CN113443970A - Synthesis method of 4-alkoxy phenol compound - Google Patents
Synthesis method of 4-alkoxy phenol compound Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a 4-alkoxy phenol compound, belonging to the field of organic chemical synthesis. The method comprises the following steps: adding aryl alkyl ether compound, catalyst dimeric rhodium acetate and oxidant iodobenzene diethyl ester into a sealed tube, then adding solvent trifluoroacetic anhydride, and heating to react to obtain the 4-alkoxy phenol compound. The invention realizes the high regioselectivity direct hydroxylation of the aryl alkyl ether compound, has wide substrate application range and high yield, has no obvious weakening of activity after amplification reaction, and still obtains higher yield. Has good practicability and industrial application prospect.
Description
Technical Field
The invention relates to a synthesis method of a 4-alkoxy phenol compound, belonging to the field of organic chemical synthesis.
Background
The 4-alkoxy phenol compounds are important structural units widely existing in drug molecules and natural products, and have remarkable biological activity. In recent years, the synthesis of such compounds has attracted considerable attention. Since it is one of the challenges in the chemical field to efficiently construct a carbon-oxygen bond by activating a carbon-hydrogen bond on a benzene ring with high regioselectivity, it is of great importance to synthesize a 4-alkoxyphenol compound in one step by selective oxidation of the carbon-hydrogen bond with an aryl alkyl ether compound as a substrate.
The traditional oxidation method cannot meet the requirements of reactivity and selectivity in the process, and the reaction process is often accompanied by competitive side reactions. At present, relevant documents report that the synthesis method of the phenol compounds mainly uses transition metal palladium and copper as catalysts and strong base as a hydroxyl source to carry out hydroxylation reaction on halogenated aromatic hydrocarbon. However, the reaction has many disadvantages, such as strict anhydrous and oxygen-free conditions, harsh conditions of high temperature and strong alkali, narrow substrate range, suitability for brominated or iodinated aromatic hydrocarbons with high activity, and the need of performing halogenated pre-functionalization on the substrate, however, the halogenation reaction with high regioselectivity on complex aromatic hydrocarbons is a challenge, which greatly limits the application of the synthetic method in practical production.
The direct hydrocarbon activation oxidation reaction is beneficial, the hydroxyl functional group is directly introduced into the compound skeleton to realize the selective activation of the carbon-hydrogen bond, the pre-functionalization of a substrate can be avoided, the reaction steps are reduced, the atom economy is improved, and the chemical process is more green and environment-friendly. Therefore, the method which is high in selectivity, green, simple, convenient and efficient is explored, and the method has important significance when being applied to synthesis of 4-alkoxy phenol compounds.
Disclosure of Invention
The technical problem solved by the invention is to provide a method for synthesizing 4-alkoxy phenol compounds, which has high regioselectivity, wide substrate application range, mild reaction conditions and simple operation, and can obtain better yield, and the method can be used for synthesizing the medicaments of the monanobenzone (monobenzone) and the pramoxine (pramocaine) simply and conveniently with high yield.
In order to realize the purpose of the invention, the following scheme is adopted for realizing the purpose:
the reaction equation is:
wherein R is1Is phenyl, keto, carbomethoxy, carbethoxy, alkyl containing bromine substituent and hydrogen; r2Is methyl, hydrogen; r3Is hydrogen, methyl, isopropyl, methoxy, fluorine, chlorine, bromine and iodine, and is mono-substituted or di-substituted on a benzene ring. The catalyst is dimeric rhodium acetate, the oxidant is diethyl iodobenzene, and the solvent is trifluoroacetic anhydride.
Preferably: r1Is phenyl, keto, carbomethoxy, carbethoxy, C1-5 alkyl, C1-5 alkyl containing bromine substituent and hydrogen; r2Is methyl, hydrogen; r3Is hydrogen, methyl, isopropyl, methoxy, fluorine, chlorine, bromine and iodine, and is mono-substituted or di-substituted on a benzene ring.
The method specifically comprises the following steps:
1) sequentially adding aryl alkyl ether compound 1, dimeric rhodium acetate and iodobenzene diethyl ester into a sealing tube, finally adding trifluoroacetic anhydride, screwing down a bottle stopper of the sealing tube, and carrying out heating reaction to obtain a target compound 4-alkoxy phenol compound 2;
2) after the reaction is finished, adding saturated sodium bicarbonate to quench the reaction, extracting with ethyl acetate, combining organic layers, distilling under reduced pressure to remove most of the solvent to obtain a crude product, and performing column chromatography separation and purification on the crude product by using petroleum ether and ethyl acetate as eluents to obtain a target product.
Preferably, the method comprises the following steps: the feeding molar ratio of the aryl alkyl ether compound 1, dimeric rhodium acetate and iodobenzene diethyl ester is 1:0.015: 1.
preferably, the method comprises the following steps: the volume ratio of the petroleum ether to the ethyl acetate is 3: 1-10: 1.
According to an embodiment of the present invention, the preparation method can prepare the moenobenzone (monobenzone)
In the presence of a catalyst and an oxidant, the benzyl phenyl ether is subjected to para-selective hydroxylation to obtain the monobenzone.
According to an embodiment of the present invention, the process produces pramoxine (pramocaine)
In the presence of a catalyst and an oxidant, the 1e para-position selective hydroxylation of the butyl phenyl ether is carried out to obtain 2e, and then the 2e and 4- (3-chloropropyl) morpholine undergo carbon-oxygen bond coupling reaction to obtain pramocaine.
The invention adopts the method to prepare the following 4-alkoxy phenol compounds:
compared with the prior art, the invention has the following advantages:
1) the technical scheme of the invention realizes that the 4-alkoxy phenol compound is obtained by one-step reaction by taking aryl alkyl ether compound as a substrate. Compared with the prior method for preparing the compound, the method avoids the pre-functionalization of a substrate, and has better atom economy, regioselectivity and functional group universality.
2) The preparation method has the advantages of simple and efficient preparation process, high yield of more than 55 percent, high yield of more than 95 percent of partial target substances, mild reaction conditions, easy separation and purification of target compounds, high yield, capability of performing amplification preparation of more than gram level, potential industrial application value, capability of recycling the trifluoroacetic anhydride as a solvent by distillation after the reaction is finished, more conformity with green chemical concept and more economic benefit.
3) The method can be used for synthesizing the spot-removing medicament, namely the moenobenzone and the local anesthetic, namely the pramoxine, and has higher practicability.
Drawings
FIG. 1 is a drawing of 2a prepared in example 11Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 is 2a of example 113Nuclear magnetic resonance spectrum of C-NMR;
FIG. 3 is 2b prepared in example 21Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 is 2b prepared in example 213Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 is 3b prepared in example 21Nuclear magnetic resonance spectrum of H-NMR;
FIG. 6 is 3b prepared in example 213Nuclear magnetic resonance spectrum of C-NMR.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Unless otherwise indicated, the starting materials and reagents reported are either commercially available or prepared by known methods.
All of the object compoundsBy NMR1H，13C) And (4) spectral data characterization.
The yields of the desired products in the following examples are isolated yields.
Example 1
Compound 1a (9mmol), dimeric rhodium acetate (0.135mmol) and iodobenzene diethyl ester (9mmol) were added to a 75mL pressure resistant tube in this order, trifluoroacetic anhydride (30mL) was then added, and the mixture was placed in an 80 ℃ oil bath and reacted for 1.5 hours with magnetic stirring. After the completion of the reaction, the reaction solution was transferred to a round-bottomed flask, trifluoroacetic anhydride was distilled off at 70 ℃, followed by extraction with ethyl acetate (60mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate: 8:1, v/v) gave the product 2a as a white solid with a yield of 80%. The compound characterization data are as follows:1H NMR(400MHz,Chloroform-d)δ7.44–7.29(m,5H),6.88–6.83(m,2H),6.79–6.73(m,2H),5.01(s,2H),4.53(s,1H)；13C NMR(101MHz,Chloroform-d)δ153.0,149.7,137.2,128.6,128.0,127.6,116.1,70.8.
example 2
Compound 1b (10mmol), dimeric rhodium acetate (0.15mmol) and iodobenzene diethyl ester (10mmol) were added to a 75mL pressure resistant tube in this order, trifluoroacetic anhydride (30mL) was then added, and the reaction was magnetically stirred in an 80 ℃ oil bath for 1 hour. After completion of the reaction, the reaction solution was transferred to a round-bottomed flask, trifluoroacetic anhydride was distilled off at 70 ℃, followed by extraction with ethyl acetate (60mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave light brown solid 2b in a yield of 95%. The compound characterization data are as follows:1H NMR(400MHz,Chloroform-d)δ6.80–6.73(m,4H),4.36(s,1H),3.90(t,J＝6.5Hz,2H),1.78–
1.69(m,2H),1.47(h,J＝7.4Hz,2H),0.96(t,J＝7.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ153.3,149.4,116.0,115.7,68.5,31.4,19.3,13.9.
the compound 2b was dissolved in 20mL of DMF (N, N-dimethylformamide), potassium carbonate and 4- (3-chloropropyl) morpholine were added, the reaction was carried out at 85 ℃ for 10 hours, after completion of the reaction, 50mL of water was added to quench the reaction, extraction was carried out with ethyl acetate (60mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 2:1, v/v) gave compound 3b as a pale yellow oil in 87% yield. The compound characterization data are as follows:1H NMR(400MHz,Chloroform-d)δ6.82(s,4H),3.97(t,J＝6.3Hz,2H),3.90(t,J＝6.5Hz,2H),3.72(t,J＝4.7Hz,4H),2.54–2.44(m,6H),1.99–1.91(m,2H),1.78–1.70(m,2H),1.48(h,J＝7.4Hz,2H),0.97(t,J＝7.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ153.3,153.0,115.4,115.4,68.3,67.0,66.7,55.6,53.8,31.5,26.6,19.3,13.9.
example 3
Compound 1c (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 1 hour with magnetic stirring. After completion of the reaction, 15mL of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave beige solid product 2c in 85% yield. The compound characterization data are as follows:1H NMR(400MHz,Chloroform-d)δ6.81–6.74(m,4H),4.71(s,1H),3.86(t,J＝6.6Hz,2H),1.78(h,J＝7.1Hz,2H),1.02(t,J＝7.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ153.2,149.4,116.1,115.7,70.4,22.7,10.5.
example 4
Compound 1d (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 1 hour. After completion of the reaction, 15mL of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave the product 2d as a beige solid in 86% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.80–6.74(m,4H),4.53(s,1H),3.98(q,J＝7.0Hz,2H),1.38(t,J＝7.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ152.9,149.5,116.1,115.7,115.7,64.3,14.9.
Example 5
Compound 1e (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 1.5 hours with magnetic stirring. After completion of the reaction, 15mL of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave product 2e as a white solid in 85% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.85–6.73(m,4H),4.67(s,1H),4.23(t,J＝6.3Hz,2H),3.61(t,J＝6.3Hz,2H)；13C NMR(101MHz,Chloroform-d)δ152.2,150.1,116.3,116.2,68.9,29.4.
Example 6
Compound 1f (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 1 hour. After completion of the reaction, 15mL of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave product 2f as a white solid with a yield of 90%. The compound characterization data are as follows:1H NMR(400MHz,Chloroform-d)δ6.81–6.75(m,4H),4.86(s,1H),3.76(s,3H)；13C NMR(101MHz,Chloroform-d)δ153.7,149.5,116.1,114.9,55.8.
example 7
1g (0.3mmol) of the compound, dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were sequentially added to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 6 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (15 mL), followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 3:1, v/v) gave 2g of a white solid product, with a yield of 70%. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.83–6.73(m,4H),5.14(s,1H),4.59(s,2H),3.81(s,3H)；13C NMR(101MHz,Chloroform-d)δ169.9,151.9,150.5,116.2,116.0,66.2,52.3.
Example 8
The compound 1h (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, then trifluoroacetic anhydride (1.5mL) was added, and finally the reaction was carried out in an oil bath at 80 ℃ with magnetic stirring for 6 hours. After completion of the reaction, 15mL of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 3:1, v/v) gave a white solid product for 2h, yield 63%. The compound is characterized by the following data1H NMR(400MHz,Methanol-d4)δ6.78–6.74(m,2H),6.72–6.68(m,2H),4.58(s,2H),2.19(s,3H)；13C NMR(101MHz,Methanol-d4)δ206.5,151.6,151.3,115.5,115.4,73.3,24.9.
Example 9
Compound 1i (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 6 hours with magnetic stirring. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (15 mL), followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 3:1, v/v) gave 2i as a colorless oily product in 79% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.81–6.69(m,4H),4.67(q,J＝6.8Hz,1H),3.76(s,3H),1.59(d,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ173.5,151.4,150.6,116.6,116.2,73.6,52.5,18.7.
Example 10
Sequentially adding 1j (0.3mmol) of compound into a 10mL pressure-resistant pipe,Rhodium acetate dimer (0.45% mmol) and diethyliodobenzene (0.3mmol) were added followed by trifluoroacetic anhydride (1.5mL) and finally placed in an 80 ℃ oil bath with magnetic stirring for 6 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (15 mL), followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 3:1, v/v) gave product 2j as a white solid in a yield of 77%. Characterization data for this compound are as follows 1H NMR (400MHz, Chloroform-d) δ 6.74(s,4H),5.59(s,1H),4.17(t, J ═ 6.3Hz,2H),3.73(s,3H),2.78(t, J ═ 6.3Hz, 2H);13C NMR(101MHz,Chloroform-d)δ172.2,152.4,150.1,116.1,115.9,64.2,52.1,34.6.
example 11
Compound 1k (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 1.5 hours with magnetic stirring. After completion of the reaction, 15mL of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave 2k as an off-white solid product in 75% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.70(dd,J＝5.8,2.8Hz,2H),6.63(dd,J＝8.7,3.0Hz,1H),4.53(s,1H),3.75(s,3H),2.24(s,3H)；13C NMR(101MHz,Chloroform-d)δ153.6,147.8,124.9,116.6,115.5,111.8,55.8,16.1.
Example 12
A10 mL pressure resistant tube was charged with 1l (0.3mmol) of the compound, dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) in this order,trifluoroacetic anhydride (1.5mL) was then added and the reaction was finally placed in an 80 ℃ oil bath with magnetic stirring for 1.5 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (15 mL), followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1, v/v) gave 2l of a colorless oily product in 76% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.70(d,J＝8.6Hz,1H),6.66(d,J＝3.0Hz,1H),6.62(dd,J＝8.6,3.1Hz,1H),3.78(s,3H),2.18(s,3H)；13C NMR(101MHz,Chloroform-d)δ152.0,149.1,128.1,118.0,112.5,111.3,56.0,16.3.
Example 13
The compound 1m (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were sequentially added to a 10mL pressure resistant tube, then trifluoroacetic anhydride (1.5mL) was added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 1.5 hours with magnetic stirring. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate (15 mL), followed by extraction with ethyl acetate (20mL × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 10:1, v/v) gave 2m as a white solid in 78% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.47(s,2H),4.71(s,1H),3.67(s,3H),2.23(s,6H)；13C NMR(101MHz,Chloroform-d)δ151.3,150.5,131.9,115.1,60.0,16.2.
Example 14
The compound 1n (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was reacted in an 80 ℃ oil bath with magnetic stirring for 1.5 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1, v/v) gave 2n as a pale yellow oily product in 79% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.72(dd,J＝5.9,2.8Hz,2H),6.61(dd,J＝8.7,3.0Hz,1H),4.58(s,1H),3.78(s,3H),3.28(hept,J＝6.9Hz,1H),1.18(d,J＝6.9Hz,6H)；13C NMR(101MHz,Chloroform-d)δ151.0,149.5,138.7,113.6,112.4,111.9,56.3,26.7,22.7.
Example 15
Compound 1o (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 1.5 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 8:1, v/v) gave 2o as a colorless oily product in a yield of 75%. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.83(d,J＝8.7Hz,1H),6.49(d,J＝2.8Hz,1H),6.39(dd,J＝8.7,2.8Hz,1H),5.24(s,1H),3.86(s,3H),3.76(s,3H)；13C NMR(101MHz,Chloroform-d)δ153.5,147.1,139.8,114.1,104.2,99.4,55.9,55.8.
Example 16
The compound 1p (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, then trifluoroacetic anhydride (1.5mL) was added, and finally the tube was placed in a 80 ℃ oil bath under magnetic forceThe reaction was stirred for 6 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 5:1, v/v) gave 2p as a white solid product in a yield of 57%. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.94(d,J＝8.9Hz,1H),6.88(d,J＝2.9Hz,1H),6.75(dd,J＝8.9,2.9Hz,1H),5.19(s,1H),3.75(s,3H)；13C NMR(101MHz,Chloroform-d)δ153.6,145.5,119.9,116.6,114.5,114.1,55.9.
Example 17
Compound 1q (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 6 hours with magnetic stirring. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 5:1, v/v) gave 2q as a yellow oily product in 67% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.91(dd,J＝3.0,0.9Hz,1H),6.81(d,J＝8.9Hz,1H),6.70(dd,J＝8.8,2.9Hz,1H),5.27(s,1H),3.84(s,3H)；13C NMR(101MHz,Chloroform-d)δ149.7,149.4,122.9,117.7,114.3,113.5,56.9.
Example 18
Compound 1r (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 10 hours. After the reaction is finishedAfter that, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 5:1, v/v) gave 2r as a beige solid product in 55% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.93(d,J＝9.1Hz,1H),6.82(d,J＝9.1Hz,1H),5.31(s,1H),3.87(s,3H)；13C NMR(101MHz,Chloroform-d)δ150.1,146.4,121.4,120.2,113.6,111.5,57.0.
Example 19
Compound 1s (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, then trifluoroacetic anhydride (1.5mL) was added, and finally placed in an 80 ℃ oil bath and magnetically stirred for an inverse 6 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate 5:1, v/v) gave a red oily product for 2s in 70% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ7.01(d,J＝2.9Hz,1H),6.94(d,J＝8.9Hz,1H),6.80(dd,J＝8.9,2.9Hz,1H),5.15(s,1H),3.75(s,3H)；13C NMR(101MHz,Chloroform-d)δ153.8,146.5,116.8,116.3,115.3,109.9,56.0.
Example 20
Compound 1t (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 6 hours with magnetic stirring. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by ethyl acetateExtraction (20 ml. times.3), washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, removal of the solvent by distillation under reduced pressure, and column chromatography (petroleum ether: ethyl acetate: 5:1, v/v) gave 2t of the product as a white powder in 71% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ7.08(d,J＝2.7Hz,1H),6.81–6.73(m,2H),4.34(s,1H),3.83(s,3H)；13C NMR(101MHz,Chloroform-d)δ150.2,150.1,120.6,115.1,113.2,111.9,56.9.
Example 21
Compound 1u (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 6 hours with magnetic stirring. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, and column chromatography separation (petroleum ether: ethyl acetate ═ 5:1, v/v) gave 2u as a yellow solid product in a yield of 76%. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ7.30(d,J＝2.9Hz,1H),6.81(dd,J＝8.8,3.0Hz,1H),6.71(d,J＝8.8Hz,1H),4.57(s,1H),3.82(s,3H)；13C NMR(101MHz,Chloroform-d)δ152.8,150.1,126.3,116.0,111.8,86.0,57.0.
Example 22
The compound 1v (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, and finally the reaction was carried out in an oil bath at 80 ℃ with magnetic stirring for 1.5 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20 ml. times.3), and the organic layer was washed with saturated brine and anhydrous sodium sulfateDrying, removal of the solvent by distillation under reduced pressure, column chromatography (petroleum ether: ethyl acetate: 5:1, v/v) gave 2v as an orange oil product in 55% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.95–6.88(m,1H),6.68(dd,J＝12.1,2.9Hz,1H),6.59(ddd,J＝8.9,2.9,1.5Hz,1H),4.97(s,1H),3.75(s,3H)；13C NMR(101MHz,Chloroform-d)δ153.6(d,9.2),151.1(d,237.6),137.3(d,14.4),117.4(d,3.2),109.8(d,3.4),102.3(d,21.7),55.9.
Example 23
Compound 1w (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 6 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 3:1, v/v) gave 2w as a colorless oily product in 79% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.70(d,J＝3.5Hz,1H),6.65(d,J＝8.6Hz,1H),6.58(dd,J＝8.7,3.0Hz,1H),4.74(s,1H),4.66(q,J＝6.8Hz,1H),3.75(s,3H),2.20(s,3H),1.58(d,J＝6.8Hz,3H)；13CNMR(101MHz,Chloroform-d)δ173.4,151.3,148.8,125.3,118.5,115.5,113.4,73.5,52.4,18.7,16.1.
Example 24
Compound 1X (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure resistant tube, trifluoroacetic anhydride (1.5mL) was then added, and finally the mixture was placed in an 80 ℃ oil bath and reacted for 1.5 hours with magnetic stirring. After the reaction was completed, 15ml of the reaction was quenched with saturated sodium bicarbonate, and thenThen, the mixture was extracted with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1, v/v) gave 2 × the product as a yellow oil in a yield of 70%. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ6.89(d,J＝3.0Hz,1H),6.81(d,J＝8.8Hz,1H),6.68(dd,J＝8.8,3.0Hz,1H),3.96(t,J＝6.5Hz,2H),1.82–1.74(m,2H),1.56–1.45(m,2H),0.97(t,J＝7.4Hz,3H)；13CNMR(101MHz,Chloroform-d)δ149.7,148.9,123.8,117.5,115.4,114.3,70.1,31.3,19.2,13.9.
Example 25
Compound 1y (0.3mmol), dimeric rhodium acetate (0.45% mmol) and iodobenzene diethyl ester (0.3mmol) were added in this order to a 10mL pressure-resistant tube, and trifluoroacetic anhydride (1.5mL) was then added, followed by reaction in an 80 ℃ oil bath with magnetic stirring for 1.5 hours. After completion of the reaction, 15ml of the reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate (20ml × 3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 10:1, v/v) gave 2y as a yellow oily product in 70% yield. The compound is characterized by the following data1H NMR(400MHz,Chloroform-d)δ7.28(d,J＝2.9Hz,1H),6.78(dd,J＝8.8,2.9Hz,1H),6.69(d,J＝8.8Hz,1H),4.75(s,1H),3.90(t,J＝6.4Hz,2H),1.88–1.80(m,2H),1.07(t,J＝7.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ152.3,150.0,126.1,116.0,113.4,87.0,71.8,22.7,10.8.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (5)
1. A method for synthesizing a 4-alkoxy phenol compound is characterized by comprising the following steps: adding an aryl alkyl ether compound 1, a catalyst rhodium diacetate dimerization and an oxidant diethyl iodobenzene into a sealed tube, then adding a solvent trifluoroacetic anhydride, and heating to react to obtain a 4-alkoxy phenol compound 2;
wherein R is1Is phenyl, keto, carbomethoxy, carbethoxy, alkyl containing a bromine substituent or hydrogen, R2Is methyl or hydrogen, R3Is hydrogen, methyl, isopropyl, methoxy, fluorine, chlorine, bromine or iodine.
2. The method for synthesizing 4-alkoxyphenol compounds according to claim 1, wherein the molar ratio of the aryl alkyl ether compound 1 to the dimeric rhodium acetate to the iodobenzene diethyl ester is 1:0.015: 1.
3. The method for synthesizing 4-alkoxyphenol compounds according to claim 1 or 2, characterized in that benzylphenyl ether compound 1a, rhodium diacetate dimer as a catalyst and diethyliodobenzene as an oxidant are added into a sealed tube, then trifluoroacetic anhydride as a solvent is added, and compound 2a is obtained by heating reaction;
4. the method for synthesizing 4-alkoxyphenol compounds according to claim 1 or 2, characterized in that a butyl phenyl ether compound 1b, a catalyst of dimeric rhodium acetate and an oxidant of diethyliodobenzene are added to a sealed tube, then a solvent of trifluoroacetic anhydride is added, and a reaction is carried out under heating to obtain a compound 2 b;
5. the method for synthesizing a 4-alkoxyphenol compound according to claim 1 or 2, wherein the 4-alkoxyphenol compound is one of the following compounds:
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| CN112010882A (en) * | 2019-05-31 | 2020-12-01 | 武汉大学 | Method for stereoselectively preparing 1, 3-disubstituted cyclohexane compounds and application |
| CN113105496A (en) * | 2021-03-19 | 2021-07-13 | 华南理工大学 | Method for synthesizing o-alkenylphenol derivative through nickel-catalyzed ring opening of benzofuran |
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| CN112010882A (en) * | 2019-05-31 | 2020-12-01 | 武汉大学 | Method for stereoselectively preparing 1, 3-disubstituted cyclohexane compounds and application |
| CN113105496A (en) * | 2021-03-19 | 2021-07-13 | 华南理工大学 | Method for synthesizing o-alkenylphenol derivative through nickel-catalyzed ring opening of benzofuran |
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| CN115784847A (en) * | 2022-11-28 | 2023-03-14 | 南昌大学 | New use of triphenylphosphine diiodide as reaction promoter |
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