CN107556262B - Preparation method of 2-substituent arooxazole - Google Patents
Preparation method of 2-substituent arooxazole Download PDFInfo
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- CN107556262B CN107556262B CN201710690197.XA CN201710690197A CN107556262B CN 107556262 B CN107556262 B CN 107556262B CN 201710690197 A CN201710690197 A CN 201710690197A CN 107556262 B CN107556262 B CN 107556262B
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Abstract
The invention adopts the reaction of phenolic compounds and aldoxime ester compounds to prepare 2-substituent aroxazole compounds. Under mild conditions, the phenol compound and aldoxime ester react in an organic solvent under the catalysis of iron to generate the corresponding 2-substituent aroxazole compound. The method has the advantages of economical and easily obtained reagents, wide substrate application range, mild reaction conditions, simple operation and the like.
Description
Technical Field
The invention relates to a method for preparing 2-substituent aroxazole compounds, which utilizes the reaction of phenolic compounds and aldoxime esters to obtain corresponding aroxazole compounds.
Background
Oxazole is an aromatic structure having both oxygen and nitrogen heteroatoms, which are widely present in natural products. The 2-substituent aroxazole compound is not only widely used for medical research due to the biological activity, but also researched and applied in fluorescent materials due to the fluorescence, and the importance of the compound is fully reflected. The synthesis of 2-substituent aroxazole compounds is mainly divided into two categories, wherein the first category is that C2 site of oxazole is directly activated by hydrocarbon to further construct 2-substituent oxazole; the second is the construction of oxazole ring by reaction of substrates containing N and O. The method for directly activating the C2 position of the oxazole by hydrocarbon comprises the following steps: coupling to amine compounds (CN 102766108A), coupling to haloaromatics (J.Am.chem. Soc.129(2007) 12404-; the method for constructing the oxazole ring by reacting substrates containing N and O comprises the following steps: reaction of 2-aminophenol with acyl chloride (CN 105339360A), heating reaction of N-o-halophenylamide under the action of Cu catalyst and strong alkali (J.org. chem.71(2006)1802-2Heating reaction under the action of O (CN 105111161A), heating reaction of N-O-halophenylamide under the action of Fe catalyst and strong base (org. Lett.10(2008) 2665-2667), reduction of 2-nitrophenolWith potassium ethylxanthate (CN106588808A), N-phenylamide directly on Cu (OTf)2And O2Heating reaction under the action (Angew. Chem. int. Ed.47(2008) 6411-. Although the existing method can effectively prepare the corresponding 2-substituent aroxazole, the hydrocarbon activation method usually uses expensive and toxic heavy metals, the economy and the environmental protection are greatly weakened, and the general method for directly constructing the oxazole ring needs higher temperature, needs strong base and strong oxidant, and is limited by the synthesis of a substrate.
Disclosure of Invention
As mentioned above, although there are many methods for preparing 2-substituted aroxazoles, each method has certain limitations. The invention aims to provide a high-efficiency iron-catalyzed synthesis method of 2-substituent aroxazole compounds, namely, corresponding 2-substituent aroxazole compounds are obtained by reacting phenolic compounds with aldoxime ester compounds. The method has the advantages of economic and easily-obtained reagents, wide substrate application range, mild reaction conditions and simple operation.
The method of the invention has the following reaction general formula:
in the formula (II) wherein R is a substituent1、R2Is alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl; r3Is arylformyl, fatty acyl and carbonate.
The solvents used in accordance with the invention are benzene and haloalkane liquids, including toluene, benzene, chlorobenzene, bromobenzene, p-xylene, mesitylene, dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, preferably toluene.
The reaction temperature according to the invention is between-10 ℃ and 100 ℃, preferably 25 ℃.
The reaction time according to the invention is between 10 minutes and 1440 minutes, preferably 720 minutes.
The iron catalyst used in accordance with the present invention includes ferric chloride, ferric bromide, ferric sulfate, ferric nitrate, ferric oxide, ferric perchlorate, ferrous chloride, ferrous sulfate and the like, preferably ferric chloride.
The amount of the catalyst used in the present invention may vary, and the ratio of the phenolic compound to the catalyst is 1:0.05 to 1:1, preferably 1: 0.3.
The material proportion can be changed based on the invention, and the ratio of the phenol to the aldoxime ester is 1: 1-1: 5, preferably 1: 3.5.
The reaction mode based on the invention can adopt a one-pot method to directly react, or adopt a mode of dripping aldoxime ester to react, and preferably adopt a mode of dripping aldoxime ester to react.
The reaction atmosphere according to the invention may be O2Ar, air, preferably O2。
The specific preparation process for implementing the method of the invention can be described as follows:
0.3 times molar weight of catalyst, 1 time molar weight of phenol and 3.5 times molar weight of aldoxime ester are dissolved in solvent, and stirred until the raw material disappears. The reaction system was depressurized to remove the solvent, dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution and water, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give a crude product. And then the pure 2-substituent group aromatic oxazole product is obtained by column chromatography separation and purification.
Compared with the existing method, the method has the following advantages:
1. the reaction raw materials are cheap and easy to obtain;
2. the reaction operation is convenient;
3. the reaction condition is mild, and the energy consumption is low;
4. the reaction system is simple, the applicability of the substrate is wide, and the yield is high.
Examples
The following examples are intended to illustrate the invention in detail, but are not intended to limit the invention.
Examples 1-22 (as shown in Table I).
Table one:
Claims (5)
1. a preparation method of 2-substituent aryl oxazole is characterized in that: at a certain temperature, reacting a phenolic compound with an aldoxime ester compound in a solvent under the action of an iron catalyst to generate a corresponding 2-substituent aryl oxazole compound, wherein the method has the following reaction general formula:
wherein: r1、R2Is aryl, substituted aryl, heteroaryl, alkyl; r3Is arylformyl, fatty acyl and carbonate; the iron catalyst is selected from ferric chloride, ferric bromide, ferric sulfate, ferric nitrate, ferric oxide, ferric perchlorate, ferrous chloride and ferrous sulfate.
2. The method according to claim 1, wherein the solvent is selected from the group consisting of toluene, benzene, chlorobenzene, bromobenzene, p-xylene, mesitylene, dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, and mixtures thereof.
3. The process of claim 1, wherein the reaction temperature is-10 deg.CoC~100oC。
4. The method according to claim 1, wherein the molar ratio of the phenolic compound to the aldoxime compound is 1: 1-5.
5. The method according to claim 1, wherein the molar ratio of the phenolic compound to the amount of the catalyst is 1:0.05 to 1.
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| CN109761848B (en) * | 2019-01-22 | 2020-09-08 | 四川大学 | Method for preparing nitrile |
| CN110551098B (en) * | 2019-06-17 | 2021-03-12 | 湖北固润科技股份有限公司 | Oxime ester photoinitiator containing five-membered aromatic heterocyclic structure and preparation and application thereof |
| CN112574135B (en) * | 2020-12-14 | 2022-09-23 | 湖南工程学院 | 4-aryl-5-thioether-2-difluoromethyl oxazole, and derivatives and synthesis method thereof |
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| CN103328467A (en) * | 2010-12-06 | 2013-09-25 | 奥蒂福尼疗法有限公司 | Hydantoin derivatives useful as KV3 inhibitors |
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| CN103328467A (en) * | 2010-12-06 | 2013-09-25 | 奥蒂福尼疗法有限公司 | Hydantoin derivatives useful as KV3 inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL EFFECTS ACCOMPANYING HYDROGEN BONDING. Ill;A. H. BLATT;《J. Org. Chem.》;19550531;第20卷(第5期);第591-602页 * |
| Novel 2-aryl-naphtho[1,2-d]oxazole derivatives as potential PTP-1B inhibitors showing antihyperglycemic activities;A. Kumar et al.;《European Journal of Medicinal Chemistry》;20080327;第44卷;第109-116页 * |
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