CN112028848A - Method for preparing isoxazoline - Google Patents

Method for preparing isoxazoline Download PDF

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CN112028848A
CN112028848A CN202010943195.9A CN202010943195A CN112028848A CN 112028848 A CN112028848 A CN 112028848A CN 202010943195 A CN202010943195 A CN 202010943195A CN 112028848 A CN112028848 A CN 112028848A
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CN112028848B (en
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万小兵
马亮
成雄略
江港钟
陶苏艳
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Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to a method for preparing isoxazoline, which comprises the following steps: olefin, diazo compound and tert-butyl nitrite react in an organic solvent at 25-50 ℃ under the action of a Lewis acid catalyst, and isoxazoline is obtained after the reaction is completed. The method takes the Lewis acid as the catalyst for synthesizing the isoxazoline, has mild reaction conditions, can be carried out at the temperature as low as room temperature, avoids the use of transition metal, and has higher product yield.

Description

Method for preparing isoxazoline
Technical Field
The invention relates to the technical field of isoxazoline synthesis, in particular to a method for preparing isoxazoline.
Background
Isoxazolines are core backbones that are widely found in natural products, pharmaceutical molecules, and agrochemicals, and are also widely used as ligand molecules for transition metals. Currently, although there are many methods for preparing isoxazolines, there are significant disadvantages, such as: the reaction conditions are harsh, the raw material preparation is complicated, and expensive and harmful transition metals and the like are needed. For example:
(1) the Xu Bin subject group reports work of preparing isoxazoline by in-situ formation of nitrile oxide intermediate from alkyne and copper nitrate and further dipolar cycloaddition with alkene, but the reaction has higher yield only under nitrogen atmosphere, meanwhile, equivalent transition metal is inevitably required to be used, and more limitations are provided for synthesis of drug molecules and the like in later real sense (see: Xu Bin; Angew. chem., int. Ed.2015,54,8795);
(2) the Kang Yanbiao topic group reports a process for the preparation of isoxazolines starting from alkenyl oximes. However, on one hand, the reaction needs to be smoothly converted under the protection of low temperature and oxygen, and on the other hand, the preparation of the alkenyl oxime is relatively complicated, so that the applicable range of the substrate is limited (see: Kang Yanbiao; adv. Synth. Catal.2016,358, 1942);
(3) recently, the Wan Xiaobing topic group reported the reaction of tert-butyl nitrite initiated diazo compounds with an olefin tri-component to produce isoxazolines. But the high temperature, transition metal and alkali are needed in the reaction, which limits the application of the method in preparing bioactive molecules (see: Wan Xiaoobing; org. Lett.2017,19,5896, CN 107118171A).
In summary, it is necessary to develop a method for effectively synthesizing isoxazoline compounds, which has abundant raw material sources, low cost, safety, simple operation, mild conditions and avoids the use of transition metals.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a method for preparing isoxazoline, which takes Lewis acid as a catalyst for synthesizing the isoxazoline, has mild reaction conditions, can be carried out at room temperature, avoids the use of transition metal and has higher product yield.
The method for preparing isoxazoline comprises the following steps:
the method comprises the following steps of reacting olefin shown in a formula (1), diazo compound shown in a formula (2) and tert-butyl nitrite in an organic solvent at 25-50 ℃ under the action of a Lewis acid catalyst, and obtaining isoxazoline shown in a formula (3) after complete reaction:
Figure BDA0002674368690000021
wherein R is1Selected from C1-C12 alkoxycarbonyl, naphthyl, phenyl or substituted phenyl, the substituents on the substituted phenyl ring being selected from C1-C6 alkyl, halogen, C1-C6 fluoroalkyl, cyano, acyloxy substituted C1-C6 alkyl or C1-C6 alkyl acrylate;
R2is selected from
Figure BDA0002674368690000022
Wherein the content of the first and second substances,
R3selected from C1-C6 alkyl, C1-C6 fluoroalkyl, benzyl, phenyl, thienyl or thienyl substituted C1-C6 alkyl;
R4selected from phenyl or benzenesulfonyl substituted C1-C6 alkyl.
Further, the dosage of the Lewis acid catalyst is 5 to 20 percent of the molar weight of the olefin. Preferably, the lewis acid catalyst is used in an amount of 10% to 20%, more preferably 10%, of the molar amount of the olefin.
Further, the Lewis acid catalyst is one or more of boron trifluoride diethyl etherate, copper trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, ferric trichloride and zinc chloride. Preferably, the lewis acid catalyst is boron trifluoride etherate.
Further, the molar ratio of the olefin, the diazo compound and the tert-butyl nitrite is 1:1:1 to 1:2: 2. Preferably, the molar ratio of olefin, diazo compound and tert-butyl nitrite is from 1:1.5:2 to 1:2:2, more preferably 1:2: 2.
Further, R1Is selected from methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, isobornyloxycarbonyl, naphthyl, phenyl or mono-substituted phenyl, wherein the substituent on the mono-substituted phenyl is selected from methyl, tert-butyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, acetoxy or methyl acrylate.
Further, R2Is selected from
Figure BDA0002674368690000023
Wherein the content of the first and second substances,
R3selected from ethyl, trifluoromethyl substituted methyl, benzyl, phenyl or thienyl substituted ethyl;
R4selected from phenyl or phenylsulfo substituted ethyl.
Preferably, the diazo compound is a compound of one of the following structural formulae:
Figure BDA0002674368690000031
further, the reaction time is 12-24 hours. Preferably, the reaction time is 12 hours.
Preferably, the reaction temperature is 25-30 ℃, more preferably 25 ℃.
Further, the organic solvent comprises one or more of petroleum ether, ethyl acetate, tetrahydrofuran, nitromethane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, toluene and 1, 2-dichloroethane. Preferably, the organic solvent is acetonitrile.
Further, the reaction was carried out in air.
Further, after the reaction is finished, the method also comprises the step of quenching the reaction by using a saturated sodium chloride solution and separating the isoxazoline.
Further, after quenching reaction, extracting the product by ethyl acetate, removing the solvent, adsorbing by silica gel, and then obtaining the product isoxazoline by column chromatography.
Taking diazo compound as ethyl diazoacetate as an example, the principle of the method for preparing isoxazoline is as follows:
Figure BDA0002674368690000032
by the scheme, the invention at least has the following advantages:
1. the method uses the Lewis acid as the catalyst to realize the three-component reaction of olefin, diazo compound and tert-butyl nitrite to prepare the isoxazoline, and compared with the prior art, which has the disadvantages of difficult raw material preparation, large raw material consumption and harsh conditions, the method has the advantages of more economical reaction, wider substrate universality, easily obtained raw materials and easier later-stage functionalization.
2. The method disclosed by the invention has mild reaction conditions, can be carried out in the air at normal temperature, has less catalyst consumption, good gram-scale reaction and simple and convenient post-treatment, and is favorable for the application in drug molecular synthesis and large-scale industrialization.
3. The method has the advantages of cheap and easily obtained raw materials such as reactants, catalysts and the like, reasonable reaction composition, no need of ligands and transition metal catalysts, high atom economy, few reaction steps, and high yield by only one-step reaction, and meets the requirements and directions of modern green chemistry and pharmaceutical chemistry.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Olefin, tert-butyl nitrite of the inventiontBuONO), catalysts and solvents are commercially available and can be purchased directly; the partial diazo compound used in the invention is a commercial product and can be directly purchased, or the diazo compound can be reacted with bromoacetyl bromide through alcohol combination to generate corresponding bromide, and the bromide is reacted with bis-p-toluenesulfonyl hydrazide (TsNHNHTs) to obtain the corresponding diazo compound.
Example one
Figure BDA0002674368690000041
To a reaction flask were added acetonitrile (40mL), compound 1a (10mmol,1.78g), compound 2a (20mmol,2.40g), compound 3(20mmol,2.17g), and boron trifluoride diethyl etherate (1mmol, 263. mu.L) as a catalyst, in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the product by using a saturated sodium chloride solution, extracting the product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product 4a, wherein the yield is 80%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.40(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),5.76(dd,J＝11.6,9.0Hz,1H),4.36(q,J＝7.1Hz,2H),3.60(dd,J＝17.8,11.6Hz,1H),3.23(dd,J＝17.8,9.0Hz,1H),1.37(t,J＝7.1Hz,3H),1.31(s,9H).；13C NMR(101MHz,CDCl3)160.5,151.7,151.1,136.3,125.69,125.66,84.9,62.0,41.1,34.5,31.2,14.0；HRMS(ESI-TOF):Anal.Calcd.For C16H21NO3+H+:276.1594,Found:276.1612(M+H+)；IR(neat,cm-1):υ2963,2906,2870,1717,1589,1245,1119,1110,923,832,749。
Example two
Figure BDA0002674368690000051
Add acetonitrile (2.0mL), Compound 1b (0.5mmol,53.2mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the product by using a saturated sodium chloride solution, extracting the product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product 4b, wherein the yield is 74%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.47-7.21(m,5H),5.77(dd,J＝11.6,8.9Hz,1H),4.35(q,J＝7.1Hz,2H),3.63(dd,J＝17.8,11.6Hz,1H),3.21(dd,J＝17.8,8.9Hz,1H),1.37(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)160.4,151.0,139.4,128.7,128.5,125.7,84.8,62.0,41.3,14.0；HRMS(ESI-TOF):Anal.Calcd.For C12H13NO3+Na+:242.0788,Found:242.0797(M+Na+)；IR(neat,cm-1):υ3064,2981,2936,2875,1713,1592,1250,1112,920,760,743,694。
EXAMPLE III
Figure BDA0002674368690000052
Add acetonitrile (2.0mL), Compound 1c (0.5mmol,61.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the product by using a saturated sodium chloride solution, extracting the product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4c, wherein the yield is 67%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.35-7.28(m,2H),7.14-7.00(m,2H),5.77(dd,J＝11.6,8.9Hz,1H),4.36(q,J＝7.1Hz,2H),3.64(dd,J＝17.8,11.6Hz,1H),3.18(dd,J＝17.8,8.9Hz,1H),1.38(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)162.7(d,J＝247.7Hz),160.3,151.1,135.2(d,J＝3.1Hz),127.7(d,J＝8.1Hz),115.7(d,J＝21.8Hz),84.2,62.1,41.4,14.0；19F NMR(376MHz,CDCl3)-113.08；HRMS(ESI-TOF):Anal.Calcd.For C12H12FNO3+H+:238.0874,Found:238.0870(M+H+)；IR(neat,cm-1):υ2985,2939,2909,1719,1512,1243,1120,920,835,751。
Example four
Figure BDA0002674368690000061
Add acetonitrile (2.0mL), Compound 1d (0.5mmol,69.3mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4d, wherein the yield is 75%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.35(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),5.76(dd,J＝11.6,8.7Hz,1H),4.36(q,J＝7.1Hz,2H),3.65(dd,J＝17.8,11.6Hz,1H),3.17(dd,J＝17.8,8.7Hz,1H),1.37(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)160.3,151.0,138.0,134.4,128.9,127.2,84.0,62.1,41.4,14.0；HRMS(ESI-TOF):Anal.Calcd.For C12H12ClNO3+Na+:276.0398,Found:276.0391(M+Na+)；IR(neat,cm-1):υ2985,2964,2938,2853,1713,1594,1252,1113,1091,920,831。
EXAMPLE five
Figure BDA0002674368690000062
Add acetonitrile (2.0mL), Compound 1e (0.5mmol,59.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4e, wherein the yield is 75%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.24-7.14(m,4H),5.73(dd,J＝11.6,9.0Hz,1H),4.35(q,J＝7.1Hz,2H),3.60(dd,J＝17.8,11.6Hz,1H),3.19(dd,J＝17.8,9.0Hz,1H),2.34(s,3H),1.37(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)160.5,151.0,138.4,136.4,129.4,125.8,84.9,62.0,41.2,21.0,14.0；HRMS(ESI-TOF):Anal.Calcd.For C13H15NO3+Na+:256.0944,Found:256.0953(M+Na+)；IR(neat,cm-1):υ3014,2981,2920,2874,1713,1593,1273,1252,1112,921,812,749。
EXAMPLE six
Figure BDA0002674368690000071
Add acetonitrile (2.0mL), Compound 1f (0.5mmol,64.6mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4f, wherein the yield is 69%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.70(d,J＝8.2Hz,2H),7.46(d,J＝8.2Hz,2H),5.86(dd,J＝11.7,8.3Hz,1H),4.36(q,J＝7.1Hz,2H),3.73(dd,J＝17.8,11.7Hz,1H),3.18(dd,J＝17.8,8.3Hz,1H),1.38(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)160.0,151.0,144.7,132.6,126.3,118.2,112.3,83.4,62.3,41.6,14.0；HRMS(ESI-TOF):Anal.Calcd.For C13H12N2O3+Na+:267.0740,Found:267.0756(M+Na+)；IR(neat,cm-1):υ3095,2959,2922,2852,2225,1717,1268,1234,1151,1116,910,828,749。
EXAMPLE seven
Figure BDA0002674368690000072
Add acetonitrile (2.0mL), Compound 1g (0.5mmol,81.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain 4g of a product, wherein the yield is 75%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.33(d,J＝8.5Hz,2H),7.10(d,J＝8.5Hz,2H),5.77(dd,J＝11.6,8.7Hz,1H),4.35(q,J＝7.1Hz,2H),3.63(dd,J＝17.8,11.6Hz,1H),3.19(dd,J＝17.8,8.7Hz,1H),2.29(s,3H),1.36(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)169.1,160.2,151.0,150.6,136.9,126.9,121.9,84.1,62.0,41.3,20.9,13.9；HRMS(ESI-TOF):Anal.Calcd.For C14H15NO5+H+:278.1023,Found:278.1028(M+H+)；IR(neat,cm-1):υ3070,2988,2939,2911,1747,1711,1249,1222,1194,1132,1114,935,916,843,752。
Example eight
Figure BDA0002674368690000081
Add acetonitrile (2.0mL), Compound 1h (0.5mmol,61.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product for 4 hours, wherein the yield is 68%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.40-7.31(m,1H),7.12-7.08(m,1H),7.08-6.99(m,2H),5.78(dd,J＝11.6,8.5Hz,1H),4.36(q,J＝7.1Hz,2H),3.66(dd,J＝17.8,11.6Hz,1H),3.19(dd,J＝17.8,8.5Hz,1H),1.38(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)162.9(d,J＝247.1Hz),160.3,151.0,142.1(d,J＝7.2Hz),130.5(d,J＝8.2Hz),121.3(d,J＝3.0Hz),115.5(d,J＝21.2Hz),112.7(d,J＝22.6Hz),83.8(d,J＝1.9Hz),62.2,41.5,14.0；19F NMR(376MHz,CDCl3)-111.87；HRMS(ESI-TOF):Anal.Calcd.For C12H12FNO3+Na+:260.0693,Found:260.0688(M+Na+)；IR(neat,cm-1):υ3068,2985,2917,2850,1718,1591,1246,1120,922,786,749。
Example nine
Figure BDA0002674368690000091
Add acetonitrile (2.0mL), Compound 1i (0.5mmol,69.3mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4i, wherein the yield is 75%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.39-7.27(m,3H),7.23-7.17(m,1H),5.76(dd,J＝11.6,8.5Hz,1H),4.36(q,J＝7.1Hz,2H),3.66(dd,J＝17.8,11.6Hz,1H),3.19(dd,J＝17.8,8.5Hz,1H),1.38(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)160.2,151.0,141.6,134.7,130.1,128.7,125.9,123.8,83.8,62.2,41.5,14.0；HRMS(ESI-TOF):Anal.Calcd.For C12H12ClNO3+Na+:276.0398,Found:276.0401(M+Na+)；IR(neat,cm-1):υ3069,2984,2938,2873,1718,1591,1245,1120,919,785,747,692。
Example ten
Figure BDA0002674368690000092
Add acetonitrile (2.0mL), Compound 1j (0.5mmol,91.5mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4j, wherein the yield is 62%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.52-7.43(m,2H),7.27-7.22(m,2H),5.75(dd,J＝11.6,8.5Hz,1H),4.36(q,J＝7.1Hz,2H),3.66(dd,J＝17.8,11.6Hz,1H),3.18(dd,J＝17.8,8.5Hz,1H),1.38(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)160.2,151.0,141.8,131.6,130.4,128.7,124.3,122.8,83.7,62.2,41.5,14.0；HRMS(ESI-TOF):Anal.Calcd.For C12H12 79BrNO3+Na+:319.9893,C12H12 81BrNO3+Na+:321.9872,Found:319.9895(M+Na+),321.9887(M+Na+)；IR(neat,cm-1):υ3064,2983,2938,2907,1717,1591,1245,1120,919,783,746,691。
EXAMPLE eleven
Figure BDA0002674368690000101
Add acetonitrile (2.0mL), Compound 1k (0.5mmol,86.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4k, wherein the yield is 66%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.66-7.57(m,2H),7.56-7.50(m,2H),5.85(dd,J＝11.6,8.6Hz,1H),4.37(q,J＝7.1Hz,2H),3.72(dd,J＝17.8,11.6Hz,1H),3.22(dd,J＝17.8,8.6Hz,1H),1.38(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)160.2,151.1,140.6,131.2(q,J＝32.5Hz),129.4,129.08,129.06,125.4(q,J＝3.7Hz),122.6(q,J＝3.8Hz),83.8,62.2,41.6,14.0；19F NMR(376MHz,CDCl3)-62.72；HRMS(ESI-TOF):Anal.Calcd.For C13H12F3NO3+Na+:310.0661,Found:310.0658(M+Na+)；IR(neat,cm-1):υ2986,2937,2878,2851,1720,1593,1326,1247,1119,1073,920,803,702。
Example twelve
Figure BDA0002674368690000102
Add acetonitrile (2.0mL), Compound 1L (0.5mmol,69.3mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain 4l of a product, wherein the yield is 63%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.52-7.43(m,1H),7.42-7.35(m,1H),7.32-7.22(m,2H),6.07(dd,J＝11.7,7.8Hz,1H),4.35(q,J＝7.1Hz,2H),3.79(dd,J＝17.9,11.7Hz,1H),3.09(dd,J＝17.9,7.8Hz,1H),1.37(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)13C NMR(101MHz,Chloroform-d)160.2,151.2,137.6,131.0,129.6,129.4,127.2,126.3,81.7,62.1,41.2,14.0；HRMS(ESI-TOF):Anal.Calcd.For C12H12ClNO3+Na+:276.0398,Found:276.0408(M+Na+)；IR(neat,cm-1):υ3068,2978,2937,2911,1719,1598,1252,1133,1112,926,749,689。
EXAMPLE thirteen
Figure BDA0002674368690000111
Add acetonitrile (2.0mL), Compound 1m (0.5mmol,77.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4m, wherein the yield is 74%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.87-7.76(m,4H),7.51-7.45(m,2H),7.37(dd,J＝8.5,1.8Hz,1H),5.91(dd,J＝11.6,8.8Hz,1H),4.35(q,J＝7.2Hz,2H),3.67(dd,J＝17.8,11.6Hz,1H),3.27(dd,J＝17.8,8.8Hz,1H),1.37(t,J＝7.2Hz,3H).；13C NMR(101MHz,CDCl3)160.4,151.1,136.6,133.1,132.9,128.9,127.9,127.6,126.5,126.4,125.1,123.1,85.0,62.1,41.3,14.0；HRMS(ESI-TOF):Anal.Calcd.For C16H15NO3+Na+:292.0944,Found:292.0948(M+Na+)；IR(neat,cm-1):υ3055,3020,2981,2940,1730,1594,1242,1132,927,824,750,740。
Example fourteen
Figure BDA0002674368690000121
Add acetonitrile (2.0mL), Compound 1n (0.5mmol,77.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4n, wherein the yield is 64%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.67(d,J＝16.0Hz,1H),7.54(d,J＝8.1Hz,2H),7.35(d,J＝8.1Hz,2H),6.45(d,J＝16.0Hz,1H),5.80(dd,J＝11.6,8.6Hz,1H),3.80(s,3H),4.36(q,J＝7.2Hz,2H),3.67(dd,J＝17.8,11.6Hz,1H),3.20(dd,J＝17.8,8.6Hz,1H),1.37(t,J＝7.2Hz,3H).；13C NMR(101MHz,CDCl3)167.1,160.3,151.0,143.8,141.58,134.6,128.4,126.2,118.4,84.2,62.1,51.6,41.4,14.0；HRMS(ESI-TOF):Anal.Calcd.For C16H17NO5+Na+:326.0999,Found:326.0982(M+Na+)；IR(neat,cm-1):υ2984,2948,2907,2845,1713,1638,1251,1164,1109,917,822。
Example fifteen
Figure BDA0002674368690000122
Add acetonitrile (2.0mL), Compound 1o (0.5mmol,43.0mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4o, wherein the yield is 70%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,DMSO-d6)5.37(dd,J＝12.2,6.9Hz,1H),4.26(q,J＝7.1Hz,2H),3.71(s,3H),3.56(dd,J＝17.8,12.2Hz,1H),3.39(dd,J＝17.8,6.9Hz,1H),1.26(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)169.5,159.4,151.6,79.3,61.7,52.5,37.4,13.9；HRMS(ESI-TOF):Anal.Calcd.For C8H11NO5+Na+:224.0529,Found:224.0521(M+Na+)；IR(neat,cm-1):υ2986,2959,2852,1739,1720,1598,1252,1216,1122,1017,916。
Example sixteen
Figure BDA0002674368690000131
Add acetonitrile (2.0mL), Compound 1p (0.5mmol,50.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4p, wherein the yield is 75%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,DMSO-d6)5.34(dd,J＝12.2,7.0Hz,1H),4.26(q,J＝7.1Hz,2H),4.17(q,J＝7.1Hz,2H),3.56(dd,J＝17.8,12.2Hz,1H),3.38(dd,J＝17.8,7.0Hz,1H),1.27(t,J＝7.1Hz,3H),1.23(t,J＝7.1Hz,3H)；13C NMR(101MHz,DMSO-d6)169.0,159.5,151.5,79.4,61.7,61.4,37.3,13.810,13.807；HRMS(ESI-TOF):Anal.Calcd.For C9H13NO5+Na+:238.0686,Found:238.0679(M+Na+)；IR(neat,cm-1):υ2985,2941,2912,1721,1598,1253,1206,1122,1018,917。
Example seventeen
Figure BDA0002674368690000132
To a reaction tube were added acetonitrile (2.0mL), compound 1q (0.5mmol,64.1mg), compound 2a (1.0mmol, 108. mu.L), compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst, in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4q, wherein the yield is 75%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,DMSO-d6)5.35(dd,J＝12.2,6.9Hz,1H),4.26(q,J＝7.1Hz,2H),4.12(t,J＝6.6Hz,2H),3.56(dd,J＝17.8,12.2Hz,1H),3.36(dd,J＝17.8,6.9Hz,1H),1.63-1.54(m,2H),1.39-1.30(m,2H),1.26(t,J＝7.1Hz,3H),0.89(t,J＝7.4Hz,3H).；13C NMR(101MHz,DMSO-d6)169.0,159.4,151.6,79.4,65.0,61.7,37.3,30.0,18.5,13.8,13.4；HRMS(ESI-TOF):Anal.Calcd.For C11H17NO5+Na+:266.0999,Found:266.0982(M+Na+)；IR(neat,cm-1):υ2962,2937,2875,1737,1722,1597,1253,1204,1122,1016,918。
EXAMPLE eighteen
Figure BDA0002674368690000141
Add acetonitrile (2.0mL), Compound 1r (0.5mmol,64.1mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4r, wherein the yield is 76%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,DMSO-d6)5.20(dd,J＝12.3,7.2Hz,1H),4.26(q,J＝7.1Hz,2H),3.53(dd,J＝17.8,12.3Hz,1H),3.29(dd,J＝17.8,7.2Hz,1H),1.44(s,9H),1.26(t,J＝7.1Hz,3H).；13C NMR(101MHz,DMSO-d6)168.0,159.5,151.4,82.2,79.9,61.6,37.2,27.5,13.8；HRMS(ESI-TOF):Anal.Calcd.For C11H17NO5+Na+:266.0999,Found:266.0980(M+Na+)；IR(neat,cm-1):υ2982,2938,1722,1596,1370,1250,1150,1122,918。
Example nineteen
Figure BDA0002674368690000142
Add acetonitrile (2.0mL), Compound 1s (0.5mmol,104.2mg), Compound 2a (1.0mmol, 108. mu.L), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 4s, wherein the yield is 76%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,DMSO-d6)5.31(dd,J＝12.1,6.6Hz,1H),4.62(td,J＝7.3,4.0Hz,1H),4.26(q,J＝7.1Hz,2H),3.55(ddd,J＝17.8,12.1,4.2Hz,1H),3.37-3.28(m,1H),1.82-1.69(m,3H),1.64(td,J＝11.6,11.2,5.3Hz,1H),1.52(td,J＝11.6,10.7,3.2Hz,1H),1.26(t,J＝7.1Hz,3H),1.16-1.04(m,2H),0.91(d,J＝2.7Hz,3H),0.83-0.74(m,6H)；13C NMR(101MHz,DMSO-d6)168.2,168.1,159.4,81.60,81.55,79.7,79.6,61.6,48.4,48.4,46.5,44.3,38.0,37.9,37.3,37.2,33.0,26.5,19.8,19.6,13.9,11.14,11.08；HRMS(ESI-TOF):Anal.Calcd.For C17H25NO5+Na+:346.1625,Found:346.1614(M+Na+)；IR(neat,cm-1):υ2956,2878,1723,1597,1252,1208,1121,1051,1013,917。
Example twenty
Figure BDA0002674368690000151
Add acetonitrile (2.0mL), Compound 1a (0.5mmol, 96. mu.L), Compound 2b (1.0mmol,170.7mg), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 5a, wherein the yield is 76%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.44-7.37(m,4H),7.32-7.23(m,3H),7.23-7.15(m,2H),5.83(dd,J＝11.6,9.1Hz,1H),3.69(dd,J＝17.8,11.6Hz,1H),3.31(dd,J＝17.8,9.1Hz,1H),1.32(s,9H)；13C NMR(101MHz,CDCl3)159.0,151.8,150.7,150.0,136.1,129.5,126.3,125.75,125.71,121.3,85.4,40.9,34.5,31.2；HRMS(ESI-TOF):Anal.Calcd.For C20H21NO3+Na+:346.1414,Found:346.1402(M+Na+)；IR(neat,cm-1):υ3064,2964,2903,2868,1749,1588,1340,1235,1193,1119,940,923,823,750,737,689。
Example twenty one
Figure BDA0002674368690000161
Add acetonitrile (2.0mL), Compound 1a (0.5mmol, 96. mu.L), Compound 2c (1.0mmol,185.5mg), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the product by using a saturated sodium chloride solution, extracting the product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product 5b, wherein the yield is 92%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.44-7.30(m,7H),7.24(d,J＝8.1Hz,2H),5.73(dd,J＝11.6,9.0Hz,1H),5.31(s,2H),3.58(dd,J＝17.8,11.6Hz,1H),3.20(dd,J＝17.8,9.0Hz,1H),1.30(s,9H).；13C NMR(101MHz,CDCl3)13C NMR(101MHz,Chloroform-d)160.3,151.7,150.9,136.2,134.8,128.53,128.49,128.46,125.662,125.658,85.0,67.4,41.0,34.5,31.2；HRMS(ESI-TOF):Anal.Calcd.For C21H23NO3+Na+:360.1570,Found:360.1577(M+Na+)；IR(neat,cm-1):υ3066,3041,2967,2951,2869,1709,1272,1245,1105,918,896,745,693。
Example twenty two
Figure BDA0002674368690000162
Add acetonitrile (2.0mL), Compound 1a (0.5mmol, 96. mu.L), Compound 2d (1.0mmol,177.0mg), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 5c, wherein the yield is 66%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.41(d,J＝8.5Hz,2H),7.26(d,J＝8.5Hz,2H),5.81(dd,J＝11.6,9.2Hz,1H),4.66(q,J＝8.2Hz,2H),3.62(dd,J＝17.8,11.6Hz,1H),3.24(dd,J＝17.8,9.2Hz,1H),1.31(s,9H)；13C NMR(101MHz,CDCl3)159.0,152.0,149.7,135.8,125.8,125.7,85.6,61.00(q,J＝37.3Hz),40.6,34.6,31.2；19F NMR(376MHz,CDCl3)-73.49；HRMS(ESI-TOF):Anal.Calcd.For C16H18F3NO3+Na+:352.1131,Found:352.1150(M+Na+)；IR(neat,cm-1):υ2970,2908,2871,1749,1734,1586,1279,1166,1147,1123,938。
Example twenty three
Figure BDA0002674368690000171
Add acetonitrile (2.0mL), Compound 1a (0.5mmol, 96. mu.L), Compound 2e (1.0mmol,206.6mg), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 5d, wherein the yield is 86%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.45-7.37(m,2H),7.28-7.24(m,2H),7.16(dd,J＝5.1,1.2Hz,1H),6.94(dd,J＝5.1,3.4Hz,1H),6.90(dd,J＝3.4,1.2Hz,1H),5.76(dd,J＝11.5,9.1Hz,1H),4.50(t,J＝6.9Hz,2H),3.59(dd,J＝17.7,11.5Hz,1H),3.29–3.18(m,3H),1.32(s,9H)；13C NMR(101MHz,CDCl3)160.3,156.1,150.9,139.0,136.2,127.0,125.82,125.76,125.73,124.2,85.1,66.0,41.0,34.6,31.2,29.0；HRMS(ESI-TOF):Anal.Calcd.For C20H23NO3S+Na+:380.1291,Found:380.1303(M+Na+)；IR(neat,cm-1):υ3106,3091,2966,2928,2860,1714,1590,1270,1247,1110,915,830,708。
Example twenty-four
Figure BDA0002674368690000181
Add acetonitrile (2.0mL), Compound 1a (0.5mmol, 96. mu.L), Compound 2f (1.0mmol,146.0mg), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 5e, wherein the yield is 69%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)8.28-8.20(m,2H),7.62-7.55(m,1H),7.51-7.42(m,2H),7.43-7.38(m,2H),7.29(d,J＝8.3Hz,2H),5.74(dd,J＝11.5,8.9Hz,1H),3.74(dd,J＝17.7,11.5Hz,1H),3.39(dd,J＝17.7,8.9Hz,1H),1.31(s,9H).；13C NMR(101MHz,CDCl3)186.2,157.4,151.7,136.5,135.7,133.5,130.3,128.3,125.731,125.728,84.1,41.5,34.5,31.2；HRMS(ESI-TOF):Anal.Calcd.For C20H21NO2+Na+:330.1465,Found:330.1459(M+Na+)；IR(neat,cm-1):υ2959,2904,2867,1652,1563,1245,930,909,704,689,674。
Example twenty-five
Figure BDA0002674368690000182
Add acetonitrile (2.0mL), Compound 1a (0.5mmol, 96. mu.L), Compound 2g (1.0mmol,250.9mg), Compound 3(1.0mmol, 121. mu.L), and boron trifluoride diethyl etherate (0.05mmol, 14. mu.L) as a catalyst to the reaction tube in that order; then reacting for 12 hours at the temperature of 25 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing the solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 5f, wherein the yield is 72%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.
1H NMR(400MHz,CDCl3)7.92(d,J＝7.7Hz,2H),7.65(t,J＝7.4Hz,1H),7.55(t,J＝7.6Hz,2H),7.40(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),5.73(dd,J＝11.5,8.9Hz,1H),3.53(t,J＝7.3Hz,2H),3.49-3.41(m,1H),3.37(t,J＝6.8Hz,2H),3.09(dd,J＝17.7,8.9Hz,1H),1.30(s,9H).；13C NMR(101MHz,CDCl3)190.6,156.9,151.8,138.3,135.9,133.8,129.3,128.0,125.63,125.59,85.5,50.2,39.0,34.4,32.3,31.1；HRMS(ESI-TOF):Anal.Calcd.For C22H25NO4S+Na+:422.1397,Found:322.1340(M+Na+)；IR(neat,cm-1):υ3064,2958,2933,2869,1692,1574,1304,1152,1087,914,823,727,687。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A process for preparing an isoxazoline comprising the steps of:
the method comprises the following steps of reacting olefin shown in a formula (1), diazo compound shown in a formula (2) and tert-butyl nitrite in an organic solvent at 25-50 ℃ under the action of a Lewis acid catalyst, and obtaining isoxazoline shown in a formula (3) after complete reaction:
Figure FDA0002674368680000011
wherein R is1Is selected from C1-C12 alkoxycarbonyl, naphthyl, phenyl or substituted phenyl, and the substituent on the substituted benzene ring is selected from unsubstituted C1-C6 alkyl, halogen, C1-C6 fluoroalkyl, cyano, C1-C6 alkyl substituted acyloxy or acrylic acid C1-C6 alkyl ester group;
R2is selected from
Figure FDA0002674368680000012
Or
Figure FDA0002674368680000013
Wherein the content of the first and second substances,
R3selected from unsubstituted C1-C6 alkyl, C1-C6 fluoroalkyl, benzyl, phenyl, thienyl or thienyl substituted C1-C6 alkyl;
R4selected from phenyl or benzenesulfonyl substituted C1-C6 alkyl.
2. The method of claim 1, wherein: the dosage of the Lewis acid catalyst is 5 to 20 percent of the molar weight of the olefin.
3. The method according to claim 1 or 2, characterized in that: the Lewis acid catalyst is one or more of boron trifluoride diethyl etherate, copper trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, ferric trichloride and zinc chloride.
4. The method of claim 1, wherein: the mol ratio of the olefin to the diazo compound to the tert-butyl nitrite is 1:1-2: 1-2.
5. The method of claim 1, wherein: r1Selected from methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, isobornyloxyCarbonyl, naphthyl, phenyl or mono-substituted phenyl, wherein the substituent on the mono-substituted phenyl is selected from methyl, tert-butyl, fluorine, chlorine, bromine, trifluoromethyl, cyano or methyl acrylate.
6. The method of claim 1, wherein: r2Is selected from
Figure FDA0002674368680000014
Or
Figure FDA0002674368680000015
Wherein the content of the first and second substances,
R3selected from ethyl, trifluoromethyl substituted methyl, benzyl, phenyl or thienyl substituted ethyl;
R4selected from phenyl or phenylsulfo substituted ethyl.
7. The method of claim 1, wherein: the reaction time is 12-24 hours.
8. The method of claim 1, wherein: the organic solvent comprises one or more of petroleum ether, ethyl acetate, tetrahydrofuran, nitromethane, dimethyl sulfoxide, N-dimethylformamide, acetonitrile, toluene and 1, 2-dichloroethane.
9. The method of claim 1, wherein: the reaction was carried out in air.
10. The method of claim 1, wherein: after the reaction is finished, the method also comprises the step of quenching the reaction by using a saturated sodium chloride solution and separating the isoxazoline.
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