Synthesis method of para-substituted biphenyl compounds

Abstract

The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of para-substituted biphenyl compounds, comprising the following steps: 1), under the protection of an inert gas, using a sulfonium salt and a diazonium salt as substrates, in a solvent, in the presence of a photocatalyst, stirring and reacting at 25°C to 100°C; obtaining a reaction solution containing para-substituted biphenyl compounds; 2), performing post-treatment on the reaction solution obtained in step 1) to obtain para-substituted biphenyl compounds. The present invention uses a diazonium salt instead of the aryl halide used therein, avoiding the generation of polluting waste liquid after the reaction, and having a wider source. The process of the present invention is simple, the reaction is widely applicable, and the substrate has good generality and tolerance.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis and relates to a preparation method of para-substituted biphenyl compounds. Background Art

[0002] Para-substituted biphenyl compounds are important organic compounds. Their structural general formula is shown in Formula 1 and they play a very important role in fields such as medicine, liquid crystal materials, and electronic components. First, the biphenyl structure is an important carrier for many drugs. For example, ethyl biphenylacetate is an antipyretic and analgesic drug with good efficacy. Second, biphenyl compounds can be applied in the field of new materials. For example, propyl-3,4-difluorobiphenyl is a monomer liquid crystal material with excellent properties. With the development of society, the demand for biphenyl compounds is increasing.

[0003]

[0004] Currently, the preparation methods of para-substituted biphenyl compounds are mainly as follows:

[0005] 1. Chen X Y, Nie X X et al. reported a synthesis method of para-substituted biphenyl compounds in Para-selective arylation and alkenylation of monosubstituted arenes using thianthrene S-oxide as a transient mediator, Chemical Communications, 2020, 56(37): 5058-5061. In this method, a sulfonium salt is used as a substrate and undergoes a coupling reaction with a phenylboronic acid derivative under the catalysis of palladium metal and in a basic environment to prepare biphenyl compounds. This method has high reaction efficiency and good selectivity, but the costs of phenylboronic acid derivatives and palladium metal are relatively high.

[0006] 2. Ma N-N, Ren J-A et al. reported a synthesis method of biphenyl compounds in Nickel-catalyzed direct cross-coupling of arylsulfonium salt with aryl bromide, Organic Letters, 2022, 24(10): 1953-1957. In this method, an onium salt and an aryl halide are used as substrates and react in the presence of a nickel catalyst, a phosphine ligand, magnesium chips, and lithium chloride to prepare biphenyl compounds. The molar ratio of magnesium chips to the substrate is 3:1, and the molar ratio of lithium chloride to the substrate is 2:1. This method requires a large number and variety of metals.

[0007] 3. Chinese Patent No. CN202211363361.3 discloses a method for synthesizing 4-alkyl-4-cyanobiphenyl, that is, bromination reaction is carried out, then the brominated biphenyl is coupled with dialkylcopper lithium, and then 4-alkyl-4-bromobiphenyl is substituted with metal cyanide to obtain 4-alkyl-4-cyanobiphenyl. Although this method reduces the activity requirements for halogenated hydrocarbons, the steps are cumbersome, and it requires halogens and other substances that pollute the environment. The use of copper lithium and metal cyanide is expensive and there is metal loss.

[0008] 4. Chinese Patent No. CN202110133894.1 discloses a method for preparing biphenyl compounds, that is, an arylboronic acid and a bromoarene are subjected to a coupling reaction under the conditions of an ethanol-water solvent and a functionalized magnetic complex heterogeneous catalyst. The catalyst of this method can be recycled, but the use of bromoarenes as substrates will produce polluting waste liquid after the reaction.

[0009] In summary, the traditional methods for preparing para-substituted biphenyl compounds need to use metal catalysts and bromoarene substrates, and have defects such as the need for precious metal raw materials, the generation of polluting waste liquid, and narrow application range. Therefore, it is necessary to improve the existing technology. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a simple, safe, green and inexpensive method for preparing para-substituted biphenyl compounds.

[0011] To solve the above technical problems, the present invention provides a method for preparing para-substituted biphenyl compounds, including the following steps:

[0012] 1), Under the protection of an inert gas, using sulfonium salt and diazonium salt as substrates, in a solvent, in the presence of a photocatalyst, stir and react (C-C coupling reaction) at a reaction temperature of 25°C to 100°C (preferably 25°C to 50°C) for 6 to 24 hours; obtain a reaction solution containing para-substituted biphenyl compounds;

[0013] The molar ratio of the diazonium salt to the sulfonium salt is 1:1.0 to 2.0 (preferably 1.2 to 1.5), and the molar ratio of the diazonium salt to the photocatalyst is 1:0.01 to 0.1 (that is, the photocatalyst is 1 to 10 mol% of the diazonium salt, preferably 4 to 8 mol%);

[0014] 2), Post-treat the reaction solution obtained in step 1) to obtain para-substituted biphenyl compounds.

[0015] As an improvement of the method for preparing para-substituted biphenyl compounds of the present invention, in step 1):

[0016] The diazonium salt is The sulfonium salt is

[0017] R is any one of the following: hydrogen, alkyl (methyl, ethyl, propyl), alkoxy (methoxy), ester group, halogen (fluoro group), keto group (ethyl ketone group);

[0018] The said R 1 is any one of the following: hydrogen, alkyl (methyl, ethyl, propyl), alkoxy (methoxy, ethoxy), ester group, halogen (fluoro group), cycloalkyl (cyclohexyl);

[0019] Y is any one of the following: TfO - , BF4 - .

[0020] In the present invention:

[0021] The diazonium salt is any one of the following: benzenediazonium tetrafluoroborate, toluenediazonium tetrafluoroborate, fluorobenzenediazonium tetrafluoroborate, p-acetylbenzenediazonium tetrafluoroborate;

[0022] The sulfonium salt is any one of the following:

[0023] 5-(4-methylphenyl)thianthrenium trifluoromethanesulfonate, 5-(4-propylphenyl)thianthrenium trifluoromethanesulfonate, 5-phenyl-thianthrenium trifluoromethanesulfonate, 5-(4-ethylphenyl)thianthrenium trifluoromethanesulfonate, 5-(4-methoxyphenyl)thianthrenium trifluoromethanesulfonate, 5-(4-fluorophenyl)thianthrenium trifluoromethanesulfonate.

[0024] As a further improvement to the preparation method of the p-substituted biphenyl compounds of the present invention:

[0025] The photocatalyst is eosin Y, Rhodamine 6G, Rhodamine B.

[0026] The light source is natural light, blue light (preferably blue light with a wavelength of 440 - 450 nm).

[0027] Note: For 1 mmol of diazonium salt, the corresponding light source power is about 45 ± 5 w.

[0028] The solvent is any one of the following: acetone, dimethyl sulfoxide (DMSO), dichloromethane (CH2Cl2), tetrahydrofuran (THF), N,N-dimethylformamide (DMF); preferably DMSO.

[0029] As a further improvement to the preparation method of the p-substituted biphenyl compounds of the present invention:

[0030] For every 0.1 - 0.5 mol (preferably 0.4 mol / L) of diazonium salt, 1 L of solvent is used.

[0031] As a further improvement to the preparation method of the para-substituted biphenyl compounds of the present invention: The post-treatment of step 2) is as follows:

[0032] After the reaction in step 1) ends (after the set reaction time arrives), add water (a small amount of water) to the reaction solution containing the para-substituted biphenyl compounds obtained in step 1) to quench the reaction, then add saturated brine for extraction, filter, and dry (add anhydrous sodium sulfate for drying), filter (filter with diatomaceous earth to remove insoluble solids), perform rotary evaporation on the filtrate to remove the solvent, and then use silica gel column chromatography for separation and purification to obtain the para-substituted biphenyl compounds as the product.

[0033] The reaction equation of the preparation method of the para-substituted biphenyl compounds of the present invention is as follows:

[0034]

[0035] The preparation method of the para-substituted biphenyl compounds of the present invention has the following technical advantages:

[0036] 1. Using sulfonium salts as substrates, they are widely sourced, easy to prepare, and low in cost.

[0037] The present invention uses diazonium salts instead of the aryl halides it used, avoiding the generation of polluting waste liquid after the reaction and having a wider source.

[0038] 2. Using photocatalysis, it avoids the use of heavy metal catalysts, reduces costs, and protects the environment.

[0039] 3. The process is simple, the reaction is widely applicable, and the substrate has good generality and tolerance.

[0040] In summary, the present invention develops a green, safe, environmentally friendly, and inexpensive preparation method for para-substituted biphenyl compounds. Specific Embodiments

[0041] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0042] The room temperature mentioned in the present invention refers to 25 - 30 °C.

[0043] Yield = actual amount of target product generated / theoretical amount of target product generated.

[0044] Example 1

[0045]

[0046] Under the protection of N2, 1.5 mmol of 5-(4-methylphenyl)thianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube, dispersed in 4 ml of DMSO. Under stirring conditions, 1 mmol of benzenediazonium tetrafluoroborate was slowly added thereto (time about 1 minute), and then 5% of the photocatalyst eosin Y was added (that is, the photocatalyst eosin Y was 5 mol% of the diazonium salt - benzenediazonium tetrafluoroborate). The reaction was stirred at room temperature and under light for 12 hours. The light source was blue light with a wavelength of 440 - 450 nm, located at a height of 5 cm above the Schlenk tube, and the light source power was 45 w.

[0047] The reaction process was monitored by TLC and HPLC. After the set reaction time arrived, the monitoring results found that the reaction was completed. Therefore, a small amount of water (about 4 ml) was added to quench the reaction, and then 4 ml of saturated brine was added for extraction. The obtained organic layer was taken, about 1 g of anhydrous sodium sulfate was added for drying, and then the dried organic layer was filtered through diatomaceous earth to remove insoluble solids. The solvent (i.e., DMSO) was removed by rotary evaporation of the filtrate. Then, the obtained crude product was separated and purified by silica gel column chromatography (eluent: n-hexane) - that is, the crude product was added to a silica gel column of 200 - 300 mesh, and n-hexane was used to rinse at a flow rate of natural gravity drop. The eluate satisfying the same polarity condition was collected, and then rotary evaporation and drying treatment were carried out to obtain pure 4-methylbiphenyl (purity ≥ 95%).

[0048] White solid, with a yield of 63.5%. The attribution of each hydrogen atom is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 7.64 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 2.44 (s, 3H). The attribution of each carbon atom is as follows: 13 13C NMR (126 MHz, Chloroform-d) δ 141.22, 138.41, 137.08, 129.55, 128.82, 128.78, 127.06, 127.04, 21.17.

[0049] Example 2

[0050]

[0051] Under the protection of N2, 1.5 mmol of 5-(4-propylphenyl)thianthrenium trifluoromethanesulfonate dispersed in 4 ml of DMSO was added to a dry and clean Schlenk tube. Under stirring conditions, 1 mmol of benzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred at room temperature and under light for 12 hours. The light source was set as in Example 1.

[0052] The reaction process was monitored by TLC and HPLC. The subsequent treatment was the same as in Example 1. Pure 4-propylbiphenyl (purity ≥ 95%) was obtained.

[0053] White solid, with a yield of 80.2%. The attribution of each hydrogen atom is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.60–7.54(m,2H),7.50(dd,J=8.2,2.1Hz,2H),7.40(td,J=7.7,1.9Hz,2H),7.33–7.27(m,1H),7.23(dd,J=8.2,2.0Hz,2H),2.66–2.58(m,2H),1.72–1.62(m,2H),0.96(td,J=7.4,2.1Hz,3H). The attribution of each carbon atom is as follows: 13 C NMR(126MHz,Chloroform-d)δ141.82,141.18,138.57,128.88,128.70,126.99,126.96,126.95,37.70,24.58,13.91.

[0054] Example 3

[0055]

[0056] Under the protection of N2, 1.5 mmol of 5-(4-propylphenyl)thianthrenium trifluoromethanesulfonate dispersed in 4 ml of DMSO was added to a dry and clean Schlenk tube. Under stirring conditions, 1 mmol of toluenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred at room temperature and under light for 12 hours. The light source was set as in Example 1.

[0057] The reaction process was monitored by TLC and HPLC. The subsequent treatment was the same as in Example 1. Pure 4-methyl-4'-propylbiphenyl (purity ≥ 95%) was obtained.

[0058] White solid, with a yield of 79.1%. The attribution of each hydrogen atom is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.59–7.53 (m, 4H), 7.30 (dd, J = 8.2, 2.3 Hz, 4H), 2.69 (dd, J = 8.6, 6.8 Hz, 2H), 2.46 (s, 3H), 1.75 (h, J = 7.4 Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H). The attribution of each carbon atom is as follows: 13 13C NMR (126 MHz, Chloroform-d) δ 141.51, 138.51, 138.32, 136.65, 129.43, 128.83, 126.82, 126.77, 37.70, 24.58, 21.08, 13.91.

[0059] Example 4

[0060]

[0061] Under the protection of N2, 1.5 mmol of 5-(4-propylphenyl)thianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube, dispersed in 4 ml of DMSO. Under stirring, 1 mmol of fluorobenzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred for 12 hours at room temperature and under light. The light source was set the same as in Example 1.

[0062] The reaction process was monitored by TLC and HPLC. The subsequent treatment was the same as in Example 1. Pure 4-fluoro-4'-propylbiphenyl (purity ≥ 95%) was obtained.

[0063] White solid, with a yield of 50.2%. The attribution of each hydrogen atom is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 7.54–7.50 (m, 2H), 7.46–7.43 (m, 2H), 7.22 (d, J = 1.8 Hz, 2H), 7.13–7.07 (m, 2H), 2.61 (dd, J = 8.7, 6.7 Hz, 2H), 1.72–1.61 (m, 2H), 0.97 (td, J = 7.4, 1.1 Hz, 3H). The attribution of each carbon atom is as follows: 13 13C NMR (126 MHz, Chloroform-d) δ 141.87, 137.61, 128.95, 128.51, 128.44, 126.83, 115.62, 115.45, 37.66, 24.58, 13.88. The attribution of each fluorine atom is as follows: 19 19F NMR (471 MHz, Chloroform-d) δ -116.26.

[0064] Example 5

[0065]

[0066] Under the protection of N2, 1.5 mmol of 5-(4-propylphenyl)thianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube and dispersed in 4 ml of DMSO. Under stirring conditions, 1 mmol of p-acetylbenzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred at room temperature and under light for 12 hours. The light source was set as in Example 1.

[0067] The reaction process was monitored by TLC and HPLC. The subsequent treatment was the same as that in Example 1. Pure 4-acetyl-4'-propylbiphenyl (purity ≥ 95%) was obtained.

[0068] White solid, with a yield of 41.2%. The attribution of each hydrogen atom is as follows: 1 H NMR (500 MHz, Chloroform-d) δ 8.05–8.00 (m, 2H), 7.70–7.66 (m, 2H), 7.58–7.54 (m, 2H), 7.31–7.27 (m, 2H), 2.66 (d, J = 7.4 Hz, 2H), 2.63 (s, 3H), 1.74–1.65 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). The attribution of each carbon atom is as follows: 13 C NMR (126 MHz, Chloroform-d) δ 197.76, 145.74, 143.03, 137.15, 135.57, 129.08, 128.89, 127.07, 126.95, 37.69, 26.62, 24.49, 13.84.

[0069] Example 6

[0070]

[0071] Under the protection of N2, 1.5 mmol of 5-phenylthianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube and dispersed in 4 ml of DMSO. Under stirring conditions, 1 mmol of benzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred at room temperature and under light for 12 hours. The light source was set as in Example 1.

[0072] The reaction process was monitored by TLC and HPLC. The subsequent treatment was the same as that in Example 1. Pure biphenyl (purity ≥ 95%) was obtained.

[0073] A white solid with a yield of 59.7%. The attribution of each hydrogen atom is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 7.66–7.62 (m, 4H), 7.48 (dd, J = 8.6, 6.9 Hz, 4H), 7.42–7.37 (m, 2H). The attribution of each carbon atom is as follows: 13 13C NMR (126 MHz, Chloroform-d) δ 141.29, 128.82, 127.32, 127.23.

[0074] Example 7

[0075]

[0076] Under the protection of N2, 1.5 mmol of 5-(4-ethylphenyl)thianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube and dispersed in 4 ml of DMSO. Under stirring conditions, 1 mmol of benzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred for 12 hours at room temperature and under light. The light source was set as in Example 1.

[0077] The reaction process was monitored by TLC and HPLC. The subsequent treatment was the same as that in Example 1. Pure 4-ethylbiphenyl (purity ≥ 95%) was obtained.

[0078] A white solid with a yield of 70.5%. The attribution of each hydrogen atom is as follows: 1 1H NMR (500 MHz, Chloroform-d) δ 7.61–7.57 (m, 2H), 7.54–7.50 (m, 2H), 7.44–7.39 (m, 2H), 7.34–7.29 (m, 1H), 7.29–7.24 (m, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). The attribution of each carbon atom is as follows: 13 13C NMR (126 MHz, Chloroform-d) δ 143.49, 141.32, 138.74, 128.84, 128.42, 127.21, 127.13, 127.09, 28.65, 15.73.

[0079] Example 8

[0080]

[0081] Under the protection of N2, 1.5 mmol of the substrate 5-(4-methoxyphenyl)thianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube, dispersed in 4 ml of DMSO. Under stirring conditions, 1 mmol of benzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred at room temperature and under light for 12 hours. The light source was set as in Example 1.

[0082] The reaction progress was monitored by TLC and HPLC. The subsequent treatment was the same as in Example 1. Pure 4-methoxybiphenyl (purity ≥ 95%) was obtained.

[0083] White solid, with a yield of 75%. The attribution of each hydrogen atom is as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.61–7.52 (m, 4H), 7.44 (dd, J = 8.5, 7.0 Hz, 2H), 7.36–7.29 (m, 1H), 7.04–6.97 (m, 2H), 3.87 (s, 3H). The attribution of each carbon atom is as follows: 13 C NMR (126 MHz, Chloroform-d) δ 159.17, 140.85, 133.80, 128.77, 128.20, 126.78, 126.70, 114.23, 55.38.

[0084] Example 9

[0085]

[0086] Under the protection of N2, 1.5 mmol of 5-(4-fluorophenyl)thianthrenium trifluoromethanesulfonate was added to a dry and clean Schlenk tube, dispersed in 4 ml of DMSO. Under stirring conditions, 1 mmol of benzenediazonium tetrafluoroborate was slowly added thereto, and then 5% of the photocatalyst eosin Y was added. The reaction was stirred at room temperature and under light for 12 hours. The light source was set as in Example 1.

[0087] The reaction progress was monitored by TLC and HPLC. The subsequent treatment was the same as in Example 1. Pure 4-fluorobiphenyl (purity ≥ 95%) was obtained.

[0088] White solid, with a yield of 41.5%. The attribution of each hydrogen atom is as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.46 (ddd, J = 8.8, 4.6, 1.8 Hz, 4H), 7.39–7.33 (m, 2H), 7.30–7.26 (m, 1H), 7.08–7.02 (m, 2H). The attribution of each carbon atom is as follows:13 13C NMR (126 MHz, Chloroform-d) δ 140.35, 128.97, 128.84, 128.78, 127.40, 127.14, 115.83, 115.66. The assignments of each fluorine atom are as follows: 19 19F NMR (471 MHz, Chloroform-d) δ -115.58.

[0089] Example 10: Change the solvent in Example 1 to that shown in Table 1 below, while keeping the volume dosage unchanged at 4 mL; the rest is the same as in Example 1. The yields obtained are compared with those in Example 1 as shown in Table 1 below.

[0090] Table 1

[0091]

[0092] Example 11: Change the molar dosage of the tolylthionium salt in Example 1, while keeping the molar dosage of the benzenediazonium tetrafluoroborate unchanged, and thus adjust the molar ratio of the benzenediazonium tetrafluoroborate to the tolylthionium salt accordingly. The rest is the same as in Example 1. The yields obtained are compared with those in Example 1 as shown in Table 2 below.

[0093] Table 2

[0094]

[0095] Example 12: Change the light source in Example 1 from blue light with a wavelength of 440 - 450 nm to natural light; the rest is the same as in Example 1. The yield obtained is 8.5%.

[0096] Comparative Example 1: Cancel the use of "eosin Y" as the photocatalyst in Example 1, and the rest is the same as in Example 1.

[0097] The result obtained is: no target product 4-methylbiphenyl is formed.

[0098] Comparative Example 2: Change the eosin Y in Example 1 to Rhodamine 6G, and the rest is the same as in Example 1.

[0099] The result obtained is: the yield of the target product decreases, only being 17.5%.

[0100] Comparative Example 3: Change the eosin Y in Example 1 to Rhodamine B, and the rest is the same as in Example 1.

[0101] The result obtained is: the yield of the target product decreases, only being 21.3%.

[0102] Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by a person skilled in the art should be considered as the protection scope of the present invention.

Claims

1. A method for synthesizing para-substituted biphenyl compounds, characterized in that It includes the following steps: 1), Under the protection of inert gas, using sulfonium salt and diazonium salt as substrates, in a solvent, in the presence of a photocatalyst, stirring and reacting at a reaction temperature of 25 °C to 100 °C and under illumination for 6 to 24 hours; obtaining a reaction solution containing para-substituted biphenyl compounds; The molar ratio of diazonium salt to sulfonium salt is 1:1.0 to 2.0, and the molar ratio of diazonium salt to photocatalyst is 1:0.01 to 0.1; The diazonium salt is The sulfonium salt is R is any one of the following: hydrogen, alkyl, alkoxy, ester group, halogen, ketone group; R 1 is any one of the following: hydrogen, alkyl, alkoxy, ester group, halogen, cycloalkyl; Y is any one of the following: TfO - , BF4 - ; The photocatalyst is any one of the following: eosin tetrabromide, rhodamine 6G, rhodamine B; The light source used for illumination is natural light or blue light; The solvent is any one of the following: acetone, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, N,N-dimethylformamide; 2) Post-treat the reaction solution obtained in step 1) to obtain para-substituted biphenyl compounds.

2. The preparation method of the para-substituted biphenyl compound according to claim 1, characterized in that In step 1): Among the above R, the alkyl is methyl, ethyl, propyl, the alkoxy is methoxy, the halogen is fluoro group, and the ketone group is ethyl ketone group; The R 1 wherein the alkyl group is methyl, ethyl, or propyl; the alkoxy group is methoxy or ethoxy; the halogen is fluoro; and the cycloalkyl group is cyclohexyl.

3. The method for preparing a para-substituted biphenyl compound according to claim 2, characterized in that In step 1): For every 0.1 to 0.5 mol of diazonium salt, 1 L of solvent is used.

4. The preparation method of the para-substituted biphenyl compound according to any one of claims 1 to 3, characterized in that The post-treatment in step 2) is: After the reaction in step 1) is completed, add water to the reaction solution containing para-substituted biphenyl compounds obtained in step 1) to quench the reaction, then add saturated brine for extraction, filter, dry, filter, rotary evaporate the solvent from the filtrate, and then use silica gel column chromatography for separation and purification to obtain the para-substituted biphenyl compounds as the product.

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