Method for direct C-H etherification of ortho-position of aryl aldehyde under catalysis of copper
By using copper catalysts and amino acid directing groups, the limitations of substrates and the numerous side reactions in the synthesis of aryl ether compounds in existing technologies have been overcome. This approach enables the efficient and clean synthesis of aryl ether compounds with high yields and good functional group tolerance.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-24
- Publication Date
- 2026-03-24
AI Technical Summary
Existing technologies for synthesizing aryl ether compounds suffer from problems such as substrate limitations, numerous side reactions, poor reproducibility, low functional group tolerance, and low atom economy.
Aryl ether compounds are directly prepared by reacting alcohols or phenols with aryl aldehydes via the ortho-CH group using copper catalysts and amino acids as directing groups. The use of inexpensive and readily available copper catalysts and stable amino acid directing groups, combined with reactions under specific conditions, achieves efficient etherification.
The method enables efficient and clean synthesis of aryl ether compounds with high yields, good functional group tolerance, and simple operation.
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Figure CN121717701A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of organic chemical synthesis, and particularly relates to a method for copper-catalyzed direct C-H etherification of ortho position of aryl aldehyde. BACKGROUND
[0002] Aryl ether is a key structural unit in medicines, natural products, agrochemicals and perfumes: 35% of drug molecules published in three major journals (CNS) from 2008 to 2024 contain aryl ether functional groups, which can improve the polarity, water solubility and metabolic stability of compounds. Typical cases: Pfizer HIV drug Lersivirine (after replacing the methyl linker with an ether bond, the drug efficacy and metabolic stability are improved), beta-blocker propranolol (the introduction of an oxymethylene linker in propanthol significantly enhances activity).
[0003] The current literature reported synthesis methods of aryl ether compounds mainly include: (1) sodium alcoholate or sodium phenolate and halogenated hydrocarbon substitution reaction to generate aryl ether compounds (Williamson ether synthesis method), which is incompatible with secondary / tertiary alcohols, requires strong base (such as NaH), and has poor functional group tolerance; (2) copper-catalyzed aryl boronic acid and alcohol oxidation coupling to form aryl ether (Chan-Lam etherification reaction), which has substrate limitations, many side reactions and poor reproducibility; (3) using acid to catalyze the activation of carbonyl or alcohol hydroxyl to promote the formation of ether bond, which has poor chemical selectivity and low functional group tolerance; (4) using reagents such as triphenylphosphine and diethyl azodicarboxylate (DEAD) to convert alcohol and phenol (or another molecule of alcohol) into ether (Mitsunobu reaction), which generates stoichiometric triphenylphosphine byproduct, and has low atom economy. SUMMARY
[0004] The present application provides a new method for synthesizing aryl ether compounds, which is clean and efficient. In order to achieve the above purpose, the present application selects copper catalyst to efficiently promote the direct preparation of aryl ether compounds from alcohol or phenol and aryl aldehyde ortho C-H.
[0005] The present application relates to a new method for copper-catalyzed etherification of aryl aldehyde ortho C-H using cheap, easily available and highly stable amino acids as guiding groups.
[0006] The technical scheme adopted by the present application is: A method for copper-catalyzed direct C-H etherification of aryl aldehyde ortho position, the method comprising: An aryl ether compound as shown in formula (III) is prepared by using aryl aldehyde as shown in formula (I) as raw material, sequentially adding alcohol or phenol as shown in formula (II), copper catalyst, guiding group (TDG), base and solvent into a reactor, and reacting at a certain temperature for a period of time in an argon atmosphere.
[0007] In formula (I) and formula (III): R1 is hydrogen, methyl, trifluoromethyl, methoxy, phenyl, iodo, isopropyl, trimethylsilyl, dimethylamino, fluoro, chloro, ester, marline, naphthyl, isoquinolyl, benzothiophenyl or phenanthryl, etc.
[0008] In formula (II) and formula (III): R2 is methyl, 4-fluorophenyl, cyclobutylmethyl, 4-tert-butylphenyl, pentafluorophenyl, 4-cyanophenyl, 4-methoxycarbonylphenyl, 3-nitrophenyl, adamantylmethyl, cyclohexyl or estrone analog, etc.
[0009] The copper catalyst is one of Cu(OAc)2, CuF2, basic copper carbonate, cuprous chloride or CuOAc.
[0010] The base is one of Na2CO3, KHCO3, K2CO3, Et3N, DIPEA, potassium phosphate, potassium tert-butoxide, sodium methoxide or sodium percarbonate, etc.
[0011] The directing group is one of β-alanine, 3-amino butyric acid, 3-amino-3-methyl butyric acid, 3-amino-3-phenylpropionic acid, 3-amino-4-phenyl butyric acid, 8-aminoquinoline, 2-(2-pyridyl)-2-propylamine, 2-picolinamide, anthranilic acid or 2-picolinohydrazide.
[0012] The solvent is one of 1,4-Dioxane, MeOH, HFIP, DMSO, THF, DCM, MeCN, DMF or EA.
[0013] The molar ratio of the aryl aldehyde to the alcohol or phenol substance is 1:1-20.
[0014] The molar ratio of the aryl aldehyde to the copper catalyst is 1:0.5-2.5.
[0015] The molar ratio of the aryl aldehyde to the directing group is 1:0.25-1.
[0016] The molar ratio of the aryl aldehyde to the base is 1:0.5-4.
[0017] The molar ratio of the aryl aldehyde to the solvent is 1:0.001-30. The experimental temperature is 60-150 ℃.
[0018] The reaction time is 10-22 h.
[0019] The above method is preferably performed according to the following steps: With formula (I) as raw material, (II) alcohol or phenol, copper catalyst, guiding group, base and solvent are sequentially added into the reactor, heated and stirred under argon atmosphere at 100-140 ℃ for 10-22 h to prepare formula (III).
[0020] In the step, the reaction liquid post-treatment method is as follows: after the reaction is completed, the reaction liquid is cooled to room temperature, the solvent is removed under reduced pressure, then diluted with ethyl acetate, washed with water for three times, the organic phase is collected, concentrated, and separated by column chromatography to obtain formula (III).
[0021] The reaction mechanism is as follows: .
[0022] The beneficial effects of the present application mainly include: 1) The copper catalyst is cheap and easy to obtain, which can efficiently promote the direct etherification of the ortho position of aryl aldehyde to obtain aryl ether compounds.
[0023] 2) The amino acid is cheap and easy to obtain, has high stability, and has high selectivity etherification of the ortho position of aldehyde group.
[0024] 3) The functional group has wide tolerance, and the corresponding aryl ether compound can be obtained in good yield.
[0025] 4) The operation process is simple and efficient. DETAILED DESCRIPTION
[0026] The present application will be further described below in combination with specific examples, but the protection scope of the present application is not limited to this.
[0027] The reaction equation of the method of the present application is as follows: .
[0028] Example 1: Preparation of o-methoxybenzaldehyde
[0029] In a 25 ml Schlenk tube, benzaldehyde (formula I, R1=H) (1.00 mmol), methanol (0.8 ml), hexafluoroisopropanol (0.2 ml), copper acetate (1.75 mmol), 3-amino-3-methylbutyric acid (0.50 mmol), potassium carbonate (2.0 mmol) were sequentially added, stirred under argon atmosphere at 120 ℃ for 18 h, after the reaction was completed, cooled to room temperature, the solvent was removed under reduced pressure, diluted with 50 mL ethyl acetate, then washed with 50 ml water for three times, concentrated, and separated by column chromatography to obtain o-methoxybenzaldehyde, purity 99%, yield 90% (calculated based on benzaldehyde).
[0030] NMR of hydrogen: 1 H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 7.83 (dd, J = 7.8,1.9 Hz, 1H), 7.60 – 7.52 (m, 1H), 7.05 – 6.97 (m, 2H), 3.93 (s, 3H). NMR of carbon: 13 C NMR (101 MHz, CDCl3) δ 189.92, 161.85, 136.00,128.59, 124.83, 120.69, 111.63, 55.66. Screening of directing group (only the directing group is different, other conditions are the same, other operation conditions are the same as example 1), the yield is shown in table 1.
[0031] Table 1 Effect of different directing group materials on reaction yield
[0032] Screening of directing group amount (only the amount of directing group is different, other conditions are the same, other operation conditions are the same as example 1), the yield is shown in table 2.
[0033] Table 2 Effect of different directing group amount on yield Guide base (TDG1) amount / mmol Yield (%) 0 0 0.25 57 0.50 90 0.75 91 1.00 91 Example 2: Preparation of 2-methoxy-6-methylbenzaldehyde
[0034] In a 25 ml Schlenk tube, 2-methylbenzaldehyde (formula I, R1=CH3) (1.00 mmol), methanol (0.8 ml), hexafluoroisopropanol (0.2 ml), copper acetate (1.25 mmol), 3-aminobutyric acid (0.50 mmol), potassium carbonate (2.0 mmol) were added in turn, stirred at 120 ℃ under argon atmosphere for 18 h, after the reaction was completed, cooled to room temperature, the solvent was removed under reduced pressure, diluted with 50 mL ethyl acetate, then washed with 50 ml water three times, concentrated column chromatography separation can get 2-methoxy-6-methylbenzaldehyde, purity 99%, yield 92% (based on 2-methylbenzaldehyde).
[0035] NMR of hydrogen: 1 H NMR (400 MHz, CDCl3) δ 10.64 (s, 1H), 7.37 (t, J = 8.1Hz, 1H), 6.81 (dd,J = 12.5, 8.0 Hz, 2H), 3.89 (s, 3H), 2.57 (s, 3H). Nuclear magnetic resonance carbon spectrum: 13 C NMR (101 MHz, CDCl3) δ 192.31, 163.18, 142.03,134.43, 124.09, 123.36, 109.05, 55.76, 21.45. Example 3: Preparation of 2-methoxy-6-trifluoromethylbenzaldehyde
[0036] In a 25 ml Schlenk tube, 2-trifluoromethylbenzaldehyde (1.00 mmol), methanol (0.8 ml), hexafluoroisopropanol (0.2 ml), copper fluoride (1.75 mmol), 3-amino-3-methylbutyric acid (0.5 mmol), sodium carbonate (2.0 mmol) were added successively under argon atmosphere, stirred at 120 °C for 18 h, after the reaction was completed, cooled to room temperature, removed the solvent under reduced pressure, diluted with 50 mL ethyl acetate, then washed with 50 ml water three times, concentrated column chromatography separation can get 2-methoxy-6-trifluoromethylbenzaldehyde, purity 99%, yield 99% (based on 2-trifluoromethylbenzaldehyde).
[0037] Nuclear magnetic resonance hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 7.58 (t, J = 8.2Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H). Nuclear magnetic resonance carbon spectrum: 13 C NMR (101 MHz, CDCl3) δ 189.64, 161.20, 133.83, 130.17(q, J=32.32HZ), 123.16 (q, J=274.74HZ), 119.07, 118.65 (q, J=6.06HZ),,115.64, 56.34. Nuclear magnetic resonance fluorine spectrum: 19 F NMR (377 MHz, CDCl3) δ -58.10. Example 4: Preparation of 2,6-dimethoxybenzaldehyde
[0038] In a 25 ml Schlenk tube, 2-methoxybenzaldehyde (formula I, R1=OMe) (1.00 mmol), methanol (0.8 ml), hexafluoroisopropanol (0.2 ml), copper acetate (1.75 mmol), 3-amino-3-methylbutyric acid (0.5 mmol), sodium carbonate (2.0 mmol) were added successively under argon atmosphere, stirred at 120 °C for 18 h. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, diluted with 50 mL ethyl acetate, then washed with 50 ml water for three times, concentrated and separated by column chromatography to obtain 2,6-dimethoxybenzaldehyde, purity 99%, yield 90% (based on 2-methoxybenzaldehyde).
[0039] Nuclear magnetic resonance hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 7.43 (t, J = 8.5Hz, 1H), 6.56 (d, J = 8.5 Hz, 2H), 3.88 (s, 6H). Nuclear magnetic resonance carbon spectrum: 13 C NMR (101 MHz, CDCl3) δ 189.46, 162.22, 135.95,114.34, 103.89, 56.06. Example 5: Preparation of 2-(4-fluorophenoxy)-6-methylbenzaldehyde
[0040] In a 25 ml Schlenk tube, 2-methoxybenzaldehyde (formula I, R1=OMe) (1.00 mmol), methanol (0.8 ml), hexafluoroisopropanol (0.2 ml), copper acetate (1.75 mmol), 3-amino-3-methylbutyric acid (0.5 mmol), sodium carbonate (2.0 mmol) were added successively under argon atmosphere, stirred at 120 °C for 18 h. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, diluted with 50 mL ethyl acetate, then washed with 50 ml water for three times, concentrated and separated by column chromatography to obtain 2,6-dimethoxybenzaldehyde, purity 99%, yield 90% (based on 2-methoxybenzaldehyde).
[0041] Nuclear magnetic resonance hydrogen spectrum: 1H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 7.33 (t, J = 7.9Hz, 1H), 7.10 – 6.92 (m, 5H), 6.69 (d, J = 8.4 Hz, 1H), 2.62 (s, 3H). Carbon NMR spectrum: 13 C NMR (101 MHz, CDCl3) δ 191.63, 161.44, 159.21 (d, J =242.7 Hz), 152.46, 142.32, 134.37, 126.66, 125.28, 120.77 (d, J = 8.4 Hz),116.63 (d, J = 23.6 Hz), 115.72, 21.37. Nuclear magnetic resonance fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -118.90. Example 6: Preparation of 2-(4-fluorophenoxy)-6-methylbenzaldehyde
[0042] In a 25 ml Shrek tube, 2-methylbenzaldehyde (Formula I, R1 = CH3) (0.2 mmol), cyclobutylmethanol (1.6 mmol), 1,4-dioxane (1.0 ml), copper fluoride (0.5 mmol), 3-aminobutyric acid (0.1 mmol), and sodium carbonate (0.4 mmol) were added sequentially. The mixture was stirred at 130 °C for 18 h under an argon atmosphere. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the mixture was diluted with 50 mL of ethyl acetate. Then, it was washed three times with 50 mL of water. The product was separated by concentrated column chromatography to obtain 2-(4-fluorophenoxy)-6-methylbenzaldehyde with a purity of 99% and a yield of 93% (based on 2-methylbenzaldehyde).
[0043] 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H), 7.34 (t, J = 8.0Hz, 1H), 6.79 (dd, J = 14.1, 8.0 Hz, 2H), 3.99 (d, J = 6.4 Hz, 2H), 2.80 (td, J= 14.4, 6.4 Hz, 1H), 2.56 (s, 3H), 2.17 – 2.09 (m, 2H), 1.92 (qt, J = 8.2, 4.4Hz, 4H). NMR Carbon spectrum: 13 C NMR (101 MHz, CDCl3) δ 192.50, 163.02, 141.92,134.44, 123.89, 123.49, 110.08, 72.51, 34.58, 24.74, 21.53, 18.57. Example 7: Preparation of 2-(4-(tert-butyl)phenoxy)-6-methylbenzaldehyde
[0044] In a 25 ml Schlenk tube, 2-methylbenzaldehyde (0.2 mmol), 4-tert- butylphenol (1.6 mmol), 1,4-dioxane (1.0 ml), copper fluoride (0.5 mmol), 3- amino-3-methylbutanoic acid (0.1 mmol), sodium carbonate (0.4 mmol) were added successively under argon atmosphere, stirred at 130 °C for 18 h, after the reaction was completed, cooled to room temperature, removed the solvent under reduced pressure, diluted with 50 mL ethyl acetate, then washed with 50 ml water three times, concentrated column chromatography separation can get 2-(4-(tert-butyl)phenoxy)-6-methylbenzaldehyde, purity 99%, yield 91% (based on 2-methylbenzaldehyde).
[0045] NMR Hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 7.42 – 7.29 (m, 3H), 6.96 (dd, J = 8.3, 6.2 Hz, 3H), 6.77 (d, J = 8.3 Hz, 1H), 2.65 (s, 3H), 1.34(s, 9H). NMR Carbon spectrum: 13 C NMR (101 MHz, CDCl3) δ 190.94, 160.56, 153.30, 145.94, 141.09, 133.24, 125.78, 125.37, 124.35, 117.66, 115.18, 33.34, 30.44, 20.41.
Claims
1. A method for copper-catalyzed direct CH etherification of ortho-aryl aldehydes, characterized in that, The method includes the following procedures: Using aryl aldehydes with structures as shown in formula (I) as raw materials, alcohols or phenols as shown in formula (II), copper catalysts, directing groups, bases, and solvents are added to a reactor, and the reaction is carried out under an argon atmosphere to prepare aryl ether compounds as shown in formula (III). The reaction equation is as follows: ， The substituent R1 in formulas (I) and (III) is hydrogen, methyl, trifluoromethyl, methoxy, phenyl, iodo, isopropyl, trimethylsilyl, dimethylamino, fluoro, chloro, ester, marinyl, naphthyl, isoquinolinyl, benzothiophene, or phenanthryl. The substituent R2 in formulas (II) and (III) is methyl, 4-fluorophenyl, cyclobutanemethyl, 4-tert-butylphenyl, pentafluorophenyl, 4-cyanophenyl, 4-methyl ester phenyl, 3-nitrophenyl, adamantanemethyl, cyclohexyl or estrone analog.
2. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The molar equivalent ratio of the aryl aldehyde shown in formula (I) to the alcohol or phenol shown in formula (II) is 1:1 to 20.
3. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The molar equivalent ratio of the aryl aldehyde to the copper catalyst shown in formula (I) is 1:0.5 to 5.
4. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The molar equivalent ratio of the aryl aldehyde to the directing group shown in formula (I) is 1:0.25~1.
5. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The molar equivalent ratio of the aryl aldehyde to the base shown in formula (I) is 1:0.5~4.
6. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The molar equivalent ratio of the aryl aldehyde to the solvent shown in formula (I) is 1:0.001~30.
7. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The reaction temperature is 60°C. o C~150 o C, the reaction time is 10h~22h.
8. The method for direct CH etherification of aryl aldehydes via copper catalysis as described in claim 1, characterized in that, The copper catalyst is Cu(OAc)2, CuF2, basic copper carbonate, cuprous chloride, or CuOAc, and the directing group is β-alanine, 3-aminobutyric acid, 3-amino-3-methylbutyric acid, 3-amino-3-phenylpropionic acid, 3-amino-4-phenylbutyric acid, 8-aminoquinoline, 2-(2-pyridyl)-2-propane, 2-pyridinecarboxamide, o-aminobenzoic acid, or 2-pyridinecarboxylhydrazide.
9. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The base is Na2CO3, KHCO3, K2CO3, Et3N, DIPEA, potassium phosphate, potassium tert-butoxide, sodium methoxide, or sodium percarbonate.
10. The method for direct ortho-CH etherification of aryl aldehydes catalyzed by copper as described in claim 1, characterized in that, The solvent is 1,4-Dioxane, MeOH, HFIP, DMSO, THF, DCM, MeCN, DMF, or EA.