyl and its structural analogues.

[0003] Summary of the Invention

[0004] This invention provides a Suzuki-Miyaura coupling reaction of o-chloronitrobenzene with arylboron compounds under palladium catalysis, yielding biphenyl compounds with various structures. Biphenyl compounds have significant development potential in medical technology, pesticides, and chemical synthesis. This chemically and regioselectively selective reaction will play a major role in organic synthesis.

[0005] The specific plan is as follows:

[0006]

[0007] A low-load palladium-catalyzed Suzuki-Miyaura coupling reaction involving di-tert-butylphenylphosphine is used to synthesize biphenyl compounds. The arylboron compound shown in Formula 1 and o-chloronitrobenzene shown in Formula 2 are mixed with a solvent in the presence of a transition metal catalyst, a phosphine ligand, and a base to carry out the Suzuki-Miyaura coupling reaction to synthesize the biphenyl compound shown in Formula 3.

[0008] The method of this invention can achieve one-pot production, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are obtained through diverse means and have high economic benefits.

[0009] Preferably, the reaction is carried out under the protection of inert nitrogen gas, which has a good protective effect.

[0010] Preferably, the synthesis takes place in the presence of a transition metal catalyst, a phosphine ligand, and a solvent.

[0011] Preferably, the transition metal catalyst is a palladium catalyst, and the base is sodium hydroxide, potassium hydroxide, triethylamine, potassium tert-butoxide, n-butyllithium, potassium carbonate, sodium bicarbonate, or sodium carbonate, preferably sodium hydroxide; the phosphine ligand is 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl, di-tert-butylphenylphosphine, 1,1′-bis(diphenylphosphine)ferrocene, chloro[2-(di-tert-butylphosphine)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, di(tri-tert-butylphosphine)palladium, or 1,2-bis(diphenylphosphine)ethane, preferably di-tert-butylphenylphosphine.

[0012] Preferably, the palladium catalyst is palladium trifluoroacetate, palladium acetate, palladium chloride, palladium on carbon, tris(dibenzylacetone)dipalladium, or tetra(triphenylphosphine)palladium.

[0013] Preferably, the palladium catalyst is palladium acetate, which has high catalytic activity.

[0014] Preferably, the solvent is safe and environmentally friendly water.

[0015] Preferably, the molar ratio of the arylboron compound represented by Formula 1, the o-chloronitrobenzene represented by Formula 2, the ligand, and the catalyst in the reaction is: 1.0–2.0: 1.0–2.0: 0.005%–0.015%: 0.0001%–0.005%.

[0016] Preferably, the method of the present invention can generate biphenyl compounds with the following structures:

[0017]

[0018]

[0019] In the presence of transition metal catalysts palladium acetate, alkali sodium hydroxide, and phosphine ligand di-tert-butylphenylphosphine, arylboronic compounds undergo a Suzuki-Miyaura coupling reaction with o-chloronitrobenzene to ultimately prepare biphenyl compounds.

[0020] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0021] The synthesis method of this invention uses inexpensive raw materials that are available through diverse means, resulting in high economic benefits.

[0022] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and saves reaction time due to fewer reaction steps, thereby improving product yield and reaction efficiency.

[0023] The operation steps required by this invention are relatively simple, without the need for extreme heating or cooling, and the reaction can be carried out under normal pressure. It is safe, convenient and energy-efficient.

[0024] This invention uses water as the sole reaction solvent, which has the following outstanding advantages: 1) The reaction system is green and environmentally friendly, avoiding the use of organic solvents; 2) It significantly reduces production costs; 3) The post-processing is simple and does not require cumbersome solvent recovery steps.

[0025] This invention uses di-tert-butylphenylphosphine as the reaction ligand, which has the following outstanding advantages: 1) The ligand is inexpensive and available on the market, effectively reducing production costs; 2) The ligand is safe and reliable and can replace traditional flammable organophosphine ligands; 3) The ligand is deactivated after reacting with the palladium catalyst in aqueous solution and will not remain in the product, effectively improving the purity of the product. Attached Figure Description

[0026] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. A is the proton NMR spectrum, and B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The carbon NMR spectrum of the product obtained in Example 1; Figure 2A The above is the proton NMR spectrum of the product obtained in Example 2. Figure 2B The carbon NMR spectrum of the product obtained in Example 2; Figure 3A The image shows the proton NMR spectrum of the product obtained in Example 3. Figure 3B The carbon NMR spectrum of the product obtained in Example 3; Figure 4AThe above is the proton NMR spectrum of the product obtained in Example 4. Figure 4B The carbon NMR spectrum of the product obtained in Example 4; Figure 5A The above is the proton NMR spectrum of the product obtained in Example 5. Figure 5B The carbon NMR spectrum of the product obtained in Example 5; Figure 6A The above is the proton NMR spectrum of the product obtained in Example 6. Figure 6B The carbon NMR spectrum of the product obtained in Example 6; Figure 7A The above is the proton NMR spectrum of the product obtained in Example 7. Figure 7B The carbon NMR spectrum of the product obtained in Example 7; Figure 8A The above is the proton NMR spectrum of the product obtained in Example 8. Figure 8B The carbon NMR spectrum of the product obtained in Example 8; Figure 9A The image shows the proton NMR spectrum of the product obtained in Example 9. Figure 9B The carbon NMR spectrum of the product obtained in Example 9; Figure 10A The above is the proton NMR spectrum of the product obtained in Example 10. Figure 10B The image shows the carbon NMR spectrum of the product obtained in Example 10. Specific Implementation

[0027] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bidex, Sigma-Aldrich, Acros, Innochem, Energy Chemical, TCI China, Alfa Aesar, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M.

[0028] Example 1

[0029] Phenylacetic acid (121.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( tBu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the cap was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether) to give a white solid (145.4 mg, yield 73%). The 1H and 1C NMR spectra of the product are A and B, respectively, and the spectral data are as follows: 1 H NMR (400MHz, CDCl3) δ7.84 (d, J=6.9Hz, 1H), 7.59 (d, J=7.1Hz, 1H), 7.51-7.36 (m, 5H), 7.32 (s, 2H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ151.2, 139.3, 138.2, 134.2, 133.9, 130.6, 130.2, 130.1, 129.8, 126.0, 79.3, 79.0, 78.7ppm.

[0030] By changing the raw materials in Example 1, the following 8 sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding nuclear magnetic resonance spectrum of the product is as follows. Figure 1A The NMR spectra of the remaining 2-8 groups correspond to the serial numbers of the respective embodiments.

[0031]

[0032] Example 2

[0033] p-Tolueneboronic acid (135.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the microwave tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( tBu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the lid was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a green oil (206.8 mg, yield 97%). The 1H and 1C NMR spectra of the product were as follows. Figure 2A and Figure 2B , 1 H NMR (400MHz, CDCl3) δ7.80 (dd, J=8.0, 1.3Hz, 1H), 7.61-7.54 (m, 1H), 7.46-7.40 (m, 2H), 7.26-7.17 (m, 4H), 2.38 (s, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ149.5, 138.3, 136.4, 134.5, 132.4, 132.1, 129.6, 128.1, 127.9, 124.2, 77.5, 77.2, 76.9, 21.4ppm.

[0034] Example 3

[0035] Naphthalene-2-boronic acid (171.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the microwave tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( t Bu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the lid was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a green solid (236.8 mg, yield 95%). The proton and carbon NMR spectra of the product are as follows. Figure 3Aand Figure 3B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ7.84-7.73 (m, 5H), 7.52-7.31 (m, 6H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ149.5, 136.5, 135.2, 133.5, 133.0, 132.7, 132.5, 12 8.6, 128.5, 128.4, 128.0, 127.2, 126.8, 126.0, 124.4, 77.7, 77.4, 77.0ppm.

[0036] Example 4

[0037] (4-phenoxyphenyl)boric acid (214.0 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a dry microwave tube (10 mL) fitted with a stir bar (10 × 5 mm), the tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( t Bu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the lid was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a green oil (250.5 mg, yield 86%). The proton and carbon NMR spectra of the product are as follows. Figure 4A and Figure 4B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ7.82 (d, J=7.9Hz, 1H), 7.59 (td, J=7.6, 1.3Hz, 1H), 7.49-7.41 (m, 2H), 7.36 (t, J=8.0Hz, 2H), 7.30-7.23 (m, 2H), 7.14 (td, J=7.3, 1.2Hz, 1H), 7.05 (ddd, J=15.8, 8.1, 1.4Hz, 4H)ppm. 13 C{ 1H}NMR (101MHz, CDCl3) δ159.5, 158.3, 151.1, 137.5, 134.1, 133.8, 131.7, 131.2, 129.9, 125.9, 125.6, 121.3, 120.3, 79.2, 78.9, 78.6ppm.

[0038] Example 5

[0039] (4-Cyanophenyl)boric acid (146.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the microwave tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( t Bu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the cap was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a white solid (219.7 mg, yield 98%). The proton and carbon NMR spectra of the product are as follows. Figure 5A and Figure 5B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ7.96 (d, J=8.1Hz, 1H), 7.72-7.65 (m, 3H), 7.57 (td, J=7.7, 1.4Hz, 1H), 7.44-7.36 (m, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ148.7, 142.6, 134.9, 133.1, 133.0, 132.5, 131.8, 129.6, 128.9, 128.1, 124.8, 118.6, 112.2, 77.5, 77.2, 76.9ppm.

[0040] Example 6

[0041] (4-(trimethylsilyl)phenyl)boronic acid (194.1 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm), the tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( t Bu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was heated in an oil bath at 120°C (500 rpm). n The mixture was stirred for 24 hours, and the resulting solution was cooled to room temperature. The lid was then opened, exposing the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), washed with 3 × 5 mL of ethyl acetate, and the solution was obtained. The solvent and volatile substances were removed using a rotary evaporator. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 150:1) to give a green oil (265.9 mg, yield 98%). The proton and carbon NMR spectra of the product are as follows: Figure 6A and Figure 6B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ7.83 (d, J=9.4Hz, 1H), 7.60-7.56 (m, 3H), 7.45 (ddd, J=14.1, 7.7, 1.5Hz, 2H), 7.30 (d, J=7.4Hz, 2H), 0.30 (d, J=0.8Hz, 9H) ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ149.4, 140.7, 137.8, 136.4, 133.8, 132.5, 132.1, 128.3, 127.2, 124.2, 77.5, 77.2, 76.9, -1.0ppm.

[0042] Example 7

[0043] Naphthalene-1-boronic acid (171.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the microwave tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( tBu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the cap was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporator. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a green solid (219.3 mg, yield 88%). The proton and carbon NMR spectra of the product are as follows. Figure 7A and Figure 7B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ8.00 (dd, J=8.1, 1.3Hz, 1H), 7.88-7.81 (m, 2H), 7.58 (td, J=7.5, 1.4Hz, 1H), 7.51-7.27 (m, 7H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ149.9, 135.7, 135.4, 133.6, 133.3, 132.8, 131.6, 128.9, 128.8, 128.7, 126.8, 126.3, 125.5, 125.0, 124.4ppm.

[0044] Example 8

[0045] (4-Formylbenzene)boric acid (149.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( tBu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the cap was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a white solid (184.0 mg, yield 81%). The proton and carbon NMR spectra of the product are as follows. Figure 8A and Figure 8B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ10.04 (s, 1H), 8.01-7.89 (m, 3H), 7.68 (td, J=7.6, 1.3Hz, 1H), 7.56 (td, J=7.8, 1.4Hz, 1H), 7.51-7.43 (m, 3H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ191.9, 148.8, 143.9, 135.9, 135.4, 133.0, 131.9, 130.1, 129.3, 128.8, 124.6, 77.6, 77.3, 77.0ppm.

[0046] Example 9

[0047] (3-Fluorophenyl)boric acid (139.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm). The microwave tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( tBu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the lid was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a green oil (210.6 mg, yield 97%). The proton and carbon NMR spectra of the product are as follows. Figure 9A and Figure 9B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ7.84 (dd, J=8.1, 1.3Hz, 1H), 7.58 (td, J=7.6, 1.3Hz, 1H), 7.46 (td, J=7.8, 1.5Hz, 1H), 7.41-7.30 (m, 2H), 7.09-6.97 (m, 3H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ162.8 (d, J c-F =246.7Hz), 149.1, 139.7 (d, J c-F =8.1Hz), 135.1 (d, J) C-F =2.1Hz), 132.8, 132.0, 130.4 (d, J C-F =8.4Hz), 128.9, 124.4, 123.9(d,J C-F =3.1Hz), 115.4 (d, J) C-F =1.9Hz), 115.1(d, d C-F =3.4Hz)ppm.

[0048] Example 10

[0049] (3,5-bis(trifluoromethyl)phenyl)boronic acid (257.9 mg, 1.0 mmol), o-chloronitrobenzene (165.4 mg, 1.05 mmol), and NaOH (39.9 mg, 1.0 equivalent) were added to a 10 mL dry microwave tube fitted with a stir bar (10 × 5 mm), the tube was sealed with a diaphragm cap, and the tube was purged with a nitrogen atmosphere. Then, 10 μL of Pd(OAc)₂ and P( tBu)2Ph solution (in 0.002M dichloromethane) (0.002 mol%). The reaction mixture was stirred in an oil bath at 120°C (500 rpm) for 24 hours. The resulting solution was then cooled to room temperature, and the cap was opened to expose the solution to air. The reaction mixture was subjected to column chromatography in silica gel (200-300 mesh), and washed with 3 × 5 mL of ethyl acetate to obtain a solution. The solvent and volatile substances were removed by rotary evaporation. The crude product was purified by silica gel column chromatography to obtain the corresponding product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 150:1) to give a white solid (254.7 mg, yield 76%). The proton and carbon NMR spectra of the product are as follows. Figure 10A and Figure 10B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ8.06 (dd, J=8.2, 1.3Hz, 1H), 7.94 (s, 1H), 7.80 (s, 2H), 7 .73 (td, J=7.6, 1.3Hz, 1H), 7.66-7.60 (m, 1H), 7.46 (dd, J=7.6, 1.5Hz, 1H)ppm. 13 C{ 1 H}NMR (101MHz, CDCl3) δ148.3, 140.3, 133.9, 133.4, 132.1 (d, J c-F =2.6Hz), 131.9 (d, J) c-F =100.8Hz), 131.8, 129.9, 128.5 (d, J C-F =3.8Hz), 125.0, 123.2 (d, J C-F =272.7Hz), 122.1(dt, J C-F =7.2, 3.3 Hz) ppm.

Claims

1. A method for synthesizing biphenyl compounds via a low-loaded palladium-catalyzed Suzuki-Miyaura coupling reaction involving di-tert-butylphenylphosphine, characterized in that: The biphenyl compounds shown in Formula 3 were synthesized by a Suzuki-Miyaura coupling reaction using arylboron compounds shown in Formula 1 and o-chloronitrobenzene shown in Formula 2, in the presence of a transition metal catalyst, phosphine ligand, and base, in combination with a solvent.

2. The synthesis method according to claim 1, characterized in that, The transition metal catalyst is a palladium catalyst.

3. The synthesis method according to claim 1, characterized in that, The alkali is sodium hydroxide, potassium hydroxide, triethylamine, potassium tert-butoxide, n-butyllithium, potassium carbonate, sodium bicarbonate, or sodium carbonate.

4. The synthesis method according to claim 2, characterized in that, The palladium catalyst is palladium trifluoroacetate, palladium acetate, palladium chloride, palladium on carbon, tris(dibenzylideneacetone)dipalladium, or tetra(triphenylphosphine)palladium.

5. The synthesis method according to claim 1, characterized in that, The reaction was carried out under the protection of the inert gas nitrogen.

6. The synthesis method according to claim 1, characterized in that, The phosphine ligands are 1,1′-binaphthyl-2,2′-bis(diphenylphosphine), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl, di-tert-butylphenylphosphine, 1,1′-bis(diphenylphosphine)ferrocene, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, or 1,2-bis(diphenylphosphine)ethane.

7. The synthesis method according to claim 1, characterized in that, The solvent is water.

8. The synthesis method according to claim 1, characterized in that, The molar ratio of the arylboron compound shown in Formula 1, the o-chloronitrobenzene shown in Formula 2, the ligand, and the catalyst in the reaction is: 1.0–2.0 : 1.0–2.0 : 0.005%–0.015% : 0.0001%–0.005%.

9. The synthesis method according to claim 1, characterized in that, The reaction temperature is 100℃~150℃.

10. The synthesis method according to claim 1, characterized in that, The arylboron compounds, o-chloronitrobenzene, and biphenyl compounds are listed in the table below:

Images