Method for constructing aromatic derivative through reductive cross-coupling reaction

Abstract

The invention discloses a method for constructing an aromatic derivative through a reductive cross-coupling reaction, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: co-dissolving aryl bromide, alkyl bromide, an iron-containing reagent, a ligand, a reducing agent and alkali in a solvent, and reacting at 45-100 DEG C for 14-18 hours to obtain an aromatic derivative; wherein the iron-containing reagent is ferrous bromide, the ligand is tetramethylethylenediamine, the alkali is lithium methoxide, the reducing agent is bis (pinacolato) diboron, and the solvent is methyl tert-butyl ether. Cheap and low-toxicity metal iron is used for replacing other transition metals for catalytic reaction, meanwhile, aryl bromide and alkyl bromide which are easy to obtain are used as reaction raw materials, construction of carbon-carbon bonds is completed through one-step reaction, and the aromatic derivative is obtained; the technical problems that precious metal or multi-metal catalysis is needed for alkyl modification of traditional transition metal catalysis aromatic compounds, and reaction substrates are difficult to obtain are solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for constructing aromatic derivatives through a reductive cross-coupling reaction. Background Art

[0002] Aromatic compounds, as the basic skeletons of many drug molecules and natural products, exploring their alkylation modification can promote the development of various fields such as biomedicine and chemical materials. Traditionally, the alkylation modification of aromatic compounds is achieved through cross-coupling of electrophilic reagents such as halides and pseudohalides with nucleophilic reagents such as Grignard reagents and organozinc reagents under the catalysis of transition metals. However, nucleophilic reagents often need to be prepared in advance and have disadvantages such as unstable properties and difficulty in storage. Currently, the developed reductive cross-coupling reaction for directly achieving the alkylation modification of aryl compounds using aryl electrophilic reagents and alkyl electrophilic reagents under the catalysis of a reducing agent and a transition metal has advantages such as simple operation and high step economy. However, the currently developed reactions mainly use transition metal catalysts such as nickel, palladium, and copper or multi-metal catalysis. These metal catalysts are either expensive or have biological toxicity, which affects the late-stage modification of drugs, and the synthesis of reaction substrates is difficult, thus limiting the development. Therefore, it is of great significance to develop environmentally friendly and effective methods, especially using cost-effective, green and non-toxic substance catalysts, and using simple and easily available reaction raw materials for the synthesis of aromatic derivatives. Summary of the Invention

[0003] Aiming at the above-mentioned prior art, the present invention provides a method for constructing aromatic derivatives through a reductive cross-coupling reaction to solve the technical problems that traditional transition metal-catalyzed alkyl modification of aromatic compounds requires noble metals or multi-metal catalysis and the reaction substrates are difficult to obtain.

[0004] To achieve the above object, the technical solution adopted by the present invention is to provide a method for constructing aromatic derivatives through a reductive cross-coupling reaction, including the following steps: dissolving an aryl bromide, an alkyl bromide, an iron-containing reagent, a ligand, a reducing agent, and a base in a solvent, and reacting at 45 - 100 °C for 14 - 18 h to obtain an aromatic derivative; the structural formula of the aryl bromide is shown as formula I, the structural formula of the alkyl bromide is shown as formula II, and the structural formula of the aromatic derivative is shown as formula III, , , ; wherein, Ar is an aryl group, a heteroaryl group, a fused aryl group, or a fused heteroaryl group, R1 is hydrogen or an alkyl group, and R2 is an alkyl group or a substituted alkyl group; The ligand is tetramethylethylenediamine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, or 2-dicyclohexylphosphino-2'-methylbiphenyl; the reducing agent is bis(pinacolato)diboron.

[0005] On the basis of the above technical solutions, the present invention can be further improved as follows.

[0006] Further, the molar ratio of the alkyl bromide, aryl bromide, iron-containing reagent, ligand, reducing agent and base is 1: 1.0-2.0: 0.1-0.2: 0.3-0.5: 1.5-3.0: 4.0-6.0.

[0007] Further, the molar ratio of the alkyl bromide, aryl bromide, iron-containing reagent, ligand, reducing agent and base is 1: 1.5: 0.15: 0.4: 2.1: 5.5.

[0008] Further, Ar is indolyl, pyridyl, naphthyl, dibenzofuranyl or phenyl.

[0009] Further, R2 is piperidinyl, cyclobutyl, ester-containing alkyl, amide-containing alkyl or chloroalkyl.

[0010] Further, the aryl bromide is one of the compounds shown in Formula 1 to Formula 5,

[0011] The alkyl bromide is one of the compounds shown in Formula 6 to Formula 10, .

[0012] Further, the iron-containing reagent is ferrous bromide, ferrous acetylacetonate or iron toluenesulfonate.

[0013] Further, the base is lithium methoxide.

[0014] Further, the solvent is methyl tert-butyl ether, n-hexane or cyclohexane.

[0015] Further, the reaction temperature is 60 °C and the reaction time is 18 h.

[0016] The beneficial effects of the present invention are as follows: The present invention uses cheap and low-toxic metal iron instead of other transition metals for catalytic reactions, and at the same time uses easily available aryl bromides and alkyl bromides as reaction raw materials to complete the construction of carbon-carbon bonds through a one-step reaction to obtain aromatic derivatives. Using transition metal iron as a catalyst, transition metal iron has the advantages of non-toxicity, low cost and environmental friendliness; the raw materials used in the reaction are commercially available, cheap and easy to obtain, expanding the scope of substrate applicability and reducing the raw material cost. This method is a general, efficient, economical and environmentally friendly method for rapidly constructing aryl derivatives. In addition, the method of the present invention can perform post-modification on a variety of natural products and drug molecule derivatives, playing an important role in drug modification and research and development, and can be widely applied to the synthesis of pharmaceutical intermediates and high-value-added fine chemicals. Detailed Embodiments

[0017] The following describes the detailed embodiments of the present invention in conjunction with the embodiments.

[0018] Embodiment 1 A method for constructing aromatic derivatives through a reductive cross-coupling reaction, the reaction formula is shown as follows:

[0019] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equivalent, FeBr2) of ferrous bromide, 9.3 mg (0.4 equivalent, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equivalents, MeOLi) of lithium methoxide, 106.7 mg (2.1 equivalents, B2pin2) of bis(pinacolato)diboron, 52.6 mg (1 equivalent) of tert-butyl 4-bromopiperidine-1-carboxylate, and 62.7 mg (1.5 equivalents) of 4-bromo-1-methyl-1H-indole. Subsequently, add 1.0 mL of methyl tert-butyl ether using a syringe and mix evenly; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases, dry with anhydrous sodium sulfate, and finally concentrate under vacuum. Use petroleum ether / ethyl acetate = 20:1 as the eluent and elute through flash column chromatography to obtain 52 mg of a clear colorless oil (Product 1), and the yield is 83%.

[0020] The product was detected using a nuclear magnetic resonance spectrometer (Agilent Technologies, model 400MR DD2), and the results were: 1 H NMR (400 MHz, CDCl3) δ 7.22-7.19 (m, 2 H), 7.08-7.07 (m, 1 H),6.96-6.94 (m, 1 H), 6.55 (d, J = 3.2 Hz, 1 H), 4.29 (m, 2 H), 3.80 (s, 3 H),3.12-3.08 (m, 1 H), 2.90-2.89 (m, 2 H), 1.98-1.94 (m, 2 H), 1.86-1.76 (m, 2H), 1.51 (s, 9 H). 1313C NMR (100 MHz, CDCl3) δ 155.0, 138.0, 136.8, 128.4, 127.1, 121.9, 115.8, 107.6, 99.1, 79.3, 44.8, 40.2, 32.8, 32.5, 28.7. Example 2 A method for constructing aromatic derivatives through reductive cross-coupling reaction, the reaction formula is shown as follows:

[0021] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equiv, FeBr2) of ferrous bromide, 9.3 mg (0.4 equiv, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equiv, MeOLi) of lithium methoxide, 106.7 mg (2.1 equiv, B2pin2) of bis(pinacolato)diboron, 26.8 mg (1 equiv) of cyclobutyl bromide, 62.7 mg (1.5 equiv) of 4-bromo-1-methyl-1H-indole, and then add 1.0 mL of methyl tert-butyl ether with a syringe and mix well; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration is 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases and dry with anhydrous sodium sulfate, and finally concentrate under vacuum. Use petroleum ether / ethyl acetate = 60:1 as the eluent and elute through flash column chromatography to obtain 18.5 mg of a clear colorless oil (Product 2), and the yield is 50%.

[0022] Use a nuclear magnetic resonance spectrometer (Agilent, model 400MR DD2) to detect the product, and the results are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.21-7.19 (m, 2 H), 7.05 (d, J = 3.2 Hz, 1 H), 7.03-7.01 (m, 1 H), 6.58 (d, J = 3.2 Hz, 1 H), 3.97 (m, 1 H), 3.79 (s, 3 H), 2.50-2.46 (m, 1 H), 2.41-2.31 (m, 2 H), 2.18-2.07 (m, 1 H), 1.97-1.88 (m, 1 H). 13 13C NMR (100 MHz, CDCl3) δ 138.4, 136.5, 127.9, 126.6, 121.6, 115.6, 107.0, 99.6, 38.6, 32.9, 29.1, 18.7. Example 3 A method for constructing aromatic derivatives through reductive cross-coupling reaction, the reaction formula is shown as follows:

[0023] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equiv., FeBr2) of ferrous bromide, 9.3 mg (0.4 equiv., TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equiv., MeOLi) of lithium methoxide, 106.7 mg (2.1 equiv., B2pin2) of bis(pinacolato)diboron, 44.6 mg (1 equiv.) of tert-butyl 4-bromobutyrate, and 62.7 mg (1.5 equiv.) of 4-bromo-1-methyl-1H-indole. Then add 1.0 mL of methyl tert-butyl ether with a syringe and mix evenly; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases, dry with anhydrous sodium sulfate, and finally concentrate under vacuum. Use petroleum ether / ethyl acetate = 10:1 as the eluent, and elute through flash column chromatography to obtain 31.1 mg of a clear colorless oil (product 3), and the yield is 60%.

[0024] Use a nuclear magnetic resonance spectrometer (Agilent, model 400MR DD2) to detect the product, and the results are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.20 - 7.14 (m, 2 H), 7.05 (d, J J = 3.2 Hz, 1 H), 6.92 (d, J J = 6.8 Hz, 1 H), 6.53 (d, J J = 3.2 Hz, 1 H), 3.79 (s, 3 H), 2.92 (t, J J = 7.6 Hz, 2 H), 2.28 (t, J= 7.6 Hz, 2 H), 2.07 - 2.00 (m, 2 H), 1.45 (s, 9 H). 13 C NMR (100 MHz, CDCl3) δ 173.1, 136.6, 134.0, 128.2, 127.7, 121.6, 118.8, 107.2, 99.2, 80.0, 35.2, 32.9, 32.6, 28.1, 25.9. Example 4 A method for constructing aromatic derivatives through a reductive cross - coupling reaction, the reaction formula is shown as follows:

[0025] The specific steps are as follows: (1) Place an 8 - mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equivalent, FeBr2) of ferrous bromide, 9.3 mg (0.4 equivalent, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equivalents, MeOLi) of lithium methoxide, 106.7 mg (2.1 equivalents, B2pin2) of bis(pinacolato)diboron, 55.4 mg (1 equivalent) of N,N - dipropyl - 5 - bromoamide, and 62.7 mg (1.5 equivalents) of 4 - bromo - 1 - methyl - 1H - indole. Then add 1.0 mL of methyl tert - butyl ether with a syringe and mix evenly; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant - temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant - temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration is 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases, dry with anhydrous sodium sulfate, and finally concentrate under vacuum. Use petroleum ether / ethyl acetate = 5:1 as the eluent and elute through flash column chromatography to obtain 23.6 mg of a clear colorless oil (product 4), and the yield is 46%.

[0026] Use a nuclear magnetic resonance spectrometer (Agilent, model 400MR DD2) to detect the product, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.14 (m, 2 H), 7.04 (d, J = 3.2 Hz, 1 H), 6.95 - 6.90 (m, 1 H), 6.52 (d, J= 3.2 Hz, 1 H), 3.78 (s, 3 H), 3.29 - 3.27 (m, 2H), 3.20 - 3.14 (m, 2 H), 2.92 (t, J = 7.6 Hz, 2 H), 2.34 - 2.27 (m, 2 H), 1.83 - 1.65 (m, 4 H), 1.59 - 1.48 (m, 4 H), 1.46 – 1.42 (m, 2 H), 0.95 - 0.87 (m, 6 H). 13 C NMR (100 MHz, CDCl3) δ 172.7, 136.6, 135.0, 128.1, 127.7, 121.6, 118.6, 106.9, 99.2, 49.6, 47.4, 33.3, 33.1, 30.4, 29.5, 25.5, 24.8, 22.3, 20.9, 11.4, 11.3. Example 5 A method for constructing aromatic derivatives through reductive cross - coupling reaction, the reaction formula is shown as follows:

[0027] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equiv, FeBr2) of ferrous bromide, 9.3 mg (0.4 equiv, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equiv, MeOLi) of lithium methoxide, 106.7 mg (2.1 equiv, B2pin2) of bis(pinacolato)diboron, 34.0 mg (1 equiv) of 1 - bromo - 4 - chlorobutane, 62.7 mg (1.5 equiv) of 4 - bromo - 1 - methyl - 1H - indole, and then add 1.0 mL of methyl tert - butyl ether with a syringe and mix well; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant - temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant - temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases, dry with anhydrous sodium sulfate, and finally concentrate under vacuum. Use petroleum ether / ethyl acetate = 20:1 as the eluent and elute through flash column chromatography to obtain 25.7 mg of a clear colorless oil (Product 5), and the yield is 58%.

[0028] Use a nuclear magnetic resonance spectrometer (Agilent, model 400MR DD2) to detect the product, and the results are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.22 - 7.13 (m, 2 H), 7.06 (d, J J = 3.2 Hz, 1 H), 6.94 - 6.89 (m, 1 H), 6.52 - 6.51 (m, 1 H), 3.80 (s, 3 H), 3.57 (t, J J = 6.8 Hz, 2H), 2.94 (t, J J = 6.8 Hz, 2 H), 1.96 - 1.82 (m, 4 H). 13 13C NMR (100 MHz, CDCl3) δ 136.6, 134.1, 128.2, 127.7, 121.6, 118.7, 107.2, 99.1, 45.0, 32.9, 32.5, 32.4, 27.6. Example 6 A method for constructing aromatic derivatives by reductive cross - coupling reaction, the reaction formula is shown as follows:

[0029] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equivalent, FeBr2) of ferrous bromide, 9.3 mg (0.4 equivalent, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equivalents, MeOLi) of lithium methoxide, 106.7 mg (2.1 equivalents, B2pin2) of bis(pinacolato)diboron, 52.6 mg (1 equivalent) of tert - butyl 4 - bromopiperidine - 1 - carboxylate, 56.1 mg (1.5 equivalents) of 2 - bromo - 6 - methoxypyridine, and then add 1.0 mL of methyl tert - butyl ether with a syringe and mix evenly; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant - temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant - temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases, dry with anhydrous sodium sulfate, and finally concentrate in vacuo. Use petroleum ether / ethyl acetate = 5:1 as the eluent, and elute through flash column chromatography to obtain 35.1 mg of a clear colorless oil (product 6), and the yield is 60%.

[0030] The product was detected using a nuclear magnetic resonance spectrometer (Agilent, model 400MR DD2), and the results were as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J J = 8.0 Hz, 1 H), 6.70 (d, J J = 7.2 Hz,1 H), 6.56 (d, J J = 8.0 Hz, 1 H), 4.22 (m, 2 H), 3.91 (s, 3 H), 2.86 - 2.80 (m, 2H), 2.76 - 2.68 (m, 1 H), 1.90 - 1.87 (m, 2 H), 1.78 - 1.68 (m, 2 H), 1.48 (s, 9H). 13 13C NMR (100 MHz, CDCl3) δ 163.5, 162.2, 154.9, 138.8, 113.3, 107.9,79.3, 53.1, 44.5, 43.8, 31.4, 28.4. Example 7 A method for constructing aromatic derivatives through reductive cross - coupling reaction, the reaction formula is shown as follows:

[0031] The specific steps are as follows: (1) Place an 8 - mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equiv, FeBr2) of ferrous bromide, 9.3 mg (0.4 equiv, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 equiv, MeOLi) of lithium methoxide, 106.7 mg (2.1 equiv, B2pin2) of bis(pinacolato)diboron, 52.6 mg (1 equiv) of tert - butyl 4 - bromopiperidine - 1 - carboxylate, 70.8 mg (1.5 equiv) of 2 - bromo - 6 - methoxynaphthalene, and then add 1.0 mL of methyl tert - butyl ether with a syringe and mix evenly; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant - temperature stirrer for reaction for 18 h; (3) Take the glass bottle out of the constant - temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. After combining the organic phases, dry with anhydrous sodium sulfate, and finally concentrate in vacuo. Use petroleum ether / ethyl acetate = 20:1 as the eluent, and elute through flash column chromatography to obtain 44.4 mg of a clear colorless oil (product 7), and the yield is 65%.

[0032] The product was detected using a nuclear magnetic resonance spectrometer (Agilent Technologies, model 400MR DD2), and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J J = 8.0 Hz, 2 H), 7.56 (s, 1 H), 7.32(d, J J = 8.4 Hz, 1 H), 7.15-7.11 (m, 2 H), 4.28 (br, 2 H), 3.91 (s, 3 H), 2.88-2.73 (m, 3 H), 1.92-1.88 (m, 2 H), 1.76-1.69 (m, 2 H), 1.50 (s, 9 H). 13 C NMR (100 MHz, CDCl3) δ 157.3, 154.9, 140.9, 133.2, 129.1, 129.0,126.9, 126.2, 124.6, 118.8, 105.5, 79.4, 55.3, 44.4, 42.5, 33.2, 28.5. Example 8 A method for constructing aromatic derivatives through a reductive cross-coupling reaction, and the reaction formula is shown as follows:

[0033] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box, weigh 6.5 mg (0.15 equiv, FeBr2) of iron(II) bromide, 9.3 mg (0.4 equiv, TMEDA) of N,N,N',N'-tetramethylethylenediamine, 41.8 mg (5.5 equiv, MeOLi) of lithium methoxide, 106.7 mg (2.1 equiv, B2pin2) of bis(pinacolato)diboron, 52.6 mg (1 equiv) of tert-butyl 4-bromopiperidine-1-carboxylate, and 74.1 mg (1.5 equiv) of 2-bromodibenzofuran. Subsequently, add 1.0 mL of methyl tert-butyl ether using a syringe and mix well; (2) Take the glass bottle out of the glove box and place it in a 60 °C constant temperature stirrer for reaction for 18 h; (3) Take out the glass bottle from the thermostatic stirrer, add 1 mL of saturated ammonium chloride solution (concentration: 6.95 mol / L) to quench it, then extract with ethyl acetate three times, 10 mL each time. Combine the organic phases, dry with anhydrous sodium sulfate, and finally concentrate under vacuum. Use petroleum ether / ethyl acetate = 20:1 as the eluent and elute through flash column chromatography to obtain 31.6 mg of a clear colorless oil (product 8), with a yield of 45%.

[0034] The product was detected using a nuclear magnetic resonance spectrometer (Agilent, model 400MR DD2), and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J J = 7.6 Hz, 1 H), 7.78 (s, 1 H), 7.56 (d, J J = 8.4 Hz, 1 H), 7.50 (d, J J = 8.4 Hz, 1 H), 7.45 (t, J J = 7.6 Hz, 1 H), 7.34 (t, J J = 7.6 Hz, 1 H), 7.29 (d, J J = 8.4 Hz, 1 H), 4.30 (m, 2 H), 2.88 - 2.77 (m, 3H), 1.93 - 1.89 (m, 2 H), 1.78 - 1.67 (m, 2 H), 1.51 (s, 9 H). 13 C NMR (100 MHz, CDCl3) δ 156.5, 154.9, 140.5, 127.0, 126.1, 124.2, 124.2, 122.6, 120.5, 118.3, 111.6, 111.4, 79.5, 44.7, 42.7, 33.8, 28.5. Example 9 A method for constructing aromatic derivatives through a reductive cross - coupling reaction, the reaction formula is shown as follows:

[0035] The specific steps are as follows: (1) Place an 8 mL glass bottle with a magnetic stir bar into the glove box. Weigh 6.5 mg (0.15 eq, FeBr2) of ferrous bromide, 9.3 mg (0.4 eq, TMEDA) of tetramethylethylenediamine, 41.8 mg (5.5 eq, MeOLi) of lithium methoxide, 106.7 mg (2.1 eq, B2pin2) of bis(pinacolato)diboron, 52.6 mg (1 eq) of tert-butyl 4-bromopiperidine-1-carboxylate, and 67.5 mg (1.5 eq) of 4-bromobenzotrifluoride. Subsequently, add 1.0 mL of methyl tert-butyl ether using a syringe and mix well. (2) Take the glass bottle out of the glove box and place it in a 60 °C constant temperature stirrer for reaction for 18 h. (3) Take the glass bottle out of the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration 6.95 mol / L) to quench the reaction. Then extract with ethyl acetate three times, 10 mL each time. Combine the organic phases and dry over anhydrous sodium sulfate. Finally, concentrate under vacuum and elute by flash column chromatography using petroleum ether / ethyl acetate = 20:1 as the eluent to obtain 52.7 mg of a clear colorless oil (product 9), with a yield of 80%.

[0036] The product was detected using a nuclear magnetic resonance spectrometer (Agilent Technologies, model 400MR DD2), and the results were as follows: 1 H NMR (400 MHz, CDCl3) 7.55 (d, J J = 8.0 Hz, 2 H), 7.30 (d, J J = 8.0 Hz, 2H), 4.26 (br, 2 H), 2.83 - 2.80 (m, 2 H), 2.77 - 2.66 (m, 1 H), 1.83 - 1.79 (m, 2H), 1.67 - 1.56 (m, 2 H), 1.48 (s, 9 H). 13 C NMR (100 MHz, CDCl3) δ 154.7, 149.7, 128.6 (q, J J = 32.2 Hz), 127.1,125.4 (q, J J = 3.8 Hz), 124.2 (q, J J = 270.4 Hz), 79.5, 44.1, 42.6, 32.9, 28.4. Comparative Example 1 A method for preparing an aromatic derivative, using ferrous bromide (FeBr2) as the catalyst, with the dosage and other preparation steps the same as in Example 1.

[0037] Comparative Example 2 A method for preparing an aromatic derivative, using ferrous acetylacetonate (Fe(acac)2) as the catalyst, with the same dosage and other preparation steps as in Example 1.

[0038] Comparative Example 3 A method for preparing an aromatic derivative, using iron(III) tosylate (Fe(OTs)3) as the catalyst, with the same dosage and other preparation steps as in Example 1.

[0039] Comparative Example 4 A method for preparing an aromatic derivative, using 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) as the ligand, with the same dosage and other preparation steps as in Example 1.

[0040] Comparative Example 5 A method for preparing an aromatic derivative, using 2-dicyclohexylphosphino-2'-methylbiphenyl (MePhos) as the ligand, with the same dosage and other preparation steps as in Example 1.

[0041] Comparative Example 6 A method for preparing an aromatic derivative, using n-hexane (Hexane) as the solvent, with the same dosage and other preparation steps as in Example 1.

[0042] The yields of Comparative Examples 1-6 are shown in Table 1. Compared with Examples 1, 2, and 3, after replacing the iron catalyst used, the yield of the aromatic derivative decreased significantly; after replacing the type of ligand and solvent, the yield of the aromatic derivative also decreased slightly. It shows that in the present invention, using aryl bromide and alkyl bromide as reaction substrates, ferrous bromide (FeBr2) as the catalyst, bis(pinacolato)diboron (B2Pin2) as the reducing agent, and under the action of a base (lithium methoxide, MeOLi) and a ligand (tetramethylethylenediamine, TMEDA), performing a reductive cross-coupling reaction is a general, efficient, economical, and environmentally friendly method for rapidly constructing aromatic derivatives.

[0043] Table 1 Yield Comparison

[0044] In the table: FeBr2 is ferrous bromide, Fe(acac)2 is ferrous acetylacetonate, Fe(OTs)3 is iron(III) tosylate, MeOLi is lithium methoxide, TMEDA is tetramethylethylenediamine, XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, MePhos is 2-dicyclohexylphosphino-2'-methylbiphenyl, MTBE is methyl tert-butyl ether, and Hexane is n-hexane.

[0045] In summary, the present invention uses inexpensive and low-toxic metal iron to replace other transition metals for catalytic reactions. At the same time, readily available aryl bromides and alkyl bromides are used as reaction raw materials to achieve the construction of carbon-carbon bonds through a one-step reaction, obtaining aromatic derivatives.

[0046] Although the specific embodiments of the present invention have been described in detail in conjunction with the embodiments, it should not be construed as a limitation on the protection scope of this patent. Within the scope described in the claims, various modifications and deformations that can be made by those skilled in the art without creative efforts still fall within the protection scope of this patent.

Claims

1. A method for constructing aromatic derivatives by reductive cross-coupling reaction, characterized in that: The following steps are involved: The aryl bromide, alkyl bromide, iron-containing reagent, ligand, reducing agent and base are dissolved in a solvent, and reacted at 45-100° C. for 14-18 hours to obtain an aromatic derivative; the aryl bromide has a structural formula as shown in Formula I, the alkyl bromide has a structural formula as shown in Formula II, and the aromatic derivative has a structural formula as shown in Formula III. 、 、 ； Wherein, Ar is aryl, heteroaryl, fused aryl or fused heteroaryl, R1 is hydrogen or alkyl, and R2 is alkyl or substituted alkyl; The ligand is tetramethylethylenediamine, 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl or 2-dicyclohexylphospho-2'-methylbiphenyl; and the reducing agent is biboric acid pinacol ester.

2. The method for constructing aromatic derivatives by reductive cross-coupling reaction according to claim 1, characterized in that: The molar ratio of the alkyl bromide, aryl bromide, iron-containing reagent, ligand, reducing agent and base is 1:1.0-2.0:0.1-0.2:0.3-0.5:1.5-3.0:4.0-6.

0.

3. The method for constructing aromatic derivatives by reductive cross-coupling reaction according to claim 2, characterized in that: The molar ratio of the alkyl bromide, aryl bromide, iron-containing reagent, ligand, reducing agent and base is 1:1.5:0.15:0.4:2.1:5.

5.

4. The method for constructing an aromatic derivative by reductive cross-coupling reaction according to any one of claims 1 to 3, characterized in that: The Ar is indolyl, pyridyl, naphthyl, dibenzofuranyl or phenyl.

5. The method for constructing aromatic derivatives by reductive cross-coupling reaction according to claim 4, characterized in that: The R2 is piperidinyl, cyclobutyl, ester-containing alkyl, amide-containing alkyl or chloroalkyl.

6. The method for constructing aromatic derivatives by reductive cross-coupling reaction according to claim 5, characterized in that: The aryl bromide is one of the compounds represented by Formula 1 to Formula 5, The alkyl bromide is one of the compounds represented by Formula 6 to Formula 10, 。 7. The method for constructing an aromatic derivative by reductive cross-coupling reaction according to any one of claims 1 to 3, characterized in that: The iron-containing reagent is ferrous bromide, ferrous acetylacetonate or ferric toluenesulfonate.

8. The method for constructing an aromatic derivative by reductive cross-coupling reaction according to any one of claims 1 to 3, characterized in that: The base is lithium methoxide.

9. The method for constructing an aromatic derivative by reductive cross-coupling reaction according to any one of claims 1 to 3, characterized in that: The solvent is methyl tert-butyl ether, n-hexane or cyclohexane.

10. The method for constructing aromatic derivatives by reductive cross-coupling reaction according to claim 1, characterized in that: The reaction temperature was 60°C and the reaction time was 18 h.

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