CN108689874B - Method for preparing 2-aryl malonamide and application thereof - Google Patents
Method for preparing 2-aryl malonamide and application thereof Download PDFInfo
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- CN108689874B CN108689874B CN201710223444.5A CN201710223444A CN108689874B CN 108689874 B CN108689874 B CN 108689874B CN 201710223444 A CN201710223444 A CN 201710223444A CN 108689874 B CN108689874 B CN 108689874B
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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Abstract
The invention provides a method for preparing 2-aryl malonamide and application thereof. The method takes 2- (cyclohexenylene) malononitrile as a raw material, and carries out aromatization-hydrolysis reaction under the action of an oxidant and water to obtain the 2-aryl malonamide in one step. Compared with the prior art, the method for preparing the 2-aryl malonamide provided by the invention has the following remarkable characteristics and advantages: (1) completely different synthetic strategies; (2) the raw materials are simple and easy to obtain; (3) high yield, no use of expensive metal catalyst, low cost, suitability for industrial production, etc.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method and application of 2-aryl malonamide.
Background
2-aryl malonamide compounds are an important class of organic synthesis intermediates. For example, 2- (2, 6-diethyl-4-methylphenyl) malonamide is an important intermediate for the preparation of the highly effective herbicide pinoxaden (WO000/78881, WO 00/78712).
The current methods for the synthesis of 2-arylmalonamide compounds are mainly prepared by hydrolysis of 2-arylmalononitrile-based compounds (WO 00/78712). The method has the problem that the raw material 2-aryl malononitrile compound is difficult to prepare, in particular to the preparation of the 2- (2, 6-disubstituted aryl) malononitrile raw material with large steric hindrance. The best method for synthesizing 2- (2, 6-disubstituted aryl) malononitrile uses corresponding aromatic amine compounds as raw materials, and the synthesis method sequentially comprises diazotization-halogenation (Sandmeyer) reaction and C-C metal catalytic coupling reaction (WO 2004/050607). In order for the metal-catalyzed coupling reaction to be of the desired yield, the halogenating reagent used in the diazotization-halogenation reaction must be a valuable bromine or iodine compound. In the diazotization-halogenation reaction process, a large amount of three-waste pollution is generated, and the problems of potential safety hazard and halogen corrosion also exist. In addition, the C-C metal catalyzed coupling reaction of the resulting sterically hindered aryl halide with malonic acid derivatives requires the use of expensive organometallic catalysts, which are costly and difficult to recover.
The present inventors have made extensive studies and experimental investigations in view of the disadvantages of the prior art, and have surprisingly found that a 2-arylmalonamide compound can be directly prepared from 2- (cyclohexenylidene) malononitrile as a raw material.
Disclosure of Invention
The invention provides a novel method for preparing a 2-aryl malonamide compound. Specifically, 2- (cyclohexenylene) malononitrile is subjected to aromatization-hydrolysis reaction under the action of an oxidant and water to obtain 2-aryl malonamide in one step, and the reaction formula is shown as follows:
wherein R is1、R2、R3、R4、R5Independently of one another, hydrogen, C1-C10 alkyl, C6-C12 aryl or heteroaryl containing one or two atoms selected from nitrogen, oxygen, sulfur.
The oxidant is peroxide, oxygen, air or oxidizing acid. Preferably hydrogen peroxide, potassium persulfate and concentrated sulfuric acid. The molar ratio of oxidizing agent to compound 1 is 0.5-2.0:1, preferably 1.0-1.2: 1.
The aromatization-hydrolysis reaction temperature is 0-100 ℃, and preferably 60-80 ℃.
The aromatization-hydrolysis reaction is carried out under the action of acid, preferably concentrated sulfuric acid.
Compared with the prior art, the method for preparing the 2-aryl malonamide provided by the invention has the following remarkable characteristics and advantages:
(1) completely different synthetic strategies;
(2) the raw materials are simple and easy to obtain;
(3) high yield, no use of expensive metal catalyst, low cost, suitability for industrial production, etc.
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 used in the present invention can be prepared by Knoevenagel condensation reaction from cyclohexenone and malononitrile (j.mol.cata.a.chem.2003,195(1-2), 263).
The first embodiment is as follows: preparation of 2- (2, 6-diethyl-4-methylphenyl) malonamide
43.0g (0.20mol) of raw material 2- (2, 6-diethyl-4-methyl-2-en-1-cyclohexylidene) malononitrile, 54.1g (0.2mol) of potassium persulfate and 5.4g (0.30mol) of water were cooled to 0 to 5 ℃. Concentrated sulfuric acid is added dropwise into the reaction system. After dropping, the temperature is raised to 70 ℃ for reaction. After the reaction is completed, the temperature is reduced, the reaction solution is poured into ice water, ethyl acetate is used for extraction twice, organic phases are combined, dried, concentrated and crystallized to obtain 40.0g of 2- (2, 6-diethyl-4-methylphenyl) malonamide, and the yield is 80%.1H NMR(MeOD,500MHz):6.99(s,2H),4.81(s,1H),2.60(q,J＝9.0Hz,4H),2.32(s,3H),1.22(t,J＝9.0Hz,6H)。13C NMR(CDCl3,125MHz):174.7,145.0,139.0,130.2,128.9,48.9,27.5,21.2,15.5。
Example two: preparation of 2- (2, 6-diethyl-4-methylphenyl) malonamide
21.4g (0.10mol) of raw material 2- (2, 6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile and 13.6g (0.12mol) of 30% hydrogen peroxide are cooled to 0-5 ℃. After dropping, heating to 60 deg.C for reaction. After the reaction is completed, the temperature is reduced, the reaction solution is poured into ice water, extraction is carried out twice by ethyl acetate, organic phases are combined, dried, concentrated and crystallized, and 10.2g of 2- (2, 6-diethyl-4-methylphenyl) malonamide is obtained.
Example three: preparation of 2- (2, 6-diethyl-4-methylphenyl) malonamide
32.1g (0.15mol) of raw material 2- (2, 6-diethyl-4-methyl-2-en-1-cyclohexylidene) malononitrile and 6.7g (0.30mol) of water were cooled to 0 to 5 ℃. Concentrated sulfuric acid is added dropwise into the reaction system. After dropping, the temperature is raised to 80 ℃ for reaction. After the reaction is completed, the temperature is reduced, the reaction solution is poured into ice water, ethyl acetate is used for extraction twice, organic phases are combined, dried, concentrated and crystallized to obtain 32.7g of 2- (2, 6-diethyl-4-methylphenyl) malonamide, and the yield is 88%.
Example four: preparation of 2- (2, 6-diethyl-4-methylphenyl) malonamide
214.3g (1.00mol) of raw material 2- (2, 6-diethyl-4-methyl-2-en-1-cyclohexylidene) malononitrile and 27.0g (1.50mol) of water were cooled to 0 to 5 ℃. Concentrated sulfuric acid is dripped into the reaction system, and oxygen is introduced into the reaction system at the same time. After dropping, the temperature is raised to 80 ℃ for reaction. After the reaction is completed, the temperature is reduced, the reaction solution is poured into ice water, ethyl acetate is used for extraction twice, organic phases are combined, dried, concentrated and crystallized to obtain 136.6g of 2- (2, 6-diethyl-4-methylphenyl) malonamide.
Example five: preparation of 2- (2, 6-diethyl-4-methylphenyl) malonamide
15.0g (0.09mol) of raw material 2- (3-methyl-2-en-1-cyclohexylidene) malononitrile, 25.7g (0.09mol) of potassium persulfate and 2.6g (0.14mol) of water were cooled to 0 to 5 ℃. Concentrated sulfuric acid is added dropwise into the reaction system. After dropping, the temperature is raised to 70 ℃ for reaction. After the reaction is completed, the temperature is reduced, the reaction solution is poured into ice water, ethyl acetate is used for extraction twice, organic phases are combined, dried, concentrated and crystallized to obtain 16.2g of 2- (3-methylphenyl) malonamide, and the yield is 89%.
Example six: preparation of 2- (2, 6-diphenyl-4-methylphenyl) malonamide
The starting materials, 2- (2, 6-diphenyl-4-methyl-2-en-1-cyclohexylidene) malononitrile, 31.0g (0.10mol), potassium persulfate, 27.0g (0.10mol) and water, 2.7g (0.15mol), were cooled to 0-5 ℃. Concentrated sulfuric acid is added dropwise into the reaction system. After dropping, the temperature is raised to 70 ℃ for reaction. After the reaction is completed, the temperature is reduced, the reaction solution is poured into ice water, extraction is carried out twice by ethyl acetate, organic phases are combined, dried, concentrated and crystallized, and 19.6g of 2- (2, 6-diphenyl-4-methylphenyl) malonamide is obtained.1H NMR(MeOD,500MHz):7.50-7.40(m,10H),7.20(s,2H),5.11(s,1H),2.44(s,3H)。
Example seven: preparation of pinoxaden
2- (2, 6-diethyl-4-methylphenyl) malonamide (12.4 g, 0.05mol) and [1,4,5 ]]10.5g (0.06mol) of oxydiazepan dihydrochlorate and 20.2g (0.20mol) of triethylamine are reacted in xylene with stirring under reflux. After the reaction is completed, the temperature is reduced, 10.8g (0.09mol) of pivaloyl chloride is added, and the reaction is carried out at room temperature. After the reaction was complete, the mixture was adjusted to acidic pH with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried, concentrated and crystallized to give the product pinoxaden, 14.4g, in 72% yield.1H NMR(CDCl3,500MHz,TMS):8.88(s,2H),4.28-4.26(m,2H),3.94-3.93(m,2H),3.89-3.83(m,4H),2.56-2.47(m,2H),2.45-2.40(m,2H),2.39(s,3H),1.12(t,J＝9.0Hz,3H),1.23(s,9H)。
Claims (10)
1. The preparation method of 2-aryl malonamide is characterized in that a compound 1 is subjected to aromatization-hydrolysis reaction under the action of an oxidant and water to obtain 2-aryl malonamide 2 in one step, and the reaction formula is as follows:
wherein R is1、R2、R3、R4、R5Independently of one another, hydrogen, C1-C10 alkyl, C6-C12 aryl or heteroaryl containing one or two atoms selected from nitrogen, oxygen, sulfur.
2. The method of claim 1, wherein R is1、R2Is C1-C3 alkyl, C6-C12 aryl, R3Is C1-C3 alkyl, R4、R5Is hydrogen.
3. The method of claim 2, wherein R is1、R2Is ethyl, R3Is methyl.
4. The method of claim 1, wherein the oxidizing agent is a peroxide, oxygen, air, an oxidizing acid; the molar ratio of the oxidant to the compound 1 is 0.5-2.0: 1.
5. The method of claim 4, wherein the oxidizing agent is potassium persulfate, concentrated sulfuric acid; the molar ratio of the oxidant to the compound 1 is 1.0-1.2: 1.
6. The process according to claim 1, wherein the reaction temperature is from 0 to 100 ℃.
7. The process according to claim 6, wherein the reaction temperature is 60 to 80 ℃.
8. A process according to any one of claims 1 to 6, characterised in that the reaction is carried out under the action of an acid.
9. The method of claim 8, wherein the acid is concentrated sulfuric acid.
10. Use of a method according to any one of claims 1 to 9 in pinoxaden synthesis.
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| CA3135512C (en) * | 2019-04-01 | 2023-08-15 | Oriental (Luzhou) Agrochemicals. Co., Ltd. | Method for preparing 2-arylmalonic acid derivative and intermediate, and use thereof |
| CN113968798B (en) * | 2020-07-24 | 2023-01-24 | 沈阳中化农药化工研发有限公司 | Cyclohexyl ester compound, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169108A (en) * | 1973-08-16 | 1979-09-25 | Sterling Drug Inc. | 5(OR 6)-[(Substituted-amino)alkyl]-2,3-naphthalenediols |
| US4327022A (en) * | 1973-08-16 | 1982-04-27 | Sterling Drug Inc. | Heterocyclic alkyl naphthols |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169108A (en) * | 1973-08-16 | 1979-09-25 | Sterling Drug Inc. | 5(OR 6)-[(Substituted-amino)alkyl]-2,3-naphthalenediols |
| US4327022A (en) * | 1973-08-16 | 1982-04-27 | Sterling Drug Inc. | Heterocyclic alkyl naphthols |
Non-Patent Citations (1)
| Title |
|---|
| A simple and Efficient Procedure for synthesis of agomelatine;G.GURUNADHAM等;《Asian journal of chemistry》;20160229;第28卷(第6期);第1367-1370页 * |
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