Regional divergent preparation method of trisubstituted benzene compound

Abstract

The invention belongs to the field of electrochemical synthesis, and discloses a method for preparing a tri-substituted benzene compound in a regional divergence mode, a ligand is adopted for regulating terminal alkyne regional divergence [2 + 2 + 2] cycloaddition reaction, and when a monodentate phosphine ligand is used, a 1, 2, 4-tri-substituted benzene compound is obtained in a regioselectivity mode; when an N, N-bidentate or O, O-bidentate ligand is used, the 1, 3, 5-trisubstituted benzene compound is selectively obtained. The method can be used for later-stage modification of natural products, and benzene compounds containing three natural product structural fragments at the same time, such as eugenol and tyrosine, are synthesized with high yield and high selectivity. The regioselectivity of the method can reach up to gt; the method has the advantages of wide raw material source, no need of multiple preparation, high atom economy, no need of noble metal catalysis, low reaction cost, no need of a reducing agent, simple reaction system, greenness and environmental protection, and very good practical application value.

Description

Technical Field

[0001] The invention belongs to the field of electrochemical synthesis, and particularly relates to a method for preparing trisubstituted benzene compounds by regiodivergent reaction. The method is to synthesize 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds from terminal alkynes by ligand-controlled regiodivergent [2+2+2] cycloaddition reaction under electrochemical and nickel catalytic systems. Background Art

[0002] Polysubstituted benzene compounds are widely used organic synthesis reagents and are important synthetic raw materials or intermediates for various chemical products, electronic materials and pharmacologically active molecules. For example, the parent nucleus of the natural product Danshen cryptospironolactone is a tetrasubstituted benzene ring. 1,3,5-Trisubstituted benzene is often used as an important monomer for the synthesis of covalent organic frameworks, liquid crystal materials, organic light-emitting diodes, dendrimers and fullerene fragments. Due to its high atom economy, transition metal-catalyzed alkyne [2+2+2] cycloaddition is one of the methods for the rapid and efficient construction of polysubstituted benzene compounds. This method often obtains a mixture of 1,2,4- and 1,3,5-trisubstituted benzenes, and the 1,2,4-isomer is the main one. The control of the reaction regioselectivity is the main problem faced by this method, and it is more valuable to develop a regiodivergent synthesis method to obtain the two isomers with high selectivity.

[0003] Currently reported methods for regulating regioselectivity include changing the solvent system and additives. For example, using cobalt as a catalyst, zinc metal as a reducing agent, and dichloromethane as a solvent, 1,3,5-trisubstituted benzene is preferentially obtained with a regioselectivity of 2.9:1; when acetonitrile is used as a solvent, 1,2,4-trisubstituted benzene is preferentially obtained with a regioselectivity of 19.2:1 (Eur. J. Org. Chem. 2008, 2293). Using nickel as a catalyst, 1,2-bis(diphenylphosphino)ethane as a bidentate phosphine ligand, zinc metal as a reducing agent, and acetonitrile as a solvent, 1,2,4-trisubstituted benzene is preferentially obtained without the addition of zinc iodide, with a regioselectivity of 32:1; when zinc iodide is added, 1,3,5-trisubstituted benzene is preferentially obtained with a regioselectivity of 24:1 (Org. Chem. Front., 2022, 9, 2357-2367). The above-mentioned methods do not have good regioselectivity, all use metallic zinc as a reducing agent, and the reaction system is not green and economical enough, which limits their practical applications. Summary of the invention

[0004] In order to overcome the shortcomings and deficiencies in the above-mentioned prior art, the purpose of the present invention is to provide a method for preparing trisubstituted benzene compounds in a regiodivergent manner; the method uses a simple and readily available monodentate phosphine ligand and an N,N-bidentate or O,O-bidentate ligand for regiodivergent regulation, and can obtain 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds with a regioselectivity of >99:1. The method can be applied to the later modification of natural products, and synthesizes benzene compounds containing three natural product structural fragments at the same time with high yield and high selectivity, such as eugenol and tyrosine. The method has more efficient control means, a wider range of ligand types, no need for metal reducing agents, a simpler, more efficient, green and environmentally friendly reaction system, and has good application value.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] A method for preparing trisubstituted benzene compounds by regiodivergence, i.e., a method for synthesizing 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds by regulating the regiodivergence [2+2+2] cycloaddition reaction of terminal alkynes with ligands and respectively with excellent regioselectivity, specifically comprising the following steps:

[0007] Dissolving the terminal alkyne, nickel catalyst, ligand, additive and electrolyte in an organic solvent, stirring until all solids are dissolved, assembling the obtained electrolyte solution into an electrolytic cell, performing constant current electrolysis at room temperature, and the current intensity is 3.3 mA / mmol based on the amount of the terminal alkyne substance. After the electrolysis is completed, according to the different types of ligands used, 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds are obtained by post-treatment;

[0008] The terminal alkyne has a structure as shown in the following formula I; the ligand is a compound having a structure as shown in the following formula L1, L2 or L3;

[0009]

[0010] R in Formula I 1 Alkyl, aryl and aromatic heterocyclic groups;

[0011] In formula L1, R 2 is one of a C1-C6 chain alkyl group, a cyclic alkyl group, and an aryl group; in formulas L2 and L3, R 3 and R 4 It is one of a C1-C6 chain alkyl group, a cyclic alkyl group, an aryl group, and a halogen substituent.

[0012] When the ligand is a compound having a structure as shown in the above formula L1, a 1,2,4-trisubstituted benzene compound having a structure as shown in the following formula II is finally prepared.

[0013] When the ligand is a compound having a structure as shown in the above formula L2 or L3, a 1,3,5-trisubstituted benzene compound having a structure as shown in the following formula III is finally prepared.

[0014]

[0015] R in Formula II and Formula III 1 As shown above, R 1 .

[0016] The molar ratio of the terminal alkyne, the nickel catalyst, the ligand, the additive and the electrolyte is 1:(0.02-0.1):(0.02-0.2):(0.1-0.5):(0.2-1).

[0017] The post-treatment is to ultrasonically clean the electrode twice with ethyl acetate after the electrolysis is completed, combine the ethyl acetate cleaning solution and combine it with the electrolyte solution in the electrolytic cell, then wash it twice with deionized water, dry the obtained organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds.

[0018] The nickel catalyst is nickel bromide, nickel chloride, nickel chloride dimethoxyethane (NiCl 2 ·DME), one or any combination of nickel acetate, nickel perchlorate, nickel acetylacetonate, and nickel nitrate.

[0019] The organic solvent is one or any combination of acetonitrile, acetone, ethyl acetate, N,N-dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide (DMA). Preferably, the organic solvent is N,N-dimethylacetamide.

[0020] The electrolyte is one or any combination of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, lithium perchlorate, and lithium tetrafluoroborate.

[0021] The additive is one or any combination of triethylamine, triethanolamine and diisopropylethylamine (DIPEA).

[0022] The anode material used in the electrolytic cell is one or any combination of platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, and foamed glassy carbon; the cathode material used in the electrolytic cell is one or any combination of foamed nickel, foamed copper, carbon fiber, carbon felt, carbon paper, glassy carbon, and foamed glassy carbon.

[0023] The anode material is carbon fiber; the cathode material is foamed glassy carbon.

[0024] The room temperature is 25°C.

[0025] The reaction equation of the above-mentioned method for preparing tri-substituted benzene compounds by regional divergence is as follows:

[0026]

[0027] Compared with the prior art, the method of the ligand-controlled nickel-catalyzed terminal alkyne regio-divergent [2+2+2] cycloaddition reaction provided by the present invention has the following advantages and beneficial effects:

[0028] (1) The regioselectivity of the product of the present invention is regulated by the ligand, the regioselectivity is high (>99%), and the regulation means is stable and efficient.

[0029] (2) The ligands used in the present invention have simple structures and a wide range of sources. They are all commercially available and do not require multi-step preparation and synthesis.

[0030] (3) The electrolysis process of the present invention replaces the use of reducing agents such as zinc powder and manganese powder, and the reaction system is simple and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the H NMR spectrum of structural formula II-1 in Example 1;

[0032] Figure 2 is the carbon NMR spectrum of structural formula II-1 in Example 1;

[0033] Figure 3 is the H NMR spectrum of structural formula II-2 in Example 2;

[0034] Figure 4 is the carbon NMR spectrum of structural formula II-2 in Example 2;

[0035] Figure 5 is the H NMR spectrum of the structural formula III-1 in Example 4;

[0036] Figure 6 is the carbon NMR spectrum of structural formula III-1 in Example 4;

[0037] Figure 7 is the nuclear magnetic resonance fluorine spectrum of structural formula III-1 in Example 4;

[0038] Figure 8 is the H NMR spectrum of structural formula III-2 in Example 5;

[0039] Fig. 9 is the carbon NMR spectrum of structural formula III-2 in Example 5;

[0040] Fig.10is the H NMR spectrum of structural formula III-3 in Example 6;

[0041] Fig.11 This is the carbon nuclear magnetic resonance spectrum of structural formula III-3 in Example 6. DETAILED DESCRIPTION

[0042] The present invention will be described in further detail below in conjunction with the examples and accompanying drawings, but the embodiments of the present invention are not limited thereto. The equipment, instruments and reagents used in the present invention are commonly used in the art. It should be understood that the examples described herein are only used to explain the present invention and are not intended to limit the present invention.

[0043] The reaction equation of the method of the present invention is as follows:

[0044]

[0045] The synthesis method of the 1,2,4-trisubstituted benzene compound with the structure shown in Formula II is as follows:

[0046] In a one-chamber electrolytic cell, the terminal alkyne shown in structural formula I, additives, Ni catalyst, monodentate phosphine ligand with structure shown in formula L1 and electrolyte are added to DMA solvent, stirred until all solids are dissolved, and the obtained electrolyte solution is assembled into an electrolytic cell together with the anode and cathode to ensure the sealing of the system. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and constant current electrolysis is performed at room temperature. After the electrolysis is completed, the electrode is ultrasonically cleaned twice with ethyl acetate, the ethyl acetate cleaning solution is combined, and combined with the electrolyte solution in the electrolytic cell, and then washed twice with deionized water, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain a 1,2,4-trisubstituted benzene compound with structure shown in formula II. The molar ratio of the terminal alkyne, nickel catalyst, ligand, additive and electrolyte is 1: (0.02-0.1): (0.02-0.2): (0.1-0.5): (0.2-1).

[0047] The synthesis method of the 1,3,5-trisubstituted benzene compound with the structure shown in formula III is as follows:

[0048] In a one-chamber electrolytic cell, the terminal alkyne shown in structural formula I, additives, Ni catalyst, bidentate ligands with structures shown in formula L2 or L3, and electrolytes are added to DMA solvent, stirred until all solids are dissolved, and the obtained electrolyte solution is assembled into an electrolytic cell together with the anode and cathode to ensure the sealing of the system. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and constant current electrolysis is performed at room temperature. After the electrolysis is completed, the electrode is ultrasonically cleaned twice with ethyl acetate, the ethyl acetate cleaning solution is combined, and combined with the electrolyte solution in the electrolytic cell, and then washed twice with deionized water, the organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain a 1,3,5-trisubstituted benzene compound with a structure shown in formula III. The molar ratio of the terminal alkyne, nickel catalyst, ligand, additive and electrolyte is 1: (0.02-0.1): (0.02-0.2): (0.1-0.5): (0.2-1).

[0049] The nickel catalyst is nickel bromide, nickel chloride, nickel chloride dimethoxyethane (NiCl 2 ·DME), nickel acetate, nickel perchlorate, nickel acetylacetonate, nickel nitrate or any combination thereof. The organic solvent is acetonitrile, acetone, ethyl acetate, N,N-dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide (DMA) or any combination thereof. The electrolyte is quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, lithium perchlorate and lithium tetrafluoroborate or any combination thereof. The additive is triethylamine, triethanolamine and diisopropylethylamine (DIPEA) or any combination thereof. The material of the anode is platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon and foamed glassy carbon or any combination thereof; the material of the cathode is foamed nickel, foamed copper, carbon fiber, carbon felt, carbon paper, glassy carbon and foamed glassy carbon or any combination thereof.

[0050] The present invention is further described below by means of specific embodiments in conjunction with the accompanying drawings:

[0051] Example 1

[0052] The equation of the synthesis method of this embodiment is as follows:

[0053]

[0054] In a one-chamber electrolytic cell, 4-cyanophenylacetylene (76 mg, 0.6 mol), DIPEA (0.24 mmol, 31 mg), NiCl 2 DME (0.03 mmol, 6.6 mg), monodentate phosphine ligand tri-n-butylphosphine (0.06 mmol, 15 μL) and nBu 4 NBF 4(0.3mmol, 99mg), added to 3mL DMA solvent, stirred thoroughly until the solid was completely dissolved, and the obtained electrolyte solution was mixed with a carbon fiber anode (0.15g) and a foamed glassy carbon cathode (0.5×2.5×0.2mm 3 ) are assembled into an electrolytic cell to ensure that the system is sealed. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and electrolysis is performed at a constant current of 2 mA for 8 hours at room temperature. The electrode is ultrasonically cleaned twice with 10 mL of ethyl acetate, the ethyl acetate cleaning liquid is combined and combined with the electrolyte solution in the electrolytic cell, and then washed twice with 30 mL of deionized water. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 62 mg of a white solid product with a yield of 81% and a selectivity of >99%. The hydrogen nuclear magnetic resonance spectrum of the product is shown in Figure 1 As shown, the carbon NMR spectrum is as follows Figure 2 As shown, the nuclear magnetic resonance characterization data of the product are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.80–7.74(m,5H),7.65(d,J=1.8Hz,1H),7.61–7.55(m,5H),7.30–7.24(m,4H). 13 C NMR (126 MHz, Chloroform-d) δ 145.08, 144.76, 144.20, 139.90, 139.65, 138.96, 132.94, 132.31, 132.26, 131.59, 130.57, 130.51, 129.54, 127.88, 127.66, 118.78, 118.62, 118.58, 111.80, 111.42, 111.33. Characterization data proved that the obtained product was a 1,2,4-trisubstituted benzene compound with the structure shown in formula II-1.

[0055] Comparative Example 1

[0056] The other steps are the same as those in Example 1, except that no phosphine ligand is added or different phosphine ligands are used, triphenylphosphine and tricyclohexylphosphine are used to replace tri-n-butylphosphine, respectively, and the reaction results are as follows: the yield of the product obtained in the comparative experiment using triphenylphosphine as a ligand is 65%, and the selectivity is 94%; the yield of the product obtained in the comparative experiment using tricyclohexylphosphine as a ligand is 70%, and the selectivity is 95%; the yield of the product obtained in the comparative experiment without adding a phosphine ligand is 10%, and the selectivity is 50%. This indicates that monodentate phosphine ligands are preferred ligands for obtaining 1,2,4-trisubstituted benzene compounds, and tri-n-butylphosphine is most preferred.

[0057] Comparative Example 2

[0058] The other steps were the same as those in Example 1, except that the nickel catalyst was nickel perchlorate. 36 mg of product was obtained with a yield of 47% and a selectivity of 94%.

[0059] Comparative Example 3

[0060] The other steps were the same as those in Example 1, except that foamed glassy carbon was used as the anode and foamed nickel was used as the cathode. 40 mg of product was obtained with a yield of 52% and a selectivity of 96%.

[0061] Comparative Example 4

[0062] The other steps were the same as those in Example 1, except that the electrolyte was tetra-n-butylammonium perchlorate. 47 mg of product was obtained with a yield of 62% and a selectivity of 98%.

[0063] Comparative Example 5

[0064] The other steps were the same as in Example 1, except that triethylamine was added as an additive, and 18 mg of product was obtained with a yield of 23% and a selectivity of 95%.

[0065] Comparative Example 6

[0066] The method described in Example 1 was followed, except that the solvent was acetonitrile, to obtain 42 mg of the product with a yield of 55% and a selectivity of 96%.

[0067] Comparative Examples 2-6 show that factors such as solvent, electrolyte, electrode material, additive, and nickel catalyst mainly affect the reaction yield and have little effect on the regioselectivity of the reaction, with selectivities all >94%, further demonstrating that the ligand-regulated reaction regioselectivity has good stability.

[0068] Example 2

[0069] The equation of the synthesis method of this embodiment is as follows:

[0070]

[0071] In a one-chamber electrolytic cell, propyne (121 mg, 0.6 mol), DIPEA (0.24 mmol, 31 mg), and NiCl 2 DME (0.03 mmol, 6.6 mg), monodentate phosphine ligand tri-n-butylphosphine (0.06 mmol, 15 μL) and nBu 4 NBF 4 (0.3mmol, 99mg), added to 3mL DMA solvent, stirred thoroughly until the solid was completely dissolved, and the obtained electrolyte solution was mixed with a carbon fiber anode (0.15g) and a foamed glassy carbon cathode (0.5×2.5×0.2mm 3) are assembled into an electrolytic cell to ensure that the system is sealed. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and electrolysis is performed at a constant current of 2 mA for 8 hours at room temperature. The electrode is ultrasonically cleaned twice with 10 mL of ethyl acetate, the ethyl acetate cleaning liquid is combined and combined with the electrolyte solution in the electrolytic cell, and then washed twice with 30 mL of deionized water. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 61 mg of a white solid product with a yield of 50% and a selectivity of >99%. The hydrogen nuclear magnetic resonance spectrum of the product is shown in Figure 3 As shown, the carbon NMR spectrum is as follows Figure 4 As shown, the nuclear magnetic resonance and high-resolution mass spectrometry characterization data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.56(s,1H),7.49(d,J=7.8Hz,1H),7.38(d,J=7.7Hz,1H),6.84(dd,J=8.1,5.6Hz,2H),6.76(d,J=8.2Hz,1H),6.72(d,J=5.3Hz ,3H),6.68–6.62(m,3H),6.02–5.90(m,3H),5.25(d,J=5.9Hz,4H),5.13(s,2H) ,5.11–5.04(m,6H),3.87(s,3H),3.84(d,J=2.4Hz,6H),3.33(d,J=6.2Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ149.75,149.69,149.58,146.47,146.37,146.35,1 37.76,137.36,135.48,135.03,133.51,133.41,133.30,128.88,127.48,127.00, 120.52,120.46,115.79,115.76,114.44,114.29,114.23,112.40,112.26,112.24 ,70.88,69.45,69.05,56.02,55.88,55.86,39.97,39.96,39.94.HRMS(EI):exact mass calculated for C 39 H 42 O 6 [M]+require m / z=606.2981, found m / z=606.2977. Characterization data prove that the obtained product is a 1,2,4-trisubstituted benzene compound with the structure shown in formula II-2.

[0072] Example 3

[0073] A series of substituted or polysubstituted terminal alkynes (substituents include but are not limited to alkyl, alkoxy, aryl, amine, hydroxyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyano, acetyl, aldehyde, carboxyl, amide, ester, sulfonamide, nitro, alkenyl, alkynyl, etc.) and heterocyclic terminal alkynes (heterocyclic includes but is not limited to pyridine and furan) were selected as raw materials. According to the method of Example 1, 30 1,2,4-trisubstituted benzene compounds were synthesized, and their structures are shown below:

[0074]

[0075] Example 4

[0076] The equation of the synthesis method of this embodiment is as follows:

[0077]

[0078] In a one-chamber electrolytic cell, 4-trifluoromethylphenylacetylene (76 mg, 0.6 mol), DIPEA (0.24 mmol, 31 mg), NiBr 2 (0.03mmol, 6.6mg), 6,6'-dimethyl-2,2'-bipyridine L2-1 (0.06mmol, 11mg) and nBu 4 NBF 4 (0.3mmol, 99mg), added to 3mL DMA solvent, stirred thoroughly until the solid was completely dissolved, and the obtained electrolyte solution was mixed with a carbon fiber anode (0.15g) and a foamed glassy carbon cathode (0.5×2.5×0.2mm 3 ) are assembled into an electrolytic cell to ensure that the system is sealed. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and electrolysis is performed at a constant current of 2 mA for 8 hours at room temperature. The electrode is ultrasonically cleaned twice with 10 mL of ethyl acetate, the ethyl acetate cleaning liquid is combined and combined with the electrolyte solution in the electrolytic cell, and then washed twice with 30 mL of deionized water. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 79 mg of a white solid product with a yield of 81% and a selectivity of >99%. The hydrogen nuclear magnetic resonance spectrum of the product is shown in Figure 5 As shown, the carbon NMR spectrum is as follows Figure 6 As shown, the NMR fluorine spectrum is as follows Figure 7 As shown, the NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ7.84(s,3H),7.79(q,J=8.5Hz,12H). 13 C NMR (101 MHz, CDCl 3)δ144.16(x3),141.69(x3),130.23(q,J=32.5Hz)(x3),127.83(x6),126.27(x3),126.12(q,J=3.7Hz)(x6),124.34(q,J=272.1Hz)(x3). 19 F NMR (376 MHz, CDCl 3 )δ-62.46. Characterization data prove that the obtained product is a 1,3,5-trisubstituted benzene compound with the structure shown in formula III-1.

[0079] Comparative Example 7

[0080]

[0081] The other steps are the same as those in Example 4, except that the ligands are different, and N,N-bidentate or O,O-bidentate ligands with structures shown in Formulas L2-2, L2-3, L2-4, L3-1, L3-2, and L3-3 are used respectively. The reaction results are as follows: the yield of the product obtained in the comparative experiment using L2-2 as the ligand is 28%, and the selectivity is 69%; the yield of the product obtained in the comparative experiment using L2-3 as the ligand is 45%, and the selectivity is >99%; the yield of the product obtained in the comparative experiment using L2-4 as the ligand is 31%, and the selectivity is >99%; the yield of the product obtained in the comparative experiment using L3-1 as the ligand is 45%, and the selectivity is 80%; the yield of the product obtained in the comparative experiment using L3-2 as the ligand is 80%, and the selectivity is >99%; the yield of the product obtained in the comparative experiment using L3-3 as the ligand is 75%, and the selectivity is >99%. The results show that N,N-bidentate or O,O-bidentate ligands are the preferred ligands for obtaining 1,3,5-trisubstituted benzene compounds, among which the effect is better when the ortho-position of the coordinating atom is sterically substituent, and the most preferred ones are 6,6'-dimethyl-2,2'-bipyridine (L2-1) and 2,2,6,6-tetramethyl-3,5-heptanedione (L3-2).

[0082] Comparative Example 8

[0083] The other steps were the same as those in Example 4, except that the nickel catalyst was nickel perchlorate. 35 mg of product was obtained with a yield of 36% and a selectivity of >99%.

[0084] Comparative Example 9

[0085] The other steps are the same as those in Example 4, except that the foamed glassy carbon is used as the anode and the foamed nickel is used as the cathode. 64 mg of product is obtained with a yield of 66% and a selectivity of >99%.

[0086] Comparative Example 10

[0087] The other steps were the same as those in Example 4, except that the electrolyte was tetra-n-butylammonium perchlorate. 69 mg of product was obtained with a yield of 71% and a selectivity of >99%.

[0088] Comparative Example 11

[0089] The other steps were the same as those in Example 4, except that triethylamine was added as an additive, and 32 mg of product was obtained with a yield of 33% and a selectivity of >99%.

[0090] Comparative Example 12

[0091] The other steps were the same as those in Example 4, except that the solvent was acetonitrile. 51 mg of product was obtained with a yield of 59% and a selectivity of >99%.

[0092] Comparative Examples 8-12 show that factors such as solvent, electrolyte, electrode material, additive, and nickel catalyst mainly affect the reaction yield and have little effect on the regioselectivity of the reaction, with selectivities all >99%, further indicating that the ligand-regulated reaction regioselectivity has good stability.

[0093] Example 5

[0094] The equation of the synthesis method of this embodiment is as follows:

[0095]

[0096] In a one-chamber electrolytic cell, propyne (200 mg, 0.6 mol), DIPEA (0.24 mmol, 31 mg), NiBr 2 (0.03mmol, 6.6mg), 6,6'-dimethyl-2,2'-bipyridine L2-1 (0.06mmol, 11mg) and nBu 4 NBF 4 (0.3mmol, 99mg), added to 3mL DMA solvent, stirred thoroughly until the solid was completely dissolved, and the obtained electrolyte solution was mixed with a carbon fiber anode (0.15g) and a foamed glassy carbon cathode (0.5×2.5×0.2mm 3 ) are assembled into an electrolytic cell to ensure that the system is sealed. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and electrolysis is performed at a constant current of 2 mA for 8 hours at room temperature. The electrode is ultrasonically cleaned twice with 10 mL of ethyl acetate, the ethyl acetate cleaning liquid is combined and combined with the electrolyte solution in the electrolytic cell, and then washed twice with 30 mL of deionized water. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 92 mg of a white solid product with a yield of 46% and a selectivity of >99%. The hydrogen nuclear magnetic resonance spectrum of the product is shown in Figure 8 As shown, the carbon NMR spectrum is as follows Fig. 9As shown below, the characterization data of nuclear magnetic resonance and high-resolution mass spectrometry are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.46(s,3H),7.04(d,J=8.6Hz,6H),6.90(d,J=8.6Hz,6H),5.06(s,6H),4.97(d,J=7.9Hz,3H),4.54(d,J=7.1Hz,3H),3.71(s,9H),3.03(tt,J=14.2,6.1Hz,6H),1.42(s,27H). 13 C NMR(101MHz,CDCl 3 )δ172.55,157.94,155.23,138.04,130.50,128.57,126.14,115.04,80.03,69.85,54.66,52.32,37.63,28.43.HRMS(ESI):exact mass calculated for C 54 H 69 N 3 O 15 [M]+require m / z=999.4729,found m / z=999.4724.The characterization data prove that the obtained product is a 1,3,5-trisubstituted benzene compound with the structure shown in Formula III-2.

[0097] Example 6

[0098] The equation of the synthesis method in this example is as follows:

[0099]

[0100] In a one-compartment electrolytic cell, eugenol-derived propyne (121 mg, 0.6 mmol) with the structure shown in Formula I-1, DIPEA (0.24 mmol, 31 mg), NiBr 2 (0.03 mmol, 6.6 mg), 6,6'-dimethyl-2,2'-bipyridine L2-1 (0.06 mmol, 11 mg) and nBu 4 NBF 4 (0.3 mmol, 99 mg) were added to 3 mL of DMA solvent, and stirred thoroughly until all the solids were dissolved. The resulting electrolyte solution and a carbon fiber anode (0.15 g) and a foamed glassy carbon cathode (0.5×2.5×0.2 mm 3) are assembled into an electrolytic cell to ensure that the system is sealed. A nitrogen flow is blown into the electrolyte solution for 15 minutes, and electrolysis is performed at a constant current of 2 mA for 8 hours at room temperature. The electrode is ultrasonically cleaned twice with 10 mL of ethyl acetate, the ethyl acetate cleaning liquid is combined and combined with the electrolyte solution in the electrolytic cell, and then washed twice with 30 mL of deionized water. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 53 mg of a white solid product with a yield of 44% and a selectivity of >99%. The hydrogen nuclear magnetic resonance spectrum of the product is shown in Fig.10 As shown, the carbon NMR spectrum is as follows Fig.11 As shown, the nuclear magnetic resonance and high-resolution mass spectrometry characterization data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.44(s,3H),6.77(d,J=8.2Hz,3H),6.72(d,J=1.9Hz,3H),6.63(dd,J=8 .2,2.0Hz,3H),5.98–5.92(m,3H),5.12(s,6H),5.08–5.04(m,6H),3.87(s,9H),3.33(d,J=6.6Hz,6H). 13 C NMR(126MHz,Chloroform-d)δ149.62,146.49,138.18,137.74,133.41,125.51,120.50,115.79,114.35,112.38,71.11,55.99,39.95.HRMS(EI):exactmass calculated for C 39 H 42 O 6 [M]+require m / z=606.2981, found m / z=606.2977. Characterization data prove that the obtained product is a 1,3,5-trisubstituted benzene compound having the structure shown in formula III-3.

[0101] Example 7

[0102] A series of substituted or polysubstituted terminal alkynes (substituents include but are not limited to alkyl, alkoxy, aryl, amine, hydroxyl, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyano, acetyl, aldehyde, carboxyl, amide, ester, sulfonamide, nitro, alkenyl, alkynyl, etc.) and heterocyclic terminal alkynes (heterocyclic rings include but are not limited to pyridine and furan) were selected as raw materials. According to the method of Example 4, 25 1,3,5-trisubstituted benzene compounds were synthesized, and their structures are shown below:

[0103]

[0104] The above content is a further detailed description of the present application in combination with specific implementation methods, but it cannot be determined that the specific implementation of the present application is limited to these descriptions, and it can be fully applied to various fields suitable for the present invention. For those familiar with the art, some simple deductions or substitutions can also be made without departing from the concept of the present application. Therefore, without departing from the general concept defined by the claims and equivalent scope, the present invention is not limited to specific details.

Claims

1. A method for preparing tri-substituted benzene compounds by regional divergence, characterized in that The steps include: Dissolving the terminal alkyne, nickel catalyst, ligand, additive and electrolyte in an organic solvent, stirring until all solids are dissolved, assembling the obtained electrolyte solution into an electrolytic cell, performing constant current electrolysis at room temperature, and the current intensity is 3.3 mA / mmol based on the amount of the terminal alkyne substance. After the electrolysis is completed, according to the different types of ligands used, 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds are obtained by post-treatment; The terminal alkyne has a structure as shown in the following formula I; the ligand is a compound having a structure as shown in the following formula L1, L2 or L3; R in Formula I 1 Alkyl, aryl and aromatic heterocyclic groups; In formula L1, R 2 is one of a C1-C6 chain alkyl group, a cyclic alkyl group, and an aryl group; in formulas L2 and L3, R 3 and R 4 It is one of a C1-C6 chain alkyl group, a cyclic alkyl group, an aryl group, and a halogen substituent.

2. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The molar ratio of the terminal alkyne, the nickel catalyst, the ligand, the additive and the electrolyte is 1:(0.02-0.1):(0.02-0.2):(0.1-0.5):(0.2-1).

3. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The post-treatment is to ultrasonically clean the electrode twice with ethyl acetate after the electrolysis is completed, combine the ethyl acetate cleaning solution and combine it with the electrolyte solution in the electrolytic cell, then wash it twice with deionized water, dry the obtained organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain 1,2,4-trisubstituted benzene compounds or 1,3,5-trisubstituted benzene compounds.

4. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The nickel catalyst is one or any combination of nickel bromide, nickel chloride, nickel chloride dimethoxyethane, nickel acetate, nickel perchlorate, nickel acetylacetonate, and nickel nitrate.

5. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The organic solvent is one or any combination of acetonitrile, acetone, ethyl acetate, N,N-dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide.

6. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 5, characterized in that: The organic solvent is N,N-dimethylacetamide.

7. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The electrolyte is one or any combination of quaternary ammonium perchlorate, quaternary ammonium tetrafluoroborate, quaternary ammonium hexafluorophosphate, lithium perchlorate, and lithium tetrafluoroborate; and the additive is one or any combination of triethylamine, triethanolamine, and diisopropylethylamine.

8. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The anode material used in the electrolytic cell is one or any combination of platinum, graphite, carbon fiber, carbon felt, carbon paper, glassy carbon, and foamed glassy carbon; the cathode material used in the electrolytic cell is one or any combination of foamed nickel, foamed copper, carbon fiber, carbon felt, carbon paper, glassy carbon, and foamed glassy carbon.

9. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 8, characterized in that: The anode material is carbon fiber; the cathode material is foamed glassy carbon.

10. The method for preparing tri-substituted benzene compounds by regional divergence according to claim 1, characterized in that: The room temperature is 25°C.

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