阅读说明：本技术 维生素e微胶束参与的异恶唑啉类化合物的水相制备方法 (Aqueous phase preparation method of isoxazoline compound participated by vitamin E micelle ) 是由 王宇光 吴梦静 刘贝 陈圆 于 2021-08-12 设计创作，主要内容包括：本发明提供了一种式(Ⅲ)所示的异恶唑啉类化合物的水相合成方法,所述方法为：以式(I)所示的苯甲醛肟为底物,在质量浓度为1wt％-5wt％的表面活性剂的水溶液中,在N-氯代丁二酰亚胺、碱性物质的共同作用下,与式(II)所示的烯类化合物在室温下反应6-16h,所得反应液经后处理,得到式(Ⅲ)所示异恶唑啉类化合物；本发明以水作为反应溶剂,减少了有机溶剂的使用量,实现了溶剂的零排放。(The invention provides a water phase synthesis method of isoxazoline compounds shown in a formula (III), which comprises the following steps: taking benzaldehyde oxime shown in a formula (I) as a substrate, reacting with an alkene compound shown in a formula (II) in an aqueous solution of a surfactant with the mass concentration of 1-5 wt% under the combined action of N-chlorosuccinimide and an alkaline substance at room temperature for 6-16h, and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazoline compound shown in a formula (III); the invention takes water as a reaction solvent, reduces the use amount of an organic solvent and realizes zero emission of the solvent.)

1. An aqueous phase synthesis method of isoxazoline compounds shown in formula (III), which is characterized in that the method comprises the following steps:

taking benzaldehyde oxime shown in a formula (I) as a substrate, reacting with an alkene compound shown in a formula (II) in an aqueous solution of a surfactant with the mass concentration of 1-5 wt% under the combined action of N-chlorosuccinimide and an alkaline substance at room temperature for 6-16h, and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazoline compound shown in a formula (III); the mass ratio of the alkene compound shown in the formula (II), the benzaldehyde oxime shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is as follows: 1:1-1.5:1-1.8: 0.5-2;

wherein R is₁、R₂、R₃Each independently is H, C₁-C₆Alkyl, phenyl, Or R₃And R₁Are linked to form a ring and form a five-membered carbocyclic ring with the carbon between the two, and R₂Is H;

the alkaline substance is selected from one of the following substances: sodium hydroxide, potassium carbonate, triethylamine, piperidine; the surfactant is tocopherol methoxypolyethylene glycol succinic acid.

2. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the volume of the aqueous solution of the surfactant is 5 to 20mL/mmol in terms of the amount of the substance of the substituted alkyne represented by the formula (II).

3. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: r₁Is phenyl, hexyl,R₂Is H, methyl or phenyl, R₃Is H or phenyl.

4. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 3, characterized in that the alkene compound of formula (II) is one of the following:

5. the method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the mass concentration of the aqueous solution of the surfactant is 2 wt%.

6. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the reaction time was 8 h.

7. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the mass ratio of the alkene compound shown in the formula (II), the benzaldehyde oxime shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is 1:1.5:1.8: 1.3.

8. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the alkaline substance is triethylamine or piperidine.

9. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the alkaline substance is triethylamine.

10. The process for the aqueous synthesis of isoxazolines of formula (III) according to claim 1, characterized in that the work-up is: extracting the reaction liquid by using ethyl acetate, combining organic phases, evaporating the solvent under reduced pressure, and mixing solid residues by using petroleum ether with the volume ratio of 1: 2: and (3) carrying out column chromatography separation on the ethyl acetate mixed solution, collecting eluent containing the target product, and carrying out reduced pressure evaporation to remove the solvent to obtain the isoxazole compound shown in the formula (III).

Technical Field

The invention relates to a water-phase synthesis method of an isoxazoline compound participated by water-soluble vitamin E micelle.

Background

Isoxazolines, a five-membered heterocyclic compound containing N, O, have been widely used as intermediates in the synthesis of natural products with biological activity. Isoxazolines also act as the molecular skeleton of drugs, for example, in the novel broad spectrum veterinary drugs like frairan, valdecoxib, which is an anti-inflammatory drug, and flucloxacillin, which is an antibacterial drug, isoxazolines all act as the molecular skeleton. In addition, it is also widely used in the synthesis of antidepressants, antituberculosis drugs, and the like. Due to their unique heterocyclic structures, isoxazolines have been the subject of intense research.

Micheli et al, 1986, achieved oxime and olefin in NaHCO₃The 1, 3-dipolar epoxidation reaction is realized in the presence of the catalyst, bromine substituted isoxazoline is generated at the same time, and then the synthesis of the three-position methoxy isoxazoline is realized under the action of alkali and methanol. The subject group of the good strategy in 2020 realized the synthesis of the final product isoxazoline derivative by the steps of 1, 3-dipolar cycloaddition and the like under the catalytic action of Cu, wherein the nitrogen source and the oxygen source of the isoxazoline derivative in the reaction are both derived from nitro compounds (formula I). Study by Xubin et al found Cu (NO)₃)₂Mediated [2+2+1 ] of alkenes and alkynes]Cyclization reaction to synthesize isoxazoline.

Is like

To reduce the impact on tolerance and regioselectivity during isoxazoline synthesis, korean ice et al first initiated a free-radical cyclization reaction of β, γ -unsaturated alkene oxime molecules in 2012 with excess TEMPO (formula two). In the reaction process, TEMPO is used as a free radical trapping agent to capture an isoxazoline skeleton intermediate, so that the target molecule isoxazoline is obtained. 2016, et al suggested that copper acetate also catalyzes the free radical reaction of β, γ -and γ, δ -unsaturated ketoximes with electron-rich aryl and aliphatic amines, and can be used to synthesize isoxazolines and their derivatives.

Formula II

However, these reactions have the disadvantages of low yield, many synthesis steps, severe reaction conditions in part, high toxicity of the catalyst used, expensive price in part, and the like. Therefore, it is desirable to establish a simple synthesis method for preparing isoxazoline by aqueous 1, 3-dipolar cycloaddition reaction involving TPGS-750-M (water-soluble vitamin E) micelles (micelle). Since 2 wt.% of the TPGS-750-M aqueous solution readily formed micelles, the hydrophilic ends (PEG ends) of the micelles faced outward, dispersed among the aqueous phase; and the oleophilic end (vitamin E end) faces inwards, so that an oleophilic environment is formed inside the micelle for the chemical reaction to complete, and the chemical reaction is carried out in the water phase. Compared with the prior method, the method has the main advantages that water is used as a solvent for reaction, the method is green and environment-friendly, the reaction condition is simple, the yield is high, and the purity is high.

Disclosure of Invention

In order to solve the problems of high pollution, more wastes and the like in the prior art, the invention provides a green and simple synthesis method of isoxazoline compounds shown in formula (III), which completes the synthesis of the isoxazoline compounds in a water phase under the participation of micro micelle formed by TPGS-750-M.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a water phase synthesis method of isoxazoline compounds shown in a formula (III), which comprises the following steps:

taking benzaldehyde oxime shown in formula (I) as a substrate, reacting with an alkene compound shown in formula (II) in an aqueous solution of a surfactant with the mass concentration of 1 wt% -5 wt% (preferably 2 wt%) under the combined action of N-chlorosuccinimide (NCS) and an alkaline substance at room temperature for 6-16h (preferably 8h), and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazoline compound shown in formula (III); the amount ratio of the alkene compound shown in the formula (II), the benzaldehyde oxime shown in the formula (I), N-chlorosuccinimide and alkaline substances is 1:1-1.5:1-1.8:0.5-2 (preferably 1:1.5:1.8: 1.3);

wherein R is₁、R₂、R₃Each independently is H, C₁-C₆Alkyl, phenyl,OrOr R₃And R₁Are linked to form a ring and form a five-membered carbocyclic ring with the carbon between the two, and R₂Is H;

the alkaline substance is selected from one of the following substances: sodium hydroxide (NaOH), potassium carbonate (K)₂CO₃) Triethylamine (Et)₃N), piperidine (preferably triethylamine or piperidine, most preferably triethylamine); the surfactant is tocopherol methoxypolyethylene glycol succinate (TPGS-750-M).

The reaction formula is as follows:

the invention recommends that the reaction be carried out under stirring conditions.

Further, the volume of the aqueous solution of the surfactant is 5 to 20mL/mmol (preferably 10mL/mmol) in terms of the amount of the substance of the substituted alkyne represented by the formula (II).

Preferably, R₁Is phenyl, hexyl,OrR₂Is H, methyl or phenyl, R₃Is H or phenyl.

Further preferably, the alkene compound represented by the formula (II) is one of the following:

further, the post-treatment comprises the following steps: extracting the reaction liquid by using ethyl acetate, combining organic phases, evaporating the solvent under reduced pressure, and mixing solid residues by using petroleum ether with the volume ratio of 1: 2: and (3) carrying out column chromatography separation on the ethyl acetate mixed solution, collecting eluent containing the target product, and carrying out reduced pressure evaporation to remove the solvent to obtain the isoxazole compound shown in the formula (III).

Further, the surfactants used in the invention, namely Sodium Dodecyl Sulfate (SDS), polyethylene glycol octyl phenyl ether (Trition X-100) and Cetyl Trimethyl Ammonium Bromide (CTAB), are commercially available products, and the tocopherol methoxypolyethylene glycol succinate (TPGS-750-M) can be a commercially available product, which is self-made in the invention, and is preferably 2 wt.% of TPGS-750-M;

further preferably, the TPGS-750-M is prepared as follows:

(1) triethylamine was added to a toluene solution of tocopherol and succinic anhydride with stirring. Stirring was then continued. After completion of the reaction, water was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were washed with 1mol/L hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure in vacuo to give a yellow liquid, which was purified using silica gel column chromatography. Removing the solvent from the eluent under vacuum reduced pressure to obtain tocopherol succinate in a white solid state;

(2) the toluene mixture containing tocopherol succinate, polyethylene glycol monomethyl ether-750 and p-toluenesulfonic acid was refluxed using a dean-Stark trap. After the reaction was completed, it was cooled to room temperature, and the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure in vacuo to give the desired product.

Compared with the prior art, the invention has the beneficial effects that: water is used as a reaction solvent, so that the use amount of an organic solvent is reduced, and zero emission of the solvent is realized; the excellent physical and chemical properties of water are fully utilized, the reaction condition is mild and efficient, and the surfactant TPGS-750-M can be recycled through treatment, so that the method completely accords with the environment-friendly principle; the reaction substrate has wide applicability, can be applied to synthesizing isoxazoline from aldoxime and olefin, and provides a simple and environment-friendly preparation method for synthesizing the isoxazoline.

Drawings

FIG. 1 is a water soluble vitamin E (TPGS-750-M)¹H NMR spectrum;

FIG. 2 is a water soluble vitamin E (TPGS-750-M)¹³C NMR spectrum.

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:

further, the surfactants Sodium Dodecyl Sulfate (SDS) and polyethylene glycol octyl phenyl ether (Trition X-100) used in the invention are commercially available products, and the tocopherol methoxypolyethylene glycol succinate solution (TPGS-750-M, water-soluble vitamin E) can be purchased, but the TPGS-750-M of the invention is self-made, and preferably 2 wt.% TPGS-750-M.

The surfactant TPGS-750-M used in the examples was self-made and the preparation method was as follows:

the first step is as follows: to a stirred solution of tocopherol (4.3g, 10mmol) and succinic anhydride (1.5g, 15mmol) in toluene (20mL) was added triethylamine (0.35mL, 2.5 mmol). Subsequently, stirring was continued at 60 ℃ for 5 h. After completion of the reaction, water (10mL) was added to the reaction mixture, followed by extraction with dichloromethane (3X 10 mL). The combined organic layers were washed with 1mol/L hydrochloric acid (3X 50mL) and water (2X 30mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude tocopherol succinate, which was finally recrystallized to give tocopherol succinate as a white solid (5.25g, 99% yield). The crystallization conditions were: the crystallization time is 26 hours, the crystallization temperature is 4 ℃, and the dosage of n-hexane/tocopherol succinate crude product is 8 mL/g.

The second step is that: a mixture of tocopherol succinate (2.97g, 5.6mmol), polyethylene glycol monomethyl ether-750 (4 g, 5.33mmol) and p-toluenesulfonic acid (0.15g, 0.79mmol) in toluene (20mL) was refluxed using a dean-Stark trap for 5 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (3X 10 mL). The combined organic layers were washed with saturated sodium bicarbonate (3 × 50mL), saturated sodium chloride (2 × 30mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure in vacuo to give the title product (6.6g, 98%) in 80% yield as a pale yellow waxy solid.

¹H NMR(400MHz,CDCl₃)δ4.27(m,2H),3.70-3.65(m,60H),3.55(m,2H),3.38 (s,3H),2.93(t,J＝7.2Hz,2H),2.79(t,J＝7.2Hz,2H),2.58(t,J＝6.8Hz,2H),2.08 (s,3H),2.01(s,3H),1.97(s,3H),1.81-1.75(m,2H),1.52(m,3H),1.38(m,3H), 1.27-1.23(m,12H),1.14(s,3H),1.07(s,3H),0.87-0.84(m,12H)；¹³C NMR(100 MHz,CDCl₃) δ 172.2,170.9,149.5,140.6,126.7,125.0,123.0,117.4, 75.1,72.0, 70.6,70.58-70.33(m, carbons), 69.1,64.0,59.0,39.4,37.55-37.29(m, carbons), 32.79-32.69(m,4C),29.2,28.9,28.0,24.816,24.805,24.5,22.8,22.7,21.1,20.6, 19.77-19.61(m, carbons), 113.0, 12.1,11.8.

Example 1: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A50 mL reaction flask was charged with 241mg (1.8mmol) NCS and 182mg (1.5mmol) benzaldoxime (I), then 10mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and after stirring at room temperature for 4 hours, 182. mu.L (1.3mmol) of Et was added in that order₃N and 104mg (1mmol) of styrene (II-1), reacting for 8 hours at room temperature, finishing the reaction, adding 15mL of ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 15mL of ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, extracting TPGS-750-M in the lower aqueous phase with dichloromethane, separating and recovering, see example 5), combining the two obtained organic phases, evaporating the solvent under reduced pressure, separating a solid residue through column chromatography, and eluting with petroleum ether: ethyl acetate (v/v, same below) 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 217.7mg of 3, 5-diphenylisoxazoline shown in the formula (III-1) as a white solid with the yield of 97.5%. Purity by HPLC 98.6%. The structure of formula (III-1) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.73(dd,J＝6.6,2.9Hz,2H),7.46-7.38(m,7H), 7.37-7.33(m,1H),5.76(dd,J＝11.0,8.3Hz,1H),3.80(dd,J＝16.5,11.0Hz,1H), 3.37(dd,J＝16.6,8.3Hz,1H)；¹³C NMR(126MHz,CDCl3)δ156.08,140.93, 130.10,129.49,128.73,128.71,128.20,126.73,125.85,82.56,43.13；GC–MS(EI):m/z 223[M⁺].

example 2: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A50 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring at room temperature for 4 hours, 7. mu.L (0.05mmol) of Et was added in succession₃N and 10.4mg (0.1mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the two organic phases, evaporating the solvent under reduced pressure, separating the residue by column chromatography, eluting the eluentIs petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 13.8mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 62%. Purity by HPLC was 95%.

Example 3: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring at room temperature for 4 hours, 21. mu.L (0.15mmol) of Et was added sequentially₃N and 10.4mg (0.1mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 21.0mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 94 percent. Purity by HPLC was 97%.

Example 4: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring the mixture at room temperature for 4 hours, 28. mu.L (0.2mmol) Et was added sequentially₃N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the 3, 5-diphenyl-4, 5-dihydroisoxazole shown in the formula (III-1)Lin 20.3mg, white solid, yield 91%. Purity by HPLC was 96.9%.

Example 5: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

To a 500mL reaction flask was added 2.41g (18mmol) NCS, 1.82g (15mmol) benzaldoxime (I-1), then 100mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and the mixture was stirred at room temperature for 4.5 hours. Then, 1.82mL (13mmol) of Et was added₃N, 1.04g (10mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 50mL of ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper ethyl acetate phase, adding 50mL of ethyl acetate into a lower water phase, stirring for 5min, standing for layering, collecting an upper ethyl acetate phase, extracting TPGS-750-M in the lower water phase twice with 50mL of dichloromethane respectively, combining dichloromethane extraction solutions, evaporating dichloromethane under reduced pressure, and recovering to obtain 1.6g of TPGS-750-M; and (3) combining the ethyl acetate phases obtained in the two steps, evaporating the solvent under reduced pressure, and separating solid residues by column chromatography, wherein the eluent is petroleum ether: ethyl acetate ═ 1: and 2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1). 2.188g of white solid, yield 98%. Purity by HPLC 98.9%.

Example 6: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS and 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and the mixture was stirred at room temperature for 4 hours, then 6mg (0.15mmol) NaOH and 10.4mg (0.1mmol) styrene (II-1) were added in that order, and reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 3.8mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 17%.

Example 7: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and after stirring the mixture at room temperature for 4 hours, 20.7mg (0.15mmol) of K was added in succession₂CO₃10.4mg (0.1mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 2min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 2min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 2.9mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 13%.

Example 8: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 30.7mg (0.13mmol) of Cs are added₂CO₃10.4mg (0.1mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After completion of the reaction, the reaction mixture was checked by TLC, and it was found that the target product (III-1) was not produced.

Example 9: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS and 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and the mixture was stirred at room temperature for 4 hours, then 13. mu.L (0.13mmol) piperidine and 10.4mg (0.1mmol) styrene (II-1) were added in that order and reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 2min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 2min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 17.2mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 77 percent. Purity by HPLC was 96%.

Example 10: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring the mixture at room temperature for 4 hours, 14. mu.L (0.1mmol) Et was added sequentially₃N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 2min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 2min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.8mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 93 percent. Purity by HPLC was 97.1%.

Example 11: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

To a 5mL reaction flask were added 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I), then 1mL of SDS (15 mol%) was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL of ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, collecting the upper organic phase, adding 2mL of ethyl acetate into the lower aqueous phase, stirring for 5min, standing for layering, collecting the upper organic phase, and collecting the lower organic phaseCombining the organic phases obtained in two times, evaporating the solvent under reduced pressure, and separating the residue by column chromatography, wherein the eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 12.7mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 57%.

Example 12: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

To a 5mL reaction flask were added 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I), then 1mL of TritonX-100 was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 15.0mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 67%.

Example 12: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) of NCS and 18.2mg (0.15mmol) of benzaldoxime (I), 1mL of CTAB was added to the flask, and after the mixture was stirred at room temperature for 4 hours, 18.2. mu.L (0.13mmol) of Et was further added₃N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the 3, 5-diphenyl-4, 5-di-benzene shown in the formula (III-1)Hydroisoxazoline 4.9mg, white solid, yield 22%.

Example 13: synthesis of 3-phenyl-3 a,5,6,6 a-tetrahydrocyclopentylisoxazoline

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 6.8mg (0.1mmol) of cyclopentene (II-2) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 18.35mg of 3-phenyl-3 a,5,6,6 a-tetrahydrocyclopentylisoxazoline shown in the formula (III-2) as a white solid with the yield of 98%. Purity by HPLC was 99%. The structure of formula (III-2) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.76-7.67(m,2H),7.44-7.37(m,3H),5.23(dd,J ＝8.8,4.9Hz,1H),4.14-3.97(m,1H),2.23-2.16(m,1H),2.01-1.94(m,1H), 1.93-1.86(m,1H),1.82-1.72(m,2H),1.61-1.50(m,1H)；¹³C NMR(126MHz, CDCl₃)δ158.47,129.60,129.41,128.67,126.92,87.71,52.06,35.84,31.59,23.44； GC-MS(EI):m/z 187[M⁺].

example 14: synthesis of 3,4, 5-triphenyl-4, 5-dihydroisoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring the mixture at room temperature for 4 hours, 18.2. mu.L (0.13mmol) Et was added sequentially₃N, 18mg (0.1mmol) of 1, 2-diphenylethylene (II-3) were reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 28.4mg of 3,4, 5-triphenyl-4, 5-dihydro-isoxazoline shown in the formula (III-3) and white solid with the yield of 95%. Purity by HPLC 98.7%. The structure of formula (III-3) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.65-7.59(m,2H),7.43-7.28(m,13H),5.55(d,J ＝5.5Hz,1H),4.71(d,J＝5.5Hz,1H)；¹³C NMR(126MHz,CDCl₃)δ157.59, 140.87,139.19,129.88,129.46,128.89,128.59,128.27,127.88,127.57,127.36,125.33,91. 75,63.30；GC-MS(EI):m/z 299[M⁺].

example 15: synthesis of 5-hexyl 3-phenyl-4, 5-dihydroisoxazoline

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 11.2mg (0.1mmol) of oct-1-ene (II-4) are reacted at room temperature for 8 h. After the reaction, 2mL of ethyl acetate was added to the reaction flask, followed by stirringStirring for 5min, standing for layering, collecting upper organic phase, adding 2mL ethyl acetate into lower water phase, stirring for 5min, standing for layering, collecting upper organic phase, mixing the organic phases, evaporating under reduced pressure to remove solvent, separating residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 21.8mg of 5-hexyl 3-phenyl-4, 5-dihydro isoxazoline shown in the formula (III-4) as a white solid with the yield of 94%. Purity by HPLC 98.3%. The structure of formula (III-4) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.72-7.64(m,2H),7.47-7.36(m,3H),4.81-4.68 (m,1H),3.40(dd,J＝16.4,10.4Hz,1H),2.98(dd,J＝16.4,8.2Hz,1H),1.87-1.76 (m,1H),1.67-1.59(m,1H),1.52-1.28(m,8H),0.91(t,J＝6.7Hz,3H)；¹³C NMR (126MHz,CDCl₃)δ156.36,129.98,129.84,128.64,126.57,81.51,39.94,35.35,31.72, 29.12,25.49,22.55,14.03；GC-MS(EI):m/z 231[M⁺].

example 16: synthesis of 5-methyl-3, 5-diphenyl-4, 5-dihydroisoxazoline

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 11.8mg (0.1mmol) of 2-phenyl-1-propene (II-5) are reacted at room temperature for 8 h. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the 5-methyl-3, 5-diphenyl-4, 5-dihydro-isoxazole shown in the formula (III-5)Oxazoline 22.5mg, white solid, yield 95%. Purity by HPLC 98.4%. The structure of formula (III-5) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.70-7.66(m,2H),7.52(dd,J＝7.9,1.6Hz,2H), 7.43-7.38(m,5H),7.31(d,J＝7.6Hz,1H),3.58-3.46(m,2H),1.83(s,3H)；¹³C NMR(126MHz,CDCl₃)δ156.16,145.51,129.98,129.92,1 2 8.68,128.51,127.38, 126.57,124.70,88.10,48.75,28.24；GC-MS(EI):m/z 237[M⁺].

example 17: synthesis of 3-phenyl-4, 5-dihydroisoxazoline-5-carboxylic acid ethyl ester

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 10.0mg (0.1mmol) of ethyl acrylate (II-6) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.6mg of 3-phenyl-4, 5-dihydro-isoxazoline-5-carboxylic acid ethyl ester shown in the formula (III-6) as a yellow solid with the yield of 94%. Purity by HPLC 98%. The structure of formula (III-6) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.89-7.80(m,2H),7.50-7.47(m,3H),5.17(s, 1H),4.29-4.25(m,2H),3.65-3.63(m,2H),1.34(t,J＝7.1Hz,3H)；13C NMR(126 MHz,CDCl₃)δ170.13,155.95,130.43,128.73,128.58,126.88,78.07,61.92,38.80,14.05； GC-MS(EI):m/z 219[M⁺].

example 19: synthesis of 3-phenyl-5- (trimethylsilyl) -4, 5-dihydroisoxazoline

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 11.4mg (0.1mmol) of allyltrimethylsilane (II-7) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 20mg of 3-phenyl-5- (trimethylsilyl) -4, 5-dihydroisoxazoline represented by the formula (III-7) as a white solid with a yield of 91%. Purity by HPLC was 97.3%. The structure of formula (III-7) is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.67(dd,J＝6.6,3.1Hz,2H),7.44-7.37(m,3H), 3.40(dd,J＝16.2,9.8Hz,1H),2.90(dd,J＝16.1,9.2Hz,1H),1.34-1.06(m,2H), 0.13(s,9H)；¹³C NMR(126MHz,CDCl₃)δ156.71,129.80,128.63,126.50,80.18, 42.15,24.29,-0.99；GC-MS(EI):m/z 219[M⁺].

example 20: synthesis of 5-phenyl-3- [ (2, 4-dinitro) ] isoxazoline

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 31.7mg (0.15mmol) 2, 4-dinitrobenzaldehyde oxime (I-12), and 1mL freshly prepared 2 wt.% TPGS-750-M was dissolved in waterThe solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively₃N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After completion of the reaction, the reaction mixture was checked by TLC, and it was found that the objective product (III-8) was not produced.

Example 21: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A50 mL reaction flask was charged with 241mg (1.8mmol) NCS and 182mg (1.5mmol) benzaldoxime (I), then 10mL of a freshly prepared 1 wt.% aqueous solution of TPGS-750-M was added to the flask, and after stirring at room temperature for 4 hours, 182. mu.L (1.3mmol) of Et was added in that order₃N and 104mg (1mmol) of styrene (II-1), reacting for 8 hours at room temperature, finishing the reaction, adding 15mL of ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 15mL of ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining organic phases obtained in two times, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 149.6 mg of 3, 5-diphenylisoxazoline shown in the formula (III-1) as a white solid with the yield of 67%.

Example 22: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline

A50 mL reaction flask was charged with 241mg (1.8mmol) NCS and 182mg (1.5mmol) benzaldoxime (I), then 10mL of a freshly prepared 5 wt.% aqueous TPGS-750-M solution was added to the flask, stirred at room temperature for 4 hours, and then 182. mu.L (1.3mmol) Et was added sequentially₃N and 104mg (1mmol) of styrene (II-1) react at room temperature for 8 hours, then the reaction is finished, 15mL of ethyl acetate is added into a reaction bottle, the mixture is stirred for 5 minutes and then stands for layering, and the upper layer is collectedAnd (3) after an organic phase, adding 15mL of ethyl acetate into a lower water phase, stirring for 5min, standing for layering, collecting an upper organic phase, (extracting TPGS-750-M in the lower water phase by using dichloromethane, separating and recovering, see example 5), combining the organic phases obtained by two times, evaporating under reduced pressure to remove the solvent, and separating a solid residue by column chromatography, wherein an eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 180.9mg of 3, 5-diphenylisoxazoline shown as the formula (III-1) as a white solid with the yield of 81 percent. Purity by HPLC was 96.1%.