CN112457173A - Simple synthesis method of meta-substituted phenol ether and phenol - Google Patents
Simple synthesis method of meta-substituted phenol ether and phenol Download PDFInfo
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Abstract
The invention relates to the technical field of biological medicines, and provides a preparation method of meta-substituted phenol ether. Taking a derivative of meta-substituted cyclohexenone as a reaction raw material, and reacting under the conditions of an alcohol solvent and an oxidant to obtain corresponding meta-substituted phenol ether; the reaction process is easy to control, the substrate range is wide, and a foundation is laid for a simpler and more convenient synthetic method for subsequently preparing the meta-substituted phenol; the invention also provides a simple and convenient synthesis method of the meta-substituted phenol, which takes the meta-substituted phenol ether prepared by the invention as a reaction raw material and is used for solving the problems of large reaction control difficulty and narrow substrate range due to the adoption of a noble metal catalyst in the process of preparing the meta-substituted phenol in the prior art.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a simple synthesis method of meta-substituted phenol ether and phenol.
Background
Meta-substituted phenol ethers and phenols are widely used in the synthesis of high value-added chemicals, such as agrochemicals, polymers, pharmaceuticals, and the like. However, since both alkoxy groups and hydroxyl groups are strong ortho-para-positioning groups, it is difficult to directly introduce meta-substituents through electrophilic substitution reaction on the benzene ring of phenol ethers or phenols.
The current preparation of phenol ethers is mainly carried out by the Williamson synthesis, i.e. using sodium phenolate and a primary halogenated hydrocarbon under alkaline conditions. This method uses phenol as a starting material, but the Williamson synthesis does not solve the problem of introducing meta substituents, since meta phenol is necessary to prepare meta phenol ethers.
In the case of meta-substituted phenols, in recent years, researchers have used noble metal palladium-catalyzed oxidation of cyclohexanone derivatives for the preparation of meta-substituted phenols (y.izawa, d.pun and s.s.stahl, Science,2011,333,209), however, fine chemicals and pharmaceuticals have very strict requirements on the heavy metal content thereof, which puts high demands on how to remove the palladium catalyst in the product. It has also been reported that the meta-substituted phenol is prepared by the direct oxidation of cyclohexenone without metal catalysis (Green chem.,2016,18,6462), however, phenol is very easily oxidized, and this method may require very careful control of the reaction process due to the oxidation of the product phenol, and the substrate application range is narrow.
Aiming at the problems, the method for searching the meta-substituted phenol ether and the phenol synthesis method which do not need noble metal catalysts, are easy to control the reaction process and have wide substrate range has important significance.
Disclosure of Invention
The invention aims to overcome at least one defect (deficiency) of the prior art, provides a simple synthesis method of the meta-substituted phenol ether, is completely different from the preparation method of the meta-substituted phenol ether in the prior art, has the advantages of easy control of the reaction process and wide substrate range, and lays a foundation for providing a simpler synthesis method for the subsequent preparation of the meta-substituted phenol.
The invention also aims to provide a simple synthesis method of the meta-substituted phenol by using the phenol ether prepared by the method as a raw material, which is used for solving the problems of high reaction control difficulty and narrow substrate range due to the adoption of a noble metal catalyst in the process of preparing the meta-substituted phenol in the prior art.
The invention adopts the technical scheme that a simple synthesis method of meta-substituted phenol ether is characterized in that a meta-substituted cyclohexenone derivative is used as a reaction raw material, and the reaction is carried out under the conditions of an alcohol solvent and an oxidant to obtain the corresponding meta-substituted phenol ether. The mass ratio of the cyclohexenone derivative to the oxidant is 1: 1.5.
the reaction equation for the meta-substituted phenol ethers of the present invention is as follows:
further, the oxidant is iodine. The iodine simple substance is different from the noble metal catalyst commonly used in the prior art, the cost is low, and the iodine simple substance is easy to remove after the reaction is finished. Iodine simple substance belongs to one of halogens, is a crystal, and other halogen simple substances can also be used as the oxidant of the application, but other halogen simple substances are gas or liquid, so that the use process is inconvenient and the selectivity is poor.
Further, the meta-substituted phenol ether is prepared by the following method:
adding a meta-substituted cyclohexenone derivative, an alcohol solvent and an iodine simple substance into a thick-wall reaction bottle, stirring until the iodine simple substance is dissolved, screwing a reaction bottle cover to seal, and magnetically stirring for 5-7 hours at 70-90 ℃; stopping stirring, adding ethyl acetate, extracting with distilled water twice, washing with saturated sodium chloride solution once, and removing water layer; the organic phase is dried over anhydrous magnesium sulfate, filtered to remove the magnesium sulfate, the solvent is evaporated on a rotary evaporator, and the corresponding meta-substituted phenol ether is obtained by column chromatography purification.
Further, the structural formula of the derivative of the meta-substituted cyclohexenone is shown as
The structural formula of the meta-substituted phenol ether is shown in the specification
Wherein R is selected from one of alkyl and ether, R1One selected from alkyl, aryl or aryl derivatives; r2Selected from one of alkyl, aryl or aryl derivatives.
Further, the meta-substituted cyclohexenone derivative is one or more of 5-methyl-3-phenylcyclohex-2-enone, 5-methyl-3-p-bromophenyl cyclohex-2-enone, 5-benzyl-3-phenylcyclohex-2-enone, 5-p-tolylmethyl-3-phenylcyclohex-2-enone, 5-p-methoxybenzyl-3-phenylcyclohex-2-enone and 5-p-chlorobenzyl-3-phenylcyclohex-2-enone.
Furthermore, the alcoholic solution is one or more of methanol, ethanol, n-butanol, isopropanol, 3-pentanol and ethylene glycol monomethyl ether, and different kinds of phenol ethers can be obtained by using different alcohol solvents.
A simple synthesis method of meta-substituted phenol, which is characterized in that meta-substituted phenol ether obtained by any one of the simple synthesis methods is used as a raw material, and corresponding meta-substituted phenol is obtained under the action of hydroiodic acid; the amount of said substance of hydroiodic acid is at least 9 times the amount of the substance of the phenol ether.
Further, the meta-substituted phenol is prepared by the following method:
adding meta-substituted phenol ether and hydroiodic acid into a reaction bottle, refluxing for 2h under stirring, and cooling; adding water and ethyl acetate, separating an organic layer, washing twice with a saturated sodium bicarbonate solution, drying the organic phase with anhydrous magnesium sulfate, filtering to remove the magnesium sulfate, evaporating the solvent by a rotary evaporator, and purifying by column chromatography to obtain the corresponding meta-substituted phenol.
Phenol ethers can be viewed as a protective group for phenols, are effective in preventing phenols from being oxidized in an oxidizing environment, and are readily converted to phenols. The invention utilizes the stability of the phenol ether to generate the meta-substituted phenol ether in situ in the process of oxidizing the meta-substituted cyclohexenone derivative so as to avoid the defect of further oxidizing phenol in an oxidizing atmosphere. The resulting phenol ethers can be converted to the corresponding phenols in hydroiodic acid in high yields.
The reaction mechanism of the invention is shown as follows, taking the synthesis of 3-methyl-5-phenyl anisole as an example:
the reaction material 5-methyl-3-phenylcyclohex-2-enone firstly generates alpha-H iodination with elementary iodine under the heating condition to obtain A, A eliminates one molecule of hydrogen iodide to obtain B, and B can be interconverted into C. Finally, the C and methanol are catalyzed by the product hydrogen iodide to finally generate the 3-methyl-5-phenyl anisole.
Compared with the prior art, the invention has the beneficial effects that:
1) the invention provides a novel simple synthesis method for preparing meta-substituted phenol ether, which has the advantages of easily obtained raw materials, easily controlled reaction process and wide substrate application range, and can adjust the meta-substituent of the phenol ether through the substituent variety of cyclohexenone and adjust the alkoxy type of the phenol ether through the variety of alcohol;
2) the meta-substituted phenol ether prepared by the method is used for synthesizing the meta-substituted phenol, the operation is simple and convenient, a noble metal oxidant is not needed, the reaction is easy to control, and the substrate range is wide.
Detailed Description
The examples of the present invention are provided for illustrative purposes only and are not to be construed as limiting the invention.
Example 1
Preparation of 3-methyl-5-phenyl anisole
5-methyl-3-phenylcyclohex-2-enone (37mg, 0.2mmol) was added sequentially to a thick-walled reaction flask,methanol (2mL) and iodine (76mg, 0.3mmol) are stirred for 5 minutes at normal temperature, after the iodine is dissolved, the cover of the reaction bottle is screwed and sealed, and the reaction bottle is magnetically stirred for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as the chromatography medium) to give 3-methyl-5-phenylanisole as a yellow oil (31mg, 78% yield).1H NMR(400MHz,CDCl3)δ7.57(dd,J＝8.2,1.1Hz,2H),7.41(t,J＝7.5Hz,2H),7.33(d,J＝7.4Hz,1H),7.00(s,1H),6.93(s,1H),6.72(s,1H),3.83(s,3H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ160.14,142.76,141.44,139.91,128.83,127.48,127.36,120.82,113.75,110.14,55.44,21.84。
Example 2
Preparation of 3-methyl-5-phenyl phenetole
Adding 5-methyl-3-phenylcyclohex-2-enone (37mg, 0.2mmol), ethanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring at normal temperature for 5 minutes, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as chromatography) to give 3-methyl-5-phenylphenyl ether as a yellow oil (36mg, 85% yield).1H NMR(400MHz,CDCl3)δ7.56(dt,J＝3.1,1.9Hz,2H),7.45–7.37(m,2H),7.36–7.29(m,1H),6.99(d,J＝0.4Hz,1H),6.93(s,1H),6.71(s,1H),4.07(q,J＝7.0Hz,2H),2.38(s,3H),1.43(t,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ159.33,142.53,141.33,139.69,128.65,127.27,127.19,120.51,114.18,110.57,63.43,21.67,14.92。
Example 3
Preparation of 3-methyl-5-phenyl benzene n-butyl ether
Adding 5-methyl-3-phenylcyclohex-2-enone (37mg, 0.2mmol), n-butanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring at normal temperature for 5 minutes, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring at the temperature of 80 ℃ for 6 hours. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as chromatography liquid) to give 3-methyl-5-phenylbenzene n-butyl ether as a pale yellow oil (43mg, 89% yield).1H NMR(400MHz,CDCl3)δ7.60–7.54(m,2H),7.44–7.37(m,2H),7.33(dt,J＝9.4,4.3Hz,1H),6.98(d,J＝0.6Hz,1H),6.93(t,J＝1.7Hz,1H),6.72(s,1H),4.00(t,J＝6.5Hz,2H),2.38(s,3H),1.78(dd,J＝8.4,6.7Hz,2H),1.56–1.45(m,3H),0.98(t,J＝7.4Hz,3H)；13C NMR(101MHz,CDCl3)δ159.73,142.70,141.53,139.84,128.81,127.43,127.37,120.61,114.38,110.75,67.88,31.61,21.84,19.47,14.05。
Example 4
Preparation of 3-methyl-5-phenyl isopropyl ether
Adding 5-methyl-3-phenylcyclohex-2-enone (37mg, 0.2mmol), isopropanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring for 5 minutes at normal temperature, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, and washing was performed with a saturated sodium chloride solutionOnce washed, the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator, and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as chromatography liquid) to give 3-methyl-5-phenylpropyl isopropyl ether as a pale yellow oil (31mg, yield 68%).1H NMR(400MHz,CDCl3)δ7.56(dt,J＝3.0,1.8Hz,2H),7.45–7.38(m,2H),7.33(dt,J＝7.3,3.8,1.2Hz,1H),6.97(s,1H),6.92(d,J＝1.8Hz,1H),6.71(s,1H),4.60(dt,J＝12.1,6.1Hz,1H),2.38(s,3H),1.36(d,J＝6.1Hz,6H)；13C NMR(101MHz,CDCl3)δ158.26,142.56,141.36,139.70,128.64,127.24,127.18,120.47,115.58,111.93,69.86,22.17,21.67。
Example 5
Preparation of 3-methyl-5-phenylbenzene (3-pentyl) ether
Adding 5-methyl-3-phenylcyclohex-2-enone (37mg, 0.2mmol), 3-pentanol (2mL), iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction flask in sequence, stirring for 5 minutes at normal temperature, screwing a reaction flask cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as chromatography) to give 3-methyl-5-phenylbenzene (3-pentyl) ether as a pale yellow oil (40mg, 72% yield).1H NMR(400MHz,CDCl3)δ7.65–7.59(m,2H),7.50–7.43(m,2H),7.38(dt,J＝9.3,4.3Hz,1H),7.02(d,J＝0.5Hz,1H),6.99(d,J＝1.8Hz,1H),6.77(s,1H),4.22(t,J＝5.8Hz,1H),2.43(s,3H),1.80–1.70(m,4H),1.03(t,J＝7.4Hz,6H)；13C NMR(101MHz,CDCl3)δ159.14,142.54,141.40,139.67,128.64,127.22,127.19,120.37,115.67,112.03,80.15,26.15,21.68,9.64。
Example 6
Preparation of 3-methyl-5-phenyl methoxy ethyl ether
Adding 5-methyl-3-phenylcyclohex-2-enone (37mg, 0.2mmol), ethylene glycol monomethyl ether (2mL), iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring at normal temperature for 5 minutes, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as chromatography liquid) to give 3-methyl-5-phenyl methoxy ethyl ether as a yellow solid (25mg, 52% yield). m.p.45-46 ℃;1H NMR(400MHz,CDCl3)δ7.59–7.54(m,2H),7.44–7.38(m,2H),7.35–7.29(m,1H),7.00(s,1H),6.97(d,J＝1.9Hz,1H),6.75(s,1H),4.19–4.13(m,2H),3.78–3.73(m,2H),3.46(s,3H),2.38(s,3H)；13C NMR(101MHz,CDCl3)δ159.17,142.52,141.22,139.71,128.67,127.31,127.18,120.86,114.27,110.75,71.13,67.30,59.24,21.68。
example 7
Preparation of 3-methyl-5-p-bromophenyl anisole
Adding 5-methyl-3-p-bromophenyl cyclohex-2-enone (53mg, 0.2mmol), methanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring for 5 minutes at normal temperature, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. Drying the organic phase over anhydrous magnesium sulfate, filtering to remove the magnesium sulfate, evaporating off the solvent on a rotary evaporator, and carrying out column chromatography (20: 1 by volume of petroleum ether-ethyl acetate)Ethyl acetate as chromatography) to give 3-methyl-5-p-bromophenyl anisole as a yellow oil (44mg, yield 80%).1H NMR(400MHz,CDCl3)δ7.57(d,J＝8.4Hz,2H),7.46(d,J＝8.4Hz,2H),6.98(s,1H),6.91(s,1H),6.76(s,1H),3.87(s,3H),2.42(s,3H)；13C NMR(101MHz,CDCl3)δ160.06,141.32,140.00,131.77,128.79,121.54,120.38,113.85,109.85,55.32,21.67。
Example 8
Preparation of 3-benzyl-5-phenylphenethyl ether
Adding 5-benzyl-3-phenylcyclohex-2-enone (52mg, 0.2mmol), ethanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring at normal temperature for 5 minutes, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as chromatography) to give 3-benzyl-5-phenylphenyl ether as a pale yellow oil (49mg, 85% yield).1H NMR(400MHz,CDCl3)δ7.59(d,J＝7.4Hz,2H),7.45(t,J＝7.5Hz,2H),7.40–7.20(m,7H),7.06(s,1H),7.00(s,1H),6.76(s,1H),4.09(q,J＝7.0Hz,2H),4.05(s,2H),1.45(t,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ159.48,142.99,142.73,141.25,140.88,128.96,128.68,128.52,127.36,127.23,126.16,120.41,114.26,111.04,63.47,42.15,14.91。
Example 9
Preparation of 3-p-tolylmethyl-5-phenylanisole
Sequentially adding 5-p-toluene into a thick-wall reaction bottleMethyl-3-phenylcyclohex-2-enone (55mg, 0.2mmol), methanol (2mL), iodine simple substance (76mg, 0.3mmol), stirring at normal temperature for 5 minutes, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring at the temperature of 80 ℃ for 6 hours. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as the chromatography medium) to give 3-p-tolylmethyl-5-phenylanisole as a colorless oil (41mg, 71% yield).1H NMR(400MHz,CDCl3)δ7.59(dd,J＝8.3,1.2Hz,2H),7.48–7.41(m,3H),7.14(d,J＝3.6Hz,4H),7.06(s,1H),6.99(d,J＝1.9Hz,1H),6.76(d,J＝1.6Hz,1H),4.00(s,2H),3.85(s,3H),2.35(s,3H)；13C NMR(101MHz,CDCl3)δ160.09,143.33,142.75,137.77,135.65,129.52,129.20,128.80,128.67,127.36,127.25,120.49,113.61,110.43,55.31,41.71,21.02。
Example 10
Preparation of 3-p-methoxybenzyl-5-phenyl anisole
Adding 5-p-methoxybenzyl-3-phenylcyclohex-2-enone (58mg, 0.2mmol), methanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction flask in sequence, stirring for 5 minutes at normal temperature, screwing a reaction flask cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as the chromatography medium) to give 3-p-methoxybenzyl-5-phenylanisole as a colorless oil (47mg, 78% yield).1H NMR(400MHz,CDCl3)δ7.58(dd,J＝5.2,3.2Hz,2H),7.47–7.41(m,2H),7.36(dt,J＝9.3,4.3Hz,1H),7.18(d,J＝8.7Hz,2H),7.04(s,1H),6.99(d,J＝2.0Hz,1H),6.87(d,J＝8.7Hz,2H),6.74(s,1H),3.98(s,2H),3.85(s,3H),3.81(s,3H)；13C NMR(101MHz,CDCl3)δ160.09,158.04,143.52,142.75,141.22,132.94,129.89,128.68,127.37,127.24,120.41,113.94,113.54,110.40,55.31,55.28,41.21。
Example 11
Preparation of 3-p-chlorobenzyl-5-phenyl anisole
Adding 5-p-chlorobenzyl-3-phenylcyclohex-2-enone (59mg, 0.2mmol), methanol (2mL) and iodine simple substance (76mg, 0.3mmol) into a thick-wall reaction bottle in sequence, stirring for 5 minutes at normal temperature, screwing a reaction bottle cover to seal after the iodine simple substance is dissolved, and magnetically stirring for 6 hours at the temperature of 80 ℃. Stirring was stopped, 20mL of ethyl acetate was added, extraction was performed twice with distilled water, washing was performed once with a saturated sodium chloride solution, and the aqueous layer was separated. The organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, evaporated on a rotary evaporator and purified by column chromatography (20: 1 by volume petroleum ether-ethyl acetate as the chromatography medium) to give 3-p-chlorobenzyl-5-phenylanisole as a colorless oil (54mg, 87% yield).1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.4Hz,2H),7.45(t,J＝7.5Hz,2H),7.37(t,J＝7.2Hz,1H),7.29(t,J＝4.0Hz,3H),7.19(d,J＝8.2Hz,2H),7.01(d,J＝6.6Hz,2H),6.72(s,1H),4.00(s,2H),3.86(s,3H)；13C NMR(101MHz,CDCl3)δ160.17,142.96,142.46,141.06,139.29,132.01,130.28,128.73,128.63,127.49,127.22,120.42,113.63,110.63,55.33,41.40。
Example 12
Preparation of 3-methyl-5-phenylphenol
3-methyl-5-phenylanisole (39mg, 0.2mmol) and 5ml hydroiodic acid (47 wt%) were added to a reaction flask, refluxed for 2 hours with stirring, and cooled. 20mL of water and 20mL of ethyl acetate were addedThe organic layer was separated, washed 2 times with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, the solvent was evaporated on a rotary evaporator, and purified by column chromatography (petroleum ether-ethyl acetate in a volume ratio of 10: 1 as a chromatography) to give 3-methyl-5-phenylphenol (34mg, yield 93%) as a colorless liquid.1H NMR(400MHz,CDCl3)δ7.55-7.57(m,2H),7.41-7.44(m,2H),7.34-7.35(m,1H),7.00(s,1H),6.87(s,1H),6.65(s,1H),4.71(s,1H),2.3(s,3H)；13C NMR(101MHz,CDCl3)δ155.77,142.86,140.89,140.12,128.69,127.41,127.12,120.76,114.93,111.24,21.49。
The yield of the phenol ether prepared by the simple and convenient synthesis method of the meta-substituted phenol ether can reach 89%, and the yield of the meta-substituted phenol prepared by taking the meta-substituted phenol ether as a raw material can reach 93%.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention claims should be included in the protection scope of the present invention claims.
Claims (8)
1. A simple synthesis method of meta-substituted phenol ether is characterized in that a meta-substituted cyclohexenone derivative is used as a reaction raw material, and the reaction is carried out under the conditions of an alcohol solvent and an oxidant to obtain the corresponding meta-substituted phenol ether.
2. The simple method for synthesizing a meta-substituted phenol ether according to claim 1, wherein the oxidant is elemental iodine.
3. The simple method for synthesizing meta-substituted phenol ether according to claim 2, wherein the meta-substituted phenol ether is prepared by the following steps:
adding a meta-substituted cyclohexenone derivative, an alcohol solvent and an iodine simple substance into a reaction bottle, stirring until the iodine simple substance is dissolved, sealing, and magnetically stirring for 5-7 hours at 70-90 ℃; stopping stirring, adding ethyl acetate, extracting with distilled water, washing with saturated sodium chloride solution, separating the water layer, drying the organic phase with anhydrous magnesium sulfate, filtering to remove magnesium sulfate, evaporating to remove the solvent, and purifying to obtain the corresponding meta-substituted phenol ether.
4. The simple method for synthesizing meta-substituted phenol ether according to claim 1, wherein the meta-substituted cyclohexenone derivative has the formula
The structural formula of the meta-substituted phenol ether is shown in the specification
Wherein R is selected from one of alkyl and ether, R1One selected from alkyl, aryl or aryl derivatives; r2Selected from one of alkyl, aryl or aryl derivatives.
5. The simple synthesis method of meta-substituted phenol ether according to claim 1, wherein the alcohol solvent is one or more of methanol, ethanol, n-butanol, isopropanol, 3-pentanol, and ethylene glycol monomethyl ether.
6. The simple method for synthesizing meta-substituted phenol ether according to claim 1, wherein the meta-substituted cyclohexenone derivative is one or more of 5-methyl-3-phenylcyclohex-2-enone, 5-methyl-3-p-bromophenyl cyclohex-2-enone, 5-benzyl-3-phenylcyclohex-2-enone, 5-p-tolylmethyl-3-phenylcyclohex-2-enone, 5-p-methoxybenzyl-3-phenylcyclohex-2-enone, and 5-p-chlorobenzyl-3-phenylcyclohex-2-enone.
7. A simple method for synthesizing meta-substituted phenol, which is characterized in that meta-substituted phenol ether obtained by the simple method of any one of claims 1 to 6 is used as a raw material to obtain corresponding meta-substituted phenol under the action of hydroiodic acid; the amount of said substance of hydroiodic acid is at least 9 times the amount of the substance of the phenol ether.
8. The simplified method for synthesizing a meta-substituted phenol according to claim 7, wherein the meta-substituted phenol is prepared by the following steps:
adding meta-substituted phenol ether and hydroiodic acid into a reaction bottle, stirring and refluxing, and cooling; adding water and ethyl acetate, separating an organic layer, washing twice by using a saturated sodium bicarbonate solution, drying the organic phase by using anhydrous magnesium sulfate, filtering to remove the magnesium sulfate, evaporating to remove the solvent, and purifying by using column chromatography to obtain the corresponding meta-substituted phenol.
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Non-Patent Citations (5)
| Title |
|---|
| HORIUCHI, C. AKIRA: ""Iodine–Cerium(IV) Ammonium Nitrate"", 《E-EROS ENCYCLOPEDIA OF REAGENTS FOR ORGANIC SYNTHESISFJPEDIA OF REAGENTS FOR ORGANIC SYNTHESIS》 * |
| KORNFELD, EDMUND C.: ""A new synthesis of cinnoline derivatives: heterocyclic steroid analogs"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| TAMURA, YASUMITSU，ET AL.: ""An improved method for the conversion of cyclohexenones into anisoles"", 《CHEMISTRY & INDUSTRY》 * |
| YU FENG LIANG,ET AL.: ""Metal-Free I2-catalyzed highly selective dehydrogenative coupling of alcohols and cyclohexenones"", 《CHIN.J.CHEM.》 * |
| 刘鹰翔: "《药物合成反应 新世纪第2版》", August 2017 * |
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