阅读说明：本技术 一种选择性合成噁唑-4-羧酸酯的反应方法 (Reaction method for selectively synthesizing oxazole-4-carboxylic ester ) 是由 卜洪忠 王晨 吴杰庆 于 2020-12-07 设计创作，主要内容包括：本发明提供了一种选择性合成噁唑-4-羧酸酯的反应方法,以芳香醛为原料、一价铜盐为催化剂、有机胺为添加剂,在溶剂以及氮气或氩气氛围下进行反应,得到噁唑-4-羧酸酯为主产物。本发明提供的合成方法具有原子经济性和高选择性的特征,使用取代苯甲醛、芳香性杂环甲醛做底物,具有廉价易得、无废酸废气产生等优点；使用金属铜盐催化,具有廉价易得、底物适用性广、后处理简单和反应选择性好等优点。(The invention provides a reaction method for selectively synthesizing oxazole-4-carboxylic ester, which takes aromatic aldehyde as a raw material, cuprous salt as a catalyst and organic amine as an additive to react in a solvent and in a nitrogen or argon atmosphere to obtain oxazole-4-carboxylic ester as a main product. The synthesis method provided by the invention has the characteristics of atom economy and high selectivity, and has the advantages of low price, easy obtainment, no waste acid and waste gas generation and the like by using substituted benzaldehyde and aromatic heterocyclic formaldehyde as substrates; the catalyst is catalyzed by copper salt, and has the advantages of low price, easy obtaining, wide substrate applicability, simple post-treatment, good reaction selectivity and the like.)

1. A reaction method for selectively synthesizing oxazole-4-carboxylic ester is characterized in that: the oxazole-4-carboxylic ester is obtained by the addition reaction of isocyano acetate and the (3 + 2) dehydrocycloof aldehyde.

2. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claim 1 wherein: the method comprises the following steps of reacting isonitrile acetate with aldehyde under the action of a catalyst and an additive, wherein the dosage of the catalyst is 5-30 mol% of the isonitrile acetate, and the oxazole-4-carboxylic ester is obtained under the condition that the dosage of the additive is 10-100 mol% of the isonitrile acetate.

3. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claim 1 wherein: the raw materials are substituted benzaldehyde and aromatic heterocyclic formaldehyde.

4. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claim 1 wherein: the catalyst is copper salt.

5. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claim 4 wherein: the copper salt is an inorganic salt of cuprous bromide or cuprous chloride.

6. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claim 1 wherein: the additive is one of triethylamine, tri-n-butylamine, triethylene diamine (1, 4-diazabicyclo [2.2.2] octane) or 4-dimethylamino pyridine.

7. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claims 1 to 6 wherein: the solvent used in the reaction method is dry N, N-dimethylformamide or dry absolute ethyl alcohol.

8. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claims 1 to 6 wherein: the gas atmosphere used in the reaction method is nitrogen or argon.

9. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claims 1 to 6 wherein: the reaction temperature adopted by the reaction method is 25-100 ℃.

10. The reaction process for the selective synthesis of oxazole-4-carboxylic acid esters according to claim 9 wherein: the reaction temperature adopted by the reaction method is 10-70 ℃.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a reaction method for selectively synthesizing oxazole-4-carboxylic ester.

Background

Many oxazole derivatives have biological activities of anticancer, antitumor, antiviral, antifungal and anti-inflammatory. Also, the oxazole core is included in many natural products such as pyrrole azoles, rhizomycins, and triisooxazole macrolides. In addition, some oxazoles have shown great potential for efficient luminescence as fluorescent probes and labels in biological or supramolecular systems. In the synthesis method of oxazole-4-carboxylate, the cycloaddition reaction of acyl halide, anhydride and isocyanic acid is mainly carried out. Sandra Battiston et al studied the cyclization of isonitrile acetates with simple acid chlorides and anhydrides in DMF catalyzed by DBU (1, 8-diazabicycloundec-7-ene) to synthesize oxazole-4-carboxylic acid esters in good yield but with a considerable amount of waste acid generated (Eur. J. Med. chem.1987,22, 283-. Wang Xiangshan et al studied the cyclization reaction of AgMOF catalyzed isonitrile acetate and benzoyl chloride, selectively prepared 2, 5-disubstituted oxazole with good yield (ChemCatChem 2019,11, 1-5). Ding Mingwu et al synthesizes isocyano (triphenylphosphine subunit) acetate from triphenylphosphine and isonitrile acetate under the action of triethylamine and carbon tetrachloride, and then synthesizes 4, 5-disubstituted oxazole through the action of benzoic acid derivatives, wherein the separation yield is more than 70% (org. chem. front.,2017,4, 2044-one 2048).

As described above, the reaction of acid chlorides, carboxylic acids and isonitrile acetates is commonly used for preparing oxazole ring derivatives, but all generate waste acids of equal mass, affect the atom economy of the reaction, and are not environment-friendly.

Disclosure of Invention

In order to overcome the defects of no atom economy, more three wastes, high cost and the like in the traditional synthesis technology of oxazole-4-carboxylic ester and the defects of low selectivity, narrow substrate range, complicated substrate preparation or high cost in the existing synthesis method of oxazole-4-carboxylic ester, the invention provides the method for preparing oxazole-4-carboxylic ester, which has the advantages of atom economy, mild reaction conditions, easily obtained raw materials and high selectivity.

The technical scheme adopted by the invention is as follows: a reaction method for selectively synthesizing oxazole-4-carboxylic ester utilizes the addition reaction of isocyano acetate and [3+2] dehydrocycloof aldehyde to obtain oxazole-4-carboxylic ester.

Further, reacting the isonitrile acetate with aldehyde under the action of a catalyst and an additive, wherein the dosage of the catalyst is 5-30 mol% of the isonitrile acetate, and the oxazole-4-carboxylic ester is obtained under the condition that the dosage of the additive is 10-100 mol% of the isonitrile acetate.

Further, the raw materials are substituted benzaldehyde and aromatic heterocyclic formaldehyde.

Further, the catalyst is a copper salt.

Further, the copper salt is an inorganic salt of cuprous, and the inorganic salt of cuprous bromide or cuprous chloride.

Further, the additive is one of triethylamine, tri-n-butylamine, triethylene diamine (1, 4-diazabicyclo [2.2.2] octane) or 4-dimethylaminopyridine.

Further, the solvent used in the reaction method is dry N, N-dimethylformamide or dry absolute ethyl alcohol.

Further, the gas atmosphere used in the reaction method is nitrogen or argon.

Further, the reaction temperature adopted by the reaction method is 25-100 ℃.

Further, the reaction temperature adopted by the reaction method is 10-70 ℃.

The beneficial effects obtained by the invention are as follows: the synthesis method provided by the invention has the characteristics of atom economy and high selectivity, and has the advantages of low price, easy obtainment, no waste acid and waste gas generation and the like by using substituted benzaldehyde and aromatic heterocyclic formaldehyde as substrates; the catalyst is catalyzed by copper salt, and has the advantages of low price, easy obtaining, wide substrate applicability, simple post-treatment, good reaction selectivity and the like.

The invention is characterized in that: (1) the reaction has atom economy, is environment-friendly and does not generate waste acid; (2) the raw materials and the catalyst are easy to obtain, and the catalyst is easy to recover; (3) has good adaptability to aromatic aldehyde substrate substituent groups and good product yield.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.

A reaction method for selectively synthesizing oxazole-4-carboxylic ester is characterized in that isonitrile acetic ester and aldehyde are reacted under the action of a catalyst and an additive, a used solvent is dry N, N-dimethylformamide or dry absolute ethyl alcohol, the gas atmosphere is nitrogen or argon, the reaction temperature adopted in the reaction method is 25-100 ℃, the usage of the catalyst is 5-30 mol% of the isonitrile acetic ester, and the usage of the additive is 10-100 mol% of the isonitrile acetic ester, so that oxazole-4-carboxylic ester is obtained as a main product. The raw materials are substituted benzaldehyde and aromatic heterocyclic formaldehyde. The catalyst is copper salt, the copper salt is inorganic salt of cuprous, and the inorganic salt of cuprous bromide or cuprous chloride. The additive is one of triethylamine, tri-n-butylamine, triethylene diamine (1, 4-diazabicyclo [2.2.2] octane) or 4-dimethylamino pyridine.

Example 1: synthesis of ethyl 5-phenyloxazole-4-carboxylate

In a 50mL stoppered tube, 3.54mmol benzaldehyde, 3.54mmol triethylamine, 0.71mmol cuprous bromide, 4mL dry N, N-dimethylformamide, and 3.54mmol ethyl isocyanoacetate were added. The reaction solution was heated at 60 ℃ for 10 hours under argon. The reaction was stopped, 30mL of water was added to the system, followed by extraction with ethyl acetate (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to obtain a crude product, which was separated by column chromatography (EA: PE ═ 1:4) to obtain ethyl 5-phenyloxazole-4-carboxylate as a pale yellow liquid with an isolated yield: 68.46 percent;¹H NMR(400 MHz,CDCl₃):δ8.14–8.01(m,2H),7.92(s,1H),7.50–7.47(m,3H),4.43(q, J＝7.1Hz,2H),1.41(t,J＝7.1Hz,3H)。

example 2: synthesis of ethyl 5- (4-chlorophenyl) oxazole-4-carboxylate

To a 50mL stoppered tube were added 3.54mmol of p-chlorobenzaldehyde, 1.77mmol of triethylenediamine, 0.71mmol of cuprous chloride, 4mL of dry absolute ethanol, and 3.54mmol of ethyl isocyanoacetate. The reaction solution was heated at 40 ℃ for 10 hours under nitrogen. The reaction was stopped, 20mL of water was added to the system, followed by extraction with ethyl acetate (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to give a crude product, which was separated by column chromatography (EA: PE ═ 1:4) to give ethyl 5- (4-chlorophenyl) oxazole-4-carboxylate as a white solid with a melting point: 101-103 ℃; separation yield: 65.55 percent;¹HNMR(400MHz,CDCl₃):δ8.05(d,J＝8.7Hz,2H),7.90(s,1H), 7.44(d,J＝8.7Hz,2H),4.41(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)。

example 3: synthesis of ethyl 5- (4-methylphenyl) oxazole-4-carboxylate

In a 50mL stoppered test tube, 3.54mmol of p-tolualdehyde, 1.77mmol of 4-dimethylaminopyridine, 0.71mmol of cuprous bromide and 4mL of driedDried N, N-dimethylformamide, 3.54mmol of ethyl isocyanoacetate. The reaction solution was heated at 50 ℃ for 12 hours under nitrogen. The reaction was stopped, 20mL of water was added to the system, followed by extraction with ethyl acetate (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to give a crude product, which was separated by column chromatography (EA: PE ═ 1:4) to give ethyl 5- (4-methylphenyl) oxazole-4-carboxylate as a white solid with a melting point: 84-85 ℃; the isolation yield was 69.71%; 1H NMR (400MHz, CDCl)₃):δ7.97(d,J＝8.4 Hz,2H),7.89(s,1H),7.29(d,J＝8.4Hz,2H),4.42(q,J＝7.1Hz,2H),2.41(s, 3H),1.41(t,J＝7.1Hz,3H)。

Example 4: synthesis of ethyl 5- (4-methoxyphenyl) oxazole-4-carboxylate

In a 50mL stoppered test tube, 3.54mmol of p-methoxybenzaldehyde, 1.77mmol of tri-n-butylamine, 1.06mmol of cuprous chloride, 4mL of dried absolute ethanol, and 3.54mmol of ethyl isocyanoacetate were added. The reaction solution was heated at 100 ℃ for 10 hours under nitrogen. The reaction was stopped, 20mL of water was added to the system, followed by extraction with ethyl acetate (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to give a crude product, which was separated by column chromatography (EA: PE ═ 1:4) to give ethyl 5- (4-methoxyphenyl) oxazole-4-carboxylate as a white solid with a melting point: 68-69 ℃; separation yield: 53.55 percent;¹H NMR(400MHz,CDCl₃):δ8.07(d,J＝9.0Hz,2H),7.86(s, 1H),7.00(d,J＝9.0Hz,2H),4.42(q,J＝7.1Hz,2H),3.87(s,3H),1.42(t,J＝ 7.1Hz,3H)。

example 5: synthesis of ethyl 5- (2-naphthyl) oxazole-4-carboxylate

In a 50mL stoppered tube, 3.54mmol of 2-naphthaldehyde, 1.77mmol of triethylenediamine, 0.71mmol of cuprous chloride, 4mL of dry absolute ethanol, and 3.54mmol of ethyl isocyanoacetate were added. The reaction solution was heated at 50 ℃ for 12 hours under nitrogen. The reaction was stopped, 20mL of water was added to the system, followed by extraction with ethyl acetate (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to give a crude product, which was separated by column chromatography (EA: PE ═ 1:4) to give ethyl 5- (2-naphthyl) oxazole-4-carboxylate as a white solid with a melting point: 94-96 ℃; the isolation yield was 63.35%;¹H NMR(400MHz,CDCl₃):δ8.68(s,1H),8.12–8.09(m,1H),7.99–7.86 (m,4H),7.59–7.51(m,2H),4.46(q,J＝7.1Hz,2H),1.43(t,J＝7.1Hz,3H)。

example 6: synthesis of ethyl 5- (2-thiazolyl) oxazole-4-carboxylate

In a 50mL stoppered tube, 3.54mmol of 2-formylthiazole, 3.54mmol of triethylamine, 0.71mmol of cuprous bromide, 4mL of dried N, N-dimethylformamide, and 3.54mmol of ethyl isocyanoacetate were added. The reaction solution was heated at 100 ℃ for 12 hours under nitrogen. The reaction was stopped, 20mL of water was added to the system, followed by extraction with ethyl acetate (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to give a crude product, which was separated by column chromatography (EA: PE ═ 1:4) to give ethyl 5- (2-thiazolyl) oxazole-4-carboxylate as a white solid with a melting point: 171 ℃ and 172 ℃; the isolation yield was 62.34%;¹H NMR(400MHz,CDCl₃):δ8.00(d,J＝3.0Hz,1H),7.94(s,1H),7.57(d,J＝3.0Hz,1H),4.44(q,J＝7.1Hz,2H), 1.40(t,J＝7.1Hz,3H)。

example 7: synthesis of ethyl 5- (2-thienyl) oxazole-4-carboxylate

In a 50mL stoppered tube, 3.54mmol of 2-thiophenecarboxaldehyde, 1.77mmol of triethylenediamine, 0.71mmol of cuprous bromide, 4mL of dry absolute ethanol, and 3.54mmol of ethyl isocyanoacetate were added. The reaction solution was heated at 100 ℃ for 10 hours under argon. Stopping the reaction, adding 20mL of water into the system, extracting with ethyl acetate (10mL multiplied by 3), combining organic layers, drying with anhydrous sodium sulfate, carrying out rotary evaporation to remove the organic solvent completely to obtain a crude product, and carrying out column chromatography separation (EA: PE ═ 1:4) to obtain 5- (2-thienyl) oxazole-4-ethyl formate as a light yellow liquid with the separation yield of 34.52%;¹H NMR (400MHz,CDCl3):δ8.11–8.07(m,1H),7.81(s,1H),7.54–7.53(m,1H), 7.17–7.15(m,1H),4.46(q,J＝7.1Hz,2H),1.44(t,J＝7.1Hz,3H)。

example 8: synthesis of ethyl 5- (4-quinolyl) oxazole-4-carboxylate

In a 50mL stoppered tube, 3.54mmol of 4-quinolinecarboxaldehyde, 3.54mmol of triethylamine, 1.06mmol of cuprous chloride, 4mL of dried N, N-dimethylformamide, and 3.54mmol of ethyl isocyanoacetate were added. In a nitrogen stripThe reaction solution was heated at 80 ℃ for 12 hours. Stopping the reaction, adding 20mL of water into the system, extracting with ethyl acetate (10mL multiplied by 3), combining organic layers, drying with anhydrous sodium sulfate, removing the organic solvent by rotary evaporation to obtain a crude product, and performing column chromatography separation (EA: PE ═ 1:4) to obtain 5- (4-quinolyl) oxazole-4-ethyl formate as a light yellow liquid; the isolation yield was 36.68%;¹H NMR (400MHz,CDCl₃):δ9.05(d,J＝4.4Hz,1H),8.22(d,J＝8.5Hz,1H),8.15(s, 1H),7.82–7.71(m,2H),7.66(d,J＝4.4Hz,1H),7.62–7.56(m,1H),4.25(q, J＝7.1Hz,2H),1.14(t,J＝7.1Hz,3H)。

example 9: synthesis of ethyl 5- (3-pyridyl) oxazole-4-carboxylate

Into a 50mL stoppered tube were added 3.54mmol of 3-pyridinecarboxaldehyde, 1.77mmol of triethylenediamine, 1.5mmol of cuprous chloride, 4mL of dried N, N-dimethylformamide, and 3.54mmol of ethyl isocyanoacetate. The reaction solution was heated at 50 ℃ for 10 hours under nitrogen. Stopping the reaction, adding 20mL of water into the system, extracting with ethyl acetate (10mL multiplied by 3), combining organic layers, drying with anhydrous sodium sulfate, removing the organic solvent by rotary evaporation to obtain a crude product, and performing column chromatography separation (EA: PE ═ 1:4) to obtain 5- (3-pyridyl) oxazole-4-ethyl formate as a light yellow liquid; the isolation yield was 39.01%;¹H NMR(400MHz,CDCl₃):δ9.24(s,1H),8.72(s,1H),8.51(d,J＝8.0Hz,1H), 8.00(s,1H),7.45(s,1H),4.44(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H)。

the above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.