CN108264449B - Preparation method of 2, 6-diethyl-4-methylphenol - Google Patents
Preparation method of 2, 6-diethyl-4-methylphenol Download PDFInfo
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- CN108264449B CN108264449B CN201611264572.6A CN201611264572A CN108264449B CN 108264449 B CN108264449 B CN 108264449B CN 201611264572 A CN201611264572 A CN 201611264572A CN 108264449 B CN108264449 B CN 108264449B
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- C07—ORGANIC CHEMISTRY
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
- C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/48—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation involving decarboxylation
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/603—Unsaturated compounds containing a keto groups being part of a ring of a six-membered ring
Abstract
The invention provides a preparation method of 2, 6-diethyl-4-methylphenol. The method adopts a synthesis strategy completely different from the prior art, 2-ethyl-3-oxohexanoate is taken as a raw material, and the raw material and 2-methylacrolein are subjected to condensation reaction under the action of alkali to obtain an intermediate 2, 6-diethyl-4-methyl-2-ene cyclohexanone and/or 2, 6-diethyl-4-methyl-3-ene cyclohexanone, and the intermediate is subjected to aromatization reaction under the action of a catalyst to obtain a target product 2, 6-diethyl-4-methylphenol. Compared with the prior art, the method has the advantages of cheap and easily obtained raw materials, no need of expensive metal catalysts and corresponding ligands, safe operation, less three wastes and the like, and is favorable for industrial production.
Description
Technical Field
The invention belongs to the field of synthesis of organic polysubstituted aromatic phenol, and particularly relates to a preparation method of 2, 6-diethyl-4-methylphenol.
Background
Organic polysubstituted aromatic phenols are an important class of organic compounds. For example, 2, 6-diethyl-4-methylphenol is an intermediate in the synthesis of the highly effective herbicide pinoxaden (WO2004/050607, WO 00/78881).
Currently, there are three methods for synthesizing 2, 6-diethyl-4-methylphenol.
The first process uses 2, 6-diethyl-4-methylaniline as the starting material (WO 2004/050607). 2, 6-diethyl-4-methylaniline is hydrolyzed by diazotization to obtain 2, 6-diethyl-4-methylphenol. The raw material 2, 6-diethyl-4-methylaniline used in the method is difficult to prepare, a large amount of three wastes are generated in the diazotization step, and meanwhile, potential safety hazards exist, so that the method is not beneficial to industrial production.
The second method starts from p-methylphenol (chem. Commun.2006, (43), 4527-4529). Reacting p-methyl phenol with ethylene under the action of metal Rh and a ligand to obtain 2, 6-diethyl-4-methyl phenol. Although the method has high yield, the method needs to use an extremely expensive metal catalyst Rh and an expensive ligand, has potential safety hazard by using ethylene gas, and is not suitable for industrial production.
The third method is the most recently reported method (Angew. chem., int. Ed.2014,53(13), 3436-. The method comprises the steps of taking 2, 6-dibromo-4-methylphenol as a raw material, firstly carrying out hydroxyl protection, then coupling with trimethylsilyl acetylene, removing a silyl protecting group, then carrying out hydrogenation reduction, and finally removing the hydroxyl protecting group to obtain the 2, 6-diethyl-4-methylphenol. The method has long route and low yield, needs a large amount of expensive metal catalysts, has more three wastes, has potential safety hazard when using hydrogen, and is not suitable for industrial production.
The invention content is as follows:
aiming at the defects in the prior art, the invention provides a novel method for preparing 2, 6-diethyl-4-methylphenol. The new method takes 2-ethyl-3-oxohexanoate (1) as a raw material, and the raw material and 2-methylacrolein (2) undergo a condensation reaction under the action of alkali to obtain 2, 6-diethyl-4-methyl-2-cyclohexenone and/or 2, 6-diethyl-4-methyl-3-cyclohexenone (3), and the latter undergoes an aromatization reaction under the action of a catalyst to obtain a target product 2, 6-diethyl-4-methylphenol (4). Specifically, the reaction formula is as follows:
wherein R is C1-C10 alkyl, C6-C12 aryl or heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur, preferably methyl and ethyl.
The alkali in the condensation reaction is one or more of organic alkali or inorganic alkali, the organic alkali is preferably sodium methoxide, and the inorganic alkali is preferably sodium hydroxide.
The molar ratio of compound 2 to compound 1 is 0.8-2.0: 1, preferably 1.2 to 1.8: 1.
the molar ratio of the alkali to the compound 1 is 1.0-3.5: 1. Preferably 2.0-2.4: 1.
The solvent of the condensation reaction is one or more of organic solvent and water, and the organic solvent is preferably tetrahydrofuran and methanol.
The condensation reaction is carried out at a temperature in the range of 0 to 150 c, preferably 60 to 80 c.
The catalyst for aromatization reaction is organic base or metal catalyst, wherein the organic base is DABCO preferably, and the metal catalyst is Pd/C preferably.
The mass ratio of the catalyst to the compound 3 in the aromatization reaction is 0.001-1.0:1, preferably 0.2-0.01: 1.
The invention provides a novel method for preparing 2, 6-diethyl-4-methylphenol. The method employs a completely different synthesis strategy compared to the prior art. In the prior art, aromatic hydrocarbon is used as a basic raw material to carry out substituent/functional group conversion to synthesize a target product. The present invention uses completely different non-aromatic compounds as raw materials, and corresponding aromatic rings are constructed through condensation and aromatization reactions. Moreover, compared with the prior art, the method has the advantages of cheap and easily obtained raw materials, no need of using expensive metal catalysts and corresponding ligands, safe operation, less three wastes and the like, and is favorable for industrial production.
Detailed Description
The following examples further illustrate some of the features of the present invention, but the invention is not limited in its content and scope by the following examples.
The starting material 1 used in the present invention may conveniently be prepared from ester compounds by claisen condensation reactions of the type well known in the art (e.g. Tetrahedron Letters,40(22),1999, 4227-.
The first embodiment is as follows: preparation of 2, 6-diethyl-4-methyl-2-cyclohexenone
Adding 6.2g (0.115mol) of sodium methoxide into methanol, stirring until the sodium methoxide is dissolved, adding7.6g (0.048mol) of methyl 2-ethyl-3-oxohexanoate as a raw material was added, the temperature was raised to 60 ℃ to react, and a methanol solution of 5.0g (0.072mol) of methacrolein was added dropwise. After the reaction is completed, the temperature is reduced, ethyl acetate is added, and the product, namely 5.8g of 2, 6-diethyl-4-methyl-2-cyclohexenone is obtained through washing, concentration and purification, wherein the yield is 72%.1H NMR(CDCl3,500MHz,TMS):δ6.44-6.42(m,1H,),2.58-2.53(m,1H,),2.22-2.12(m,2H),2.10-2.05(m,1H),1.14-1.12(m,3H),1.01-0.91(m,10H)。13C NMR(CDCl3,125MHz):δ201.46,148.82,139.94,47.81,35.86,31.83,22.386,22.08,21.55,13.51,12.79。
Example two: preparation of 2, 6-diethyl-4-methyl-2-cyclohexenone and 2, 6-diethyl-4-methyl-3-cyclohexenone
4.6g (0.115mol) of sodium hydroxide was added to tetrahydrofuran, 8.3g (0.048mol) of ethyl 2-ethyl-3-oxohexanoate as a raw material was added, the mixture was heated to reflux, and a solution of methacrolein 5.0g (0.072mol) in tetrahydrofuran was added dropwise. After the reaction is completed, the temperature is reduced, ethyl acetate is added, and the mixture is washed by water and concentrated to obtain 6.5g of a mixture of 2, 6-diethyl-4-methyl-2-cyclohexenone and 2, 6-diethyl-4-methyl-3-cyclohexenone, wherein the yield is 81%, and the ratio of the two is 90:10 by GC-MS measurement.
Example three: preparation of 2, 6-diethyl-4-methyl-2-cyclohexenone
40.0g (1.00mol) of sodium hydroxide was added to THF/H2O to the mixed solution was stirred until sodium hydroxide was dissolved, 93.1g (0.50mol) of ethyl 2-ethyl-3-oxohexanoate as a raw material was added, the mixture was heated to reflux reaction, and 42.0g (0.60mol) of a THF solution of methacrolein was added dropwise. After the reaction is completed, the temperature is reduced, ethyl acetate is added, and 58.2g of the product 2, 6-diethyl-4-methyl-2-cyclohexenone is obtained by washing, concentrating and purifying, wherein the yield is 70%.
Example four: preparation of 2, 6-diethyl-4-methyl-2-cyclohexenone and 2, 6-diethyl-4-methyl-3-cyclohexenone
Sodium hydroxide 24.0g (0.60mol) was added to THF/H2O to the mixed solution was stirred until sodium hydroxide was dissolved, 46.5g (0.25mol) of ethyl 2-ethyl-3-oxohexanoate as a raw material was added, the mixture was heated to reflux, and a solution of methacrolein 31.5g (0.45mol) in THF was added dropwise. After the reaction is completedCooling, adding ethyl acetate, washing with water, and concentrating to obtain 35.3g of 2, 6-diethyl-4-methyl-2-cyclohexenone and 2, 6-diethyl-4-methyl-3-cyclohexenone with a yield of 85%. The ratio of the two was 86:14 as determined by GC-MS.
Example five: preparation of 2, 6-diethyl-4-methylphenol
1.7g (0.01mol) of 2, 6-diethyl-4-methyl-2-cyclohexenone prepared in example one and 0.2g (10%) of DABCO were stirred in tetrahydrofuran at room temperature. After the reaction was completed, the reaction solution was washed with 1N hydrochloric acid and water in this order, and concentrated to obtain 1.2g of 2, 6-diethyl-4-methylphenol as a product with a yield of 75%.1H NMR(CDCl3,500MHz,TMS):δ6.44-6.42(m,1H,),2.58-2.53(m,1H,),2.22-2.12(m,2H),2.10-2.05(m,1H),1.14-1.12(m,3H),1.01-0.91(m,1)。13C NMR(CDCl3,125MHz):δ201.46,148.82,139.94,47.81,35.86,31.83,22.386,22.08,21.55,13.51,12.79。
Example six: preparation of 2, 6-diethyl-4-methylphenol
1.7g (0.01mol) of a mixture of 2, 6-diethyl-4-methyl-2-cyclohexenone and 2, 6-diethyl-4-methyl-3-cyclohexenone prepared in example two and 0.09g (5%) of Pd/C were reacted in N, N-dimethylacetamide under heating at 140 ℃. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined organic phases were washed with water and concentrated to give 1.5g of 2, 6-diethyl-4-methylphenol, 95% yield.
Example seven: preparation of 2, 6-diethyl-4-methylphenol
5.0g (0.03mol) of 2, 6-diethyl-4-methyl-2-cyclohexenone prepared in example III and 1.0g (20%) of DABCO were stirred in toluene at room temperature. After the reaction was completed, the reaction mixture was washed with 1N hydrochloric acid and water in this order, and concentrated to give 4.0g of 2, 6-diethyl-4-methylphenol, which was a product with a yield of 81%.
Example eight: preparation of 2, 6-diethyl-4-methylphenol
The 2, 6-diethyl-4-methyl-2-cyclohexenone and 2, 6-diethyl-4-methyl-3-cyclohexenone prepared in example IV (3.4 g, 0.02mol) and Pd/C (0.04 g, 1%) were reacted in N, N-dimethylacetamide under heating at 140 ℃. After the reaction was complete, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined organic phases were washed with water and concentrated to give 3.0g of 2, 6-diethyl-4-methylphenol, 95% yield.
Claims (2)
1. A method for preparing 2, 6-diethyl-4-methylphenol is characterized in that a compound (1) is used as a raw material and is subjected to condensation reaction with 2-methylacrolein (2) under the action of alkali to obtain an intermediate 2, 6-diethyl-4-methyl-2-ene cyclohexanone and/or 2, 6-diethyl-4-methyl-3-ene cyclohexanone (3), the compound 3 is subjected to aromatization reaction under the action of a catalyst to obtain a target product 2, 6-diethyl-4-methylphenol (4), and the reaction formula is represented as follows:
wherein R is methyl or ethyl;
the alkali is sodium methoxide or sodium hydroxide;
the molar ratio of the alkali to the compound 1 is 2.0-2.4: 1;
the molar ratio of the compound 2 to the compound 1 is 1.2-1.8: 1;
the solvent of the condensation reaction is one or more of tetrahydrofuran, methanol and water;
the catalyst is DABCO or Pd/C;
the mass ratio of the catalyst to the compound 3 in the aromatization reaction is 0.2-0.01: 1.
2. The method for preparing the compound (3) is characterized in that the compound (1) is used as a raw material and is subjected to condensation reaction with 2-methylacrolein (2) under the action of alkali to obtain the compound (3), and the compound is represented by a reaction formula as follows:
wherein R is methyl or ethyl;
the alkali is sodium methoxide or sodium hydroxide;
the molar ratio of the alkali to the compound 1 is 2.0-2.4: 1;
the molar ratio of the compound 2 to the compound 1 is 1.2-1.8: 1;
the solvent of the condensation reaction is one or more of tetrahydrofuran, methanol and water.
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| CN112479843B (en) * | 2020-12-03 | 2022-08-05 | 万华化学集团股份有限公司 | Preparation method of 5-methyl-3-cyclohexenone and application thereof in preparation of m-cresol |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004050607A1 (en) * | 2002-12-05 | 2004-06-17 | Syngenta Participations Ag | Process for the preparation of phenylmalonic acid dinitriles |
| CN104130128A (en) * | 2014-07-21 | 2014-11-05 | 浙江省诸暨合力化学对外贸易有限公司 | Synthetic method of phenoxyl acetate and intermediate thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004050607A1 (en) * | 2002-12-05 | 2004-06-17 | Syngenta Participations Ag | Process for the preparation of phenylmalonic acid dinitriles |
| CN104130128A (en) * | 2014-07-21 | 2014-11-05 | 浙江省诸暨合力化学对外贸易有限公司 | Synthetic method of phenoxyl acetate and intermediate thereof |
Non-Patent Citations (4)
| Title |
|---|
| Byong-Don Chong,等.Highly Efficient Synthesis of Methyl-Substituted Conjugate Cyclohexenones.《J. Org. Chem》.1997,第62卷 * |
| Highly Efficient Synthesis of Methyl-Substituted Conjugate Cyclohexenones;Byong-Don Chong,等;《J. Org. Chem》;19971231;第62卷;第9323页Scheme 1化合物4、第9324页Table 1、第9325页左栏倒数第2段 * |
| Jingwu Zhang,等.Reaction-activated palladium catalyst for dehydrogenation of substituted cyclohexanones to phenols and H2 without oxidants and hydrogen acceptors.《Chem. Sci》.2015,第6卷 * |
| Reaction-activated palladium catalyst for dehydrogenation of substituted cyclohexanones to phenols and H2 without oxidants and hydrogen acceptors;Jingwu Zhang,等;《Chem. Sci》;20151231;第6卷;第4679页Table 3 条目1 * |
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