WO2022206010A1 - Simple preparation method for isoxazolines - Google Patents

Simple preparation method for isoxazolines Download PDF

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WO2022206010A1
WO2022206010A1 PCT/CN2021/136208 CN2021136208W WO2022206010A1 WO 2022206010 A1 WO2022206010 A1 WO 2022206010A1 CN 2021136208 W CN2021136208 W CN 2021136208W WO 2022206010 A1 WO2022206010 A1 WO 2022206010A1
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isoxazoline
nmr
mhz
cdcl
olefin
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PCT/CN2021/136208
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French (fr)
Chinese (zh)
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万小兵
马亮
成雄略
江港钟
陶苏艳
李星星
杨金炜
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苏州大学
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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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16

Definitions

  • the invention relates to a method for preparing isoxazoline, belonging to the technical field of organic synthesis.
  • Isoxazolines are the core skeletons that widely exist in natural products, drug molecules, bioactive molecules, pesticides and functional materials. In addition, it has also been used as a ligand for transition metal catalysis. Chemists have developed a series of methods for the preparation of isoxazolines, but they all have obvious shortcomings, such as: requiring a large excess of oxidant or dehydrating agent; expensive raw materials or complicated preparation; harsh reaction conditions; expensive and harmful transition metals, etc. .
  • the purpose of the present invention is to provide a method for preparing isoxazoline, which has the advantages of abundant raw material sources, wide universality of reaction substrates, simple operation, mild reaction conditions and the like.
  • the technical scheme adopted in the present invention is: a simple preparation method of isoxazoline, using aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst. Under the following conditions, the isoxazoline is obtained by reaction in an organic solvent.
  • the product that the present invention obtains is isoxazoline, and its chemical structural formula is: .
  • the general formula of the chemical structure of the aldehyde is: ;
  • the general chemical structure of the alkene is: ;
  • the general formula of chemical structure of described nitrite is: .
  • R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl, such as aryl or substituted aryl:
  • R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone group;
  • R 4 , R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl, phosphoric acid Ester group;
  • R 6 is selected from tert-butyl, n-butyl, isobutyl, isopropyl.
  • the copper catalyst is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide; preferably, the copper catalyst is cupric chloride.
  • the amount of the copper catalyst is 5-20% of the mole of the olefin; the preferred amount of the copper catalyst is 10% of the mole of the olefin.
  • the invention also discloses a method for preparing isoxazoline without metal catalyst. After mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, olefin, nitrite, organic solvent and alkali are added to react to obtain Isoxazoline; wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows: .
  • R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ;
  • R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group;
  • R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl.
  • R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine;
  • R 2 is selected from aryl, ester group, such as phenyl, -COOEt, substituted phenyl.
  • the benzaldehyde compound and p-toluenesulfonyl hydrazide are stirred in an alcohol solvent at 60° C. for 30 minutes, the methanol solvent is removed, and olefin, nitrite, organic solvent and alkali are added to react to obtain isoxazole. morpholino.
  • the reaction temperature of the reaction is 25-80°C; the reaction time is 12-24 hours; the preferred reaction temperature is 65°C; and the reaction time is 24 hours.
  • the reaction is carried out in the presence of a base, and the bases used are TMEDA, DABCO, and sodium carbonate; and the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform, N , N -dimethylmethane amide.
  • the base is preferably an organic amine, such as TMEDA, and the organic solvent is tetrahydrofuran.
  • the amount of the aldehyde compound is 1 to 1.5 times the mole of the olefin; the amount of p-toluenesulfonyl hydrazide is 1 to 1.5 times the mole of the olefin, and the amount of nitrite is 3 to 5 times the mole of the olefin;
  • the dosage is 1 to 1.8 times the mole weight of olefin; preferably, the dosage of the aldehyde compound is 1.3 times the mole weight of olefin; the dosage of p-toluenesulfonyl hydrazide is 1.4 times the mole weight of olefin, and the dosage of nitrite is the mole weight of olefin 4 times the amount of the base, and the amount of the base is 1.5 times the molar amount of the olefin.
  • the reaction of the present invention is carried out in air. After the reaction, it was quenched with saturated sodium chloride solution, extracted with ethyl acetate, the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether. Isoxazoline.
  • the preparation method of the present invention is shown as follows: The invention also discloses the isoxazoline prepared according to the above method.
  • the present invention has the following advantages compared with the prior art: the present invention uses CuCl 2 as a catalyst to realize the multi-component reaction of aldehyde, p-toluenesulfonyl hydrazide, olefin and tert-butyl nitrite to prepare Isoxazoline is more economical in reaction, more widely applicable to substrates, easy to obtain raw materials, and easier to functionalize later, compared with the prior art, which is difficult to prepare raw materials, large amount of raw materials and harsh conditions.
  • the method disclosed by the invention has mild reaction conditions, cheap catalyst and less dosage, good gram-scale reaction, convenient post-processing, and is beneficial to the application in drug molecule synthesis and large-scale industrialization.
  • the reactants, additives, bases, catalysts and other raw materials used in the invention are cheap and easy to obtain, the reaction composition is reasonable, no ligand is required, and the reaction steps are few, and the functionalized isoxazoline can be obtained by only one step of reaction, which is in line with green chemistry and medicine. Chemistry requirements and directions.
  • the present invention discloses a catalyst-free method for preparing isoxazoline, which avoids the use of transition metals and is favorable for further use in the synthesis of drug molecules and biologically active molecules.
  • the aldehyde, olefin, p-toluenesulfonyl hydrazide, alkali, nitrite, catalyst and solvent of the present invention are all marketable commodities and can be purchased directly.
  • the specific operation method and test method of the experiment are conventional methods in the field, and the reaction is carried out in a conventional environment.
  • test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum
  • the product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether .
  • Example 2 On the basis of Example 1, the reaction conditions were changed by a single factor: the THF (2.0 mL) added for the second time was replaced with acetone (2.0 mL), and the yield was 84%.
  • Tetramethylethylenediamine TMEDA was replaced with N,N-dimethylethanolamine DABCO (0.75 mmol), yield: 68%.
  • Tetramethylethylenediamine TMEDA was replaced by sodium carbonate (0.75 mmol), yield: 16%.
  • Tetramethylethylenediamine TMEDA was replaced with potassium carbonate (0.75 mmol) in ⁇ 1% yield.
  • Tetramethylethylenediamine TMEDA was replaced with sodium hydroxide (0.75 mmol) in ⁇ 1% yield.
  • Example 3 On the basis of Example 1, omitting the copper catalyst: in the air, to a test tube with a magnetic stirrer, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially.
  • test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum
  • the product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 61%.
  • R 1 is phenyl.
  • benzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent MeOH was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were sequentially added.
  • test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4 .
  • Embodiment 6 On the basis of Embodiment 4, compound 1 and compound 2 are replaced, and the rest remain unchanged to obtain the following product.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

Disclosed in the present invention is a simple preparation method for isoxazolines, comprising: using aldehyde, p-toluenesulfonyl hydrazide, olefin, and tert-butyl nitrite as a substrate, using copper chloride as a catalyst, using tetramethylethylenediamine (TMEDA) as an alkali, and efficiently synthesizing a series of isoxazoline compounds buy using a one-pot two-step method. The advantages are as follows: the catalyst is cheap, the reaction is economical, substrate universality is wider, raw materials are easy to obtain, later stage functionalization is more convenient, reaction conditions are mild, and the gram-scale reaction is good; and in particular, in the present invention, a product can be obtained at a moderate yield in the absence of catalyst, post-treatment is simple and convenient, and it is beneficial to an application in drug molecule synthesis and large-scale industrialization, thereby satisfying the requirements and directions of contemporary green chemistry and pharmaceutical chemistry.

Description

一种异噁唑啉的简单制备方法A kind of simple preparation method of isoxazoline 技术领域technical field
本发明涉及一种制备异噁唑啉的方法，属于有机合成技术领域。The invention relates to a method for preparing isoxazoline, belonging to the technical field of organic synthesis.
背景技术Background technique
异噁唑啉是广泛存在于天然产物、药物分子、生物活性分子、农药以及功能材料的核心骨架。另外，它也被用作过渡金属催化的配体。化学家们发展了一系列制备异噁唑啉的方法，但均有明显的缺点，比如：需要大过量的氧化剂或脱水剂；原料昂贵或制备繁琐；反应条件苛刻；需要昂贵有害的过渡金属等。例如：（1）从炔烃和硝酸铜出发原位生成腈氧化物中间体再进一步与烯烃偶极环加成制备异噁唑啉的工作，但是反应必须在氮气氛下才能有着更高的产率，与此同时，该方法不可避免需要使用当量的过渡金属硝酸铜（价格昂贵且有毒有害），不适合药物分子的合成（参见： Angew. Chem., Int. Ed. 2015 , 54, 8795）；（2）亚硝酸叔丁酯引发的重氮化合物与烯烃三组分制备异噁唑啉的反应。但反应中需要用到制备繁琐而且危险的重氮化合物，限制了其在制备生物活性分子中的应用（参见： Chem. Sci., 2021, 12, 774）。综上，很有必要开发一种原料来源丰富、成本低廉、安全、操作简便的方法来高效率的合成异噁唑啉类化合物。 Isoxazolines are the core skeletons that widely exist in natural products, drug molecules, bioactive molecules, pesticides and functional materials. In addition, it has also been used as a ligand for transition metal catalysis. Chemists have developed a series of methods for the preparation of isoxazolines, but they all have obvious shortcomings, such as: requiring a large excess of oxidant or dehydrating agent; expensive raw materials or complicated preparation; harsh reaction conditions; expensive and harmful transition metals, etc. . For example: (1) In-situ generation of nitrile oxide intermediates from alkynes and copper nitrate, and further dipolar cycloaddition with alkenes to prepare isoxazolines, but the reaction must be under nitrogen atmosphere to have higher yields At the same time, this method inevitably requires the use of equivalent transition metal copper nitrate (expensive and toxic), which is not suitable for the synthesis of drug molecules (see: Angew. Chem., Int. Ed. 2015 , 54, 8795) ; (2) The reaction of three-component preparation of isoxazoline from diazonium compounds and olefins initiated by t-butyl nitrite. However, the complex and dangerous diazonium compounds are required to be prepared in the reaction, which limits its application in the preparation of biologically active molecules (see: Chem. Sci., 2021, 12 , 774). In conclusion, it is necessary to develop a method with abundant raw material sources, low cost, safety and simple operation to synthesize isoxazolines with high efficiency.
技术问题technical problem
本发明的目的是提供一种制备异噁唑啉的方法，该方法具有原料来源丰富、反应底物普适性广，操作简便，反应条件温和等优点。The purpose of the present invention is to provide a method for preparing isoxazoline, which has the advantages of abundant raw material sources, wide universality of reaction substrates, simple operation, mild reaction conditions and the like.
技术解决方案technical solutions
为达到上述发明目的，本发明采用的技术方案是：一种异噁唑啉的简单制备方法，以醛、对甲苯磺酰肼、烯烃和亚硝酸酯为反应底物，在碱与铜催化剂存在下，在有机溶剂中反应得到异噁唑啉。In order to achieve the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is: a simple preparation method of isoxazoline, using aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst. Under the following conditions, the isoxazoline is obtained by reaction in an organic solvent.
本发明得到的产物为异噁唑啉，其化学结构式为：
Figure 913331dest_path_image001
。 The product that the present invention obtains is isoxazoline, and its chemical structural formula is:
Figure 913331dest_path_image001
.
本发明中，所述醛的化学结构通式为：
Figure 113368dest_path_image002
；所述烯烃的化学结构通式为：
Figure 106732dest_path_image003
；所述亚硝酸酯的化学结构通式为：
Figure 782432dest_path_image004
。 In the present invention, the general formula of the chemical structure of the aldehyde is:
Figure 113368dest_path_image002
; The general chemical structure of the alkene is:
Figure 106732dest_path_image003
; The general formula of chemical structure of described nitrite is:
Figure 782432dest_path_image004
.
上述结构式中，R 1选自芳基、取代芳基、杂芳香基、萘基或者烯基，比如芳基或者取代芳基为：
Figure 253865dest_path_image005
，R 2、R 3独立的选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基；R 4、R 5独立的选自氢、烷基、芳基、酯基、醚、酰胺基、羰基、硅基、羟基、缩醛、氰基、卤素、炔基、羧基、磷酸酯基；R 6选自叔丁基、正丁基、异丁基、异丙基。 In the above structural formula, R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl, such as aryl or substituted aryl:
Figure 253865dest_path_image005
, R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone group; R 4 , R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl, phosphoric acid Ester group; R 6 is selected from tert-butyl, n-butyl, isobutyl, isopropyl.
上述技术方案中，将醛、对甲苯磺酰肼在醇溶剂中混合后，再加入烯烃、亚硝酸酯、有机溶剂、铜催化剂、碱，反应得到异噁唑啉；优选的，将醛、对甲苯磺酰肼在甲醇中，60℃下搅拌30分钟后，除去甲醇，再加入烯烃、亚硝酸酯、有机溶剂、铜催化剂、碱，反应得到异噁唑啉。In the above technical scheme, after the aldehyde and p-toluenesulfonyl hydrazide are mixed in an alcohol solvent, olefin, nitrite, an organic solvent, a copper catalyst, and a base are added to react to obtain isoxazoline; Tosylhydrazide was stirred in methanol at 60° C. for 30 minutes, methanol was removed, and olefin, nitrite, organic solvent, copper catalyst, and base were added to react to obtain isoxazoline.
上述技术方案中，所述铜催化剂为氯化铜、氯化亚铜、溴化亚铜或者碘化亚铜；优选的，所述铜催化剂为氯化铜。In the above technical solution, the copper catalyst is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide; preferably, the copper catalyst is cupric chloride.
上述技术方案中，所述铜催化剂用量为烯烃摩尔量的5～20%；优选的铜催化剂用量为烯烃摩尔量的10%。In the above technical solution, the amount of the copper catalyst is 5-20% of the mole of the olefin; the preferred amount of the copper catalyst is 10% of the mole of the olefin.
本发明还公开了一种无金属催化剂制备异噁唑啉的方法，将苯甲醛化合物、对甲苯磺酰肼在甲醇溶剂中混合后，再加入烯烃、亚硝酸酯、有机溶剂、碱，反应得到异噁唑啉；其中，所述苯甲醛化合物的化学结构通式如下：
Figure 573988dest_path_image006
。 The invention also discloses a method for preparing isoxazoline without metal catalyst. After mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, olefin, nitrite, organic solvent and alkali are added to react to obtain Isoxazoline; wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows:
Figure 573988dest_path_image006
.
所述烯烃的化学结构通式为R 2-CH 2CH 2；所述亚硝酸酯的化学结构通式为O=N-OR 6。 The general chemical structure of the alkene is R 2 -CH 2 CH 2 ; the general chemical structure of the nitrite is O=N-OR 6 .
所述异噁唑啉的化学结构通式如下：
Figure 738253dest_path_image007
。 The general formula of the chemical structure of the isoxazoline is as follows:
Figure 738253dest_path_image007
.
式中，R 1选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基；R 2选自烷基、芳基、酯基、羰基、醚、酰胺基、硅基、羟基、缩苯甲醛化合物、氰基、卤素、炔基、羧基或者磷酸酯基；R 6选自叔丁基、正丁基、异丁基或者异丙基。优选的，R 1选自氢、烷基、氟、氯、溴；R 2选自芳基、酯基，比如苯基、-COOEt、取代苯基。 In the formula, R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ; R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group; R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl. Preferably, R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine; R 2 is selected from aryl, ester group, such as phenyl, -COOEt, substituted phenyl.
上述技术方案中，将苯甲醛化合物、对甲苯磺酰肼在醇溶剂中，60℃下搅拌30分钟后，除去甲醇溶剂，再加入烯烃、亚硝酸酯、有机溶剂、碱，反应得到异噁唑啉。In the above technical scheme, the benzaldehyde compound and p-toluenesulfonyl hydrazide are stirred in an alcohol solvent at 60° C. for 30 minutes, the methanol solvent is removed, and olefin, nitrite, organic solvent and alkali are added to react to obtain isoxazole. morpholino.
本发明中，所述反应的反应温度为25～80℃；反应时间为12～24小时；优选的反应温度为65℃；反应时间为24小时。In the present invention, the reaction temperature of the reaction is 25-80°C; the reaction time is 12-24 hours; the preferred reaction temperature is 65°C; and the reaction time is 24 hours.
本发明中，所述反应在碱存在下进行，所使用的碱为TMEDA、DABCO、碳酸钠；所述有机溶剂为乙酸乙酯、四氢呋喃、乙腈、丙酮、氯仿、 N, N-二甲基甲酰胺。优选的，碱优选有机胺，比如为TMEDA，有机溶剂为四氢呋喃。 In the present invention, the reaction is carried out in the presence of a base, and the bases used are TMEDA, DABCO, and sodium carbonate; and the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform, N , N -dimethylmethane amide. Preferably, the base is preferably an organic amine, such as TMEDA, and the organic solvent is tetrahydrofuran.
本发明中，所述醛化合物用量为烯烃摩尔量的1～1.5倍；对甲苯磺酰肼用量为烯烃摩尔量的1～1.5倍，亚硝酸酯用量为烯烃摩尔量的3～5倍；碱的用量为烯烃摩尔量的1～1.8倍；优选的，所述醛化合物用量为烯烃摩尔量的1.3倍；对甲苯磺酰肼用量为烯烃摩尔量的1.4倍，亚硝酸酯用量为烯烃摩尔量的4倍，碱的用量为烯烃摩尔量的1.5倍。In the present invention, the amount of the aldehyde compound is 1 to 1.5 times the mole of the olefin; the amount of p-toluenesulfonyl hydrazide is 1 to 1.5 times the mole of the olefin, and the amount of nitrite is 3 to 5 times the mole of the olefin; The dosage is 1 to 1.8 times the mole weight of olefin; preferably, the dosage of the aldehyde compound is 1.3 times the mole weight of olefin; the dosage of p-toluenesulfonyl hydrazide is 1.4 times the mole weight of olefin, and the dosage of nitrite is the mole weight of olefin 4 times the amount of the base, and the amount of the base is 1.5 times the molar amount of the olefin.
本发明的反应在空气中进行。反应结束后，用饱和氯化钠溶液淬灭，再用乙酸乙酯萃取后，利用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉。The reaction of the present invention is carried out in air. After the reaction, it was quenched with saturated sodium chloride solution, extracted with ethyl acetate, the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether. Isoxazoline.
本发明的制备方法示意如下：
Figure 386403dest_path_image008
Figure 458264dest_path_image009
本发明还公开了根据上述方法制备得到的异噁唑啉。 The preparation method of the present invention is shown as follows:
Figure 386403dest_path_image008
Figure 458264dest_path_image009
The invention also discloses the isoxazoline prepared according to the above method.
有益效果beneficial effect
由于上述技术方案的运用，本发明与现有技术相比具有下列优点：本发明使用CuCl 2为催化剂实现了醛、对甲苯磺酰肼、烯烃和亚硝酸叔丁酯的多组分反应来制备异噁唑啉，与现有技术中的原料预制备难、原料用量大和条件苛刻相比，反应更经济、底物普适性更广、原料易得、后期官能团化更易。本发明公开的方法反应条件温和，催化剂廉价而且用量少，克级规模反应良好，后处理简便，有利于在药物分子合成和大规模工业化中的应用。本发明使用的反应物、添加剂、碱、催化剂等原料廉价易得，反应组成合理，无需配体，反应步骤少，仅需一步反应即可得到官能团化的异噁唑啉，符合绿色化学和药物化学的要求和方向。尤其是，本发明公开了无催化剂制备异噁唑啉的方法，避免了过渡金属的使用，有利于进一步用于药物分子与生物活性分子的合成中。 Due to the application of the above technical solutions, the present invention has the following advantages compared with the prior art: the present invention uses CuCl 2 as a catalyst to realize the multi-component reaction of aldehyde, p-toluenesulfonyl hydrazide, olefin and tert-butyl nitrite to prepare Isoxazoline is more economical in reaction, more widely applicable to substrates, easy to obtain raw materials, and easier to functionalize later, compared with the prior art, which is difficult to prepare raw materials, large amount of raw materials and harsh conditions. The method disclosed by the invention has mild reaction conditions, cheap catalyst and less dosage, good gram-scale reaction, convenient post-processing, and is beneficial to the application in drug molecule synthesis and large-scale industrialization. The reactants, additives, bases, catalysts and other raw materials used in the invention are cheap and easy to obtain, the reaction composition is reasonable, no ligand is required, and the reaction steps are few, and the functionalized isoxazoline can be obtained by only one step of reaction, which is in line with green chemistry and medicine. Chemistry requirements and directions. In particular, the present invention discloses a catalyst-free method for preparing isoxazoline, which avoids the use of transition metals and is favorable for further use in the synthesis of drug molecules and biologically active molecules.
本发明的实施方式Embodiments of the present invention
下面结合实施例对本发明作进一步描述：本发明的醛、烯烃、对甲苯磺酰肼、碱、亚硝酸酯、催化剂和溶剂皆为市场化商品，可直接购买。实验具体操作方法以及测试方法为本领域常规方法，反应在常规环境中进行。The present invention will be further described below in conjunction with the examples: the aldehyde, olefin, p-toluenesulfonyl hydrazide, alkali, nitrite, catalyst and solvent of the present invention are all marketable commodities and can be purchased directly. The specific operation method and test method of the experiment are conventional methods in the field, and the reaction is carried out in a conventional environment.
实施例一。Example 1.
Figure 101735dest_path_image010
。
Figure 101735dest_path_image010
.
空气中，向具有磁力搅拌子的试管中，添加对溴苯甲醛（0.65 mmol），对甲苯磺酰肼（0.7 mmol）和MeOH（1 mL），将混合物在60 ℃下搅拌30分钟。 真空除去溶剂后，依次加入CuCl 2（0.05 mmol），THF（2.0 mL），丙烯酸乙酯（0.5 mmol），TMEDA（0.75 mmol），TBN（2.0 mmol）和THF（2.0 mL）。 将试管用封口膜密封，并在65 ℃下搅拌24 h，用饱和氯化钠溶液淬灭，再用乙酸乙酯萃取后，利用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉 3aa 。产率：88%; mp: 66-68 oC; 1H NMR (400 MHz, CDCl 3) δ 7.51 (s, 4H), 5.15 (dd, J = 10.5, 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.592 (d, J = 7.9 Hz, 1H), 3.586 (d, J = 10.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.9, 155.1, 131.9, 128.2, 127.4, 124.7, 78.2, 62.0, 38.5, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12H 12 79BrNNaO 3 +: 319.9893, C 12H 12 81BrNNaO 3 +: 321.9872, Found: 319.9881, 321.9890; IR (neat, cm -1): υ 2972, 2933, 1738, 1195, 1160, 1008, 890, 821。丙烯酸乙酯反应放大到20mmol规模，同样的条件，产率为85%。 In air, to a test tube with a magnetic stirring bar, p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially. The test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum The product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 88%; mp: 66-68 o C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 4H), 5.15 (dd, J = 10.5, 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.592 (d, J = 7.9 Hz, 1H), 3.586 (d, J = 10.5 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz) , CDCl 3 ) δ 169.9, 155.1, 131.9, 128.2, 127.4, 124.7, 78.2, 62.0, 38.5, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 79 BrNNaO 3 + : 319.9893 , C H 12 81 BrNNaO 3 + : 321.9872, Found: 319.9881, 321.9890; IR (neat, cm -1 ): υ 2972, 2933, 1738, 1195, 1160, 1008, 890, 821. The ethyl acrylate reaction was scaled up to 20 mmol, and the yield was 85% under the same conditions.
实施例二 在实施例一的基础上，反应条件做单因素变化：将第二次加入的THF（2.0 mL）更换为丙酮（2.0 mL），产率：84%。Example 2 On the basis of Example 1, the reaction conditions were changed by a single factor: the THF (2.0 mL) added for the second time was replaced with acetone (2.0 mL), and the yield was 84%.
将第二次加入的THF（2.0 mL）更换为乙腈（2.0 mL），产率：54%。The second addition of THF (2.0 mL) was replaced with acetonitrile (2.0 mL), yield: 54%.
将亚硝酸叔丁酯TBN更换为亚硝酸异丙酯（2.0 mmol），产率：79%。The tert-butyl nitrite TBN was replaced with isopropyl nitrite (2.0 mmol), yield: 79%.
将亚硝酸叔丁酯TBN更换为亚硝酸正丁酯（2.0 mmol），产率：68%。The tert-butyl nitrite TBN was replaced with n-butyl nitrite (2.0 mmol), yield: 68%.
将CuCl 2（0.05 mmol）更换为CuCl（0.05 mmol），产率：77%。 Replaced CuCl2 ( 0.05 mmol) with CuCl (0.05 mmol), yield: 77%.
将CuCl 2（0.05 mmol）更换为CuBr（0.05 mmol），产率：83%。 Replaced CuCl2 ( 0.05 mmol) with CuBr (0.05 mmol), yield: 83%.
将CuCl 2（0.05 mmol）更换为CuI（0.05 mmol），产率：56%。 Replaced CuCl2 ( 0.05 mmol) with CuI (0.05 mmol), yield: 56%.
将CuCl 2（0.05 mmol）更换为Cu(OAc) 2（0.05 mmol），产率：58%。 CuCl2 (0.05 mmol) was replaced by Cu(OAc) 2 ( 0.05 mmol), yield: 58%.
将四甲基乙二胺TMEDA 更换为N,N-二甲基乙醇胺DABCO（0.75 mmol），产率：68%。Tetramethylethylenediamine TMEDA was replaced with N,N-dimethylethanolamine DABCO (0.75 mmol), yield: 68%.
将四甲基乙二胺TMEDA 更换为碳酸钠（0.75 mmol），产率：16%。Tetramethylethylenediamine TMEDA was replaced by sodium carbonate (0.75 mmol), yield: 16%.
将四甲基乙二胺TMEDA 更换为碳酸钾（0.75 mmol），产率<1%。Tetramethylethylenediamine TMEDA was replaced with potassium carbonate (0.75 mmol) in <1% yield.
将四甲基乙二胺TMEDA 更换为氢氧化钠（0.75 mmol），产率<1%。Tetramethylethylenediamine TMEDA was replaced with sodium hydroxide (0.75 mmol) in <1% yield.
省略TMEDA，产率<1%。Omit TMEDA, yield <1%.
实施例三 在实施例一的基础上，省略铜催化剂：空气中，向具有磁力搅拌子的试管中，添加对溴苯甲醛（0.65 mmol），对甲苯磺酰肼（0.7 mmol）和MeOH（1 mL），将混合物在60 ℃下搅拌30分钟。 真空除去溶剂后，依次加入丙烯酸乙酯（0.5 mmol），TMEDA（0.75 mmol），TBN（2.0 mmol）和THF（2.0 mL）。将试管用封口膜密封，并在65 ℃下搅拌24 h，用饱和氯化钠溶液淬灭，再用乙酸乙酯萃取后，利用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉 3aa 。产率：61%。 Example 3 On the basis of Example 1, omitting the copper catalyst: in the air, to a test tube with a magnetic stirrer, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially. The test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum The product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 61%.
实施例四。Example four.
Figure 594159dest_path_image011
。
Figure 594159dest_path_image011
.
以化合物1为苯甲醛为例，即R 1为苯基。空气中，向具有磁力搅拌子的试管中，添加苯甲醛（0.65 mmol），对甲苯磺酰肼（0.7 mmol）和MeOH（1 mL），将混合物在60 ℃下搅拌30分钟。 真空除去溶剂MeOH后，依次加入CuCl 2（0.05 mmol），THF（2.0 mL），丙烯酸乙酯（0.5 mmol），TMEDA（0.75 mmol），TBN（2.0 mmol）和THF（2.0 mL）。将试管用封口膜密封，并在65 ℃下搅拌24 h。用饱和氯化钠溶液淬灭，再用乙酸乙酯萃取后，利用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉 4 。产率：93%； 1H NMR (400 MHz, CDCl 3) δ 7.69 – 7.63 (m, 2H), 7.43 – 7.35 (m, 3H), 5.14 (dd, J = 10.4, 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.623 (d, J = 7.9 Hz, 1H), 3.617 (d, J = 10.4 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.0, 155.9, 130.3, 128.6, 128.4, 126.8, 78.0, 61.8, 38.7, 14.0; Anal. Calcd. For C 12H 13NNaO 3 +: 242.0788, Found: 242.0778; IR (neat, cm -1): υ 2976, 2936, 2906, 1750, 1209, 1182, 1035, 901, 762, 695。上述产物化合物4的结构式如下： 
Figure 57501dest_path_image012
。 Taking compound 1 as benzaldehyde as an example, that is, R 1 is phenyl. In air, to a test tube with a magnetic stirring bar, benzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent MeOH was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were sequentially added. The test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4 . Yield: 93%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.63 (m, 2H), 7.43 - 7.35 (m, 3H), 5.14 (dd, J = 10.4, 7.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.623 (d, J = 7.9 Hz, 1H), 3.617 (d, J = 10.4 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0 , 155.9 , 130.3 , 128.6, 128.4, 126.8, 78.0, 61.8, 38.7, 14.0; , cm -1 ): υ 2976, 2936, 2906, 1750, 1209, 1182, 1035, 901, 762, 695. The structural formula of above-mentioned product compound 4 is as follows:
Figure 57501dest_path_image012
.
  保持反应条件不变，仅仅更换化合物1，得到的产物以及表征如下：
Figure 933053dest_path_image013
。 Keeping the reaction conditions unchanged, only replacing compound 1, the obtained products and their characterizations are as follows:
Figure 933053dest_path_image013
.
产率：87% yield; 1H NMR (400 MHz, CDCl 3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 10.5, 7.8 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.615 (d, J = 7.8 Hz, 1H), 3.608 (d, J = 10.5 Hz, 1H), 2.37 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.2, 155.8, 140.7, 129.4, 126.8, 125.7, 77.9, 61.9, 38.9, 21.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13H 15NNaO 3 +: 256.0944, Found: 256.0956; IR (neat, cm -1): υ 2978, 2960, 2927, 1752, 1204, 1183, 1030, 901, 819。 Yield: 87% yield; 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 10.5, 7.8 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.615 (d, J = 7.8 Hz, 1H), 3.608 (d, J = 10.5 Hz, 1H), 2.37 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.2, 155.8, 140.7, 129.4, 126.8, 125.7, 77.9, 61.9, 38.9, 21.4, 14.0; HRMS (ESI-TOF) : Anal. Calcd. For C 13 H 15 NNaO 3 + : 256.0944, Found: 256.0956; IR (neat, cm -1 ): υ 2978, 2960, 2927, 1752, 1204, 1183, 1030, 901, 819.
Figure 165451dest_path_image014
。
Figure 165451dest_path_image014
.
产率：91%; 1H NMR (400 MHz, CDCl 3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 5.12 (dd, J = 10.2, 8.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.64 – 3.59 (m, 2H), 1.32-1.26 (m, 12H); 13C NMR (100 MHz, CDCl 3) δ 170.1, 155.7, 153.7, 126.6, 125.6, 125.5, 77.8, 61.7, 38.8, 34.7, 31.0, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C 16H 21NNaO 3 +: 298.1414, Found: 298.1427; IR (neat, cm -1): υ 2983, 2938, 1735, 1513, 1203, 1158, 893, 836。 Yield: 91%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 5.12 (dd, J = 10.2, 8.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.64 – 3.59 (m, 2H), 1.32-1.26 (m, 12H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.1, 155.7, 153.7, 126.6, 125.6, 125.5, 77.8, 61.7, 38.8, 34.7, 31.0, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 21 NNaO 3 + : 298.1414, Found: 298.1427; IR (neat, cm -1 ): υ 2983, 2938, 1735, 1513, 1203, 1158, 893, 836.
Figure 343623dest_path_image015
。
Figure 343623dest_path_image015
.
产率：85%; 1H NMR (400 MHz, CDCl 3) δ 7.59 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.11 (dd, J = 10.3, 8.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.593 (d, J = 8.0 Hz, 1H), 3.587 (d, J = 10.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.3, 161.2, 155.4, 128.4, 121.0, 114.1, 77.8, 61.8, 55.3, 39.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13H 15NNaO 4 +: 272.0893, Found: 272.0890; IR (neat, cm -1): υ 2980, 2938, 2840, 1735, 1608, 1516, 1252, 1202, 1177, 1019, 888, 832。 Yield: 85%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.11 (dd, J = 10.3, 8.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.593 (d, J = 8.0 Hz, 1H), 3.587 (d, J = 10.3 Hz, 1H), 1.30 ( t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.3, 161.2, 155.4, 128.4, 121.0, 114.1, 77.8, 61.8, 55.3, 39.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 4 + : 272.0893, Found: 272.0890; IR (neat, cm -1 ): υ 2980, 2938, 2840, 1735, 1608, 1516, 1252, 1202, 1177, 1019, 888 , 832.
Figure 294262dest_path_image016
。
Figure 294262dest_path_image016
.
产率：84%; mp: 63-65 oC; 1H NMR (400 MHz, CDCl 3) δ 7.54 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 5.12 (dd, J = 10.3, 8.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.67 – 3.48 (m, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.0, 155.4, 141.9, 127.0, 125.6, 124.7, 77.9, 61.8, 38.6, 14.9, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13H 15NNaO 3S +: 288.0665, Found: 288.0675; IR (neat, cm -1): υ 2989, 2921, 1748, 1199, 1032, 1022, 894, 817。 Yield: 84%; mp: 63-65 oC ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 5.12 ( dd, J = 10.3, 8.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.67 – 3.48 (m, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H) ); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0, 155.4, 141.9, 127.0, 125.6, 124.7, 77.9, 61.8, 38.6, 14.9, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 3 S + : 288.0665, Found: 288.0675; IR (neat, cm -1 ): υ 2989, 2921, 1748, 1199, 1032, 1022, 894, 817.
Figure 973505dest_path_image017
。
Figure 973505dest_path_image017
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产率：73%; 1H NMR (400 MHz, CDCl 3) δ7.89 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 5.20 (dd, J = 10.5, 7.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.65 (d, J = 7.9 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.7, 154.9, 131.2 (q, J = 32.7 Hz), 129.9, 129.4, 129.3, 126.9 (q, J = 3.7 Hz), 123.6 (q, J = 272.3 Hz), 123.6 (q, J = 3.8 Hz), 78.4, 62.1, 38.4, 14.0; 19F NMR (376 MHz, CDCl 3) δ -62.9; HRMS (ESI-TOF): Anal. Calcd. For C 13H 12F 3NNaO 3 +: 310.0661, Found: 310.0648; IR (neat, cm -1): υ 2979, 2938, 2907, 1738, 1311, 1165, 1122, 1098, 900, 803, 693。 Yield: 73%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 5.20 (dd, J = 10.5, 7.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.65 (d, J = 7.9 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.7, 154.9, 131.2 (q, J = 32.7 Hz), 129.9, 129.4, 129.3, 126.9 (q, J = 3.7 Hz), 123.6 (q, J = 272.3 Hz), 123.6 (q, J = 3.8 Hz), 78.4, 62.1, 38.4, 14.0; 19 F NMR (376 MHz, CDCl 3 ) δ -62.9; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 12 F 3 NNaO 3 + : 310.0661, Found: 310.0648; IR (neat, cm -1 ): υ 2979, 2938, 2907, 1738, 1311, 1165, 1122, 1098, 900, 803, 693.
Figure 60409dest_path_image018
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Figure 60409dest_path_image018
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产率：71%; 1H NMR (400 MHz, CDCl 3) δ 7.87 – 7.82 (m, 1H), 7.43 – 7.35 (m, 1H), 7.18 – 7.13 (m, 1H), 7.12 – 7.06 (m, 1H), 5.14 (dd, J = 10.0, 8.6 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.72 – 3.68 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.0, 160.3 (d, J = 252.7 Hz), 152.7 (d, J = 3.0 Hz), 132.1 (d, J = 8.6 Hz), 129.1 (d, J = 3.0 Hz), 124.4 (d, J = 3.4 Hz), 116.6 (d, J = 11.5 Hz), 116.3 (d, J = 22.0 Hz), 78.1 (d, J = 2.3 Hz), 61.8, 40.4 (d, J = 7.7 Hz), 14.0; 19F NMR (376 MHz, CDCl 3) δ -112.5; HRMS (ESI-TOF): Anal. Calcd. For C 12H 12FNNaO 3 +: 260.0693, Found: 260.0684; IR (neat, cm -1): υ 2983, 2929, 2854, 1736, 1454, 1203, 1027, 898, 758。 Yield: 71%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 – 7.82 (m, 1H), 7.43 – 7.35 (m, 1H), 7.18 – 7.13 (m, 1H), 7.12 – 7.06 (m, 1H), 5.14 (dd, J = 10.0, 8.6 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.72 – 3.68 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0, 160.3 (d, J = 252.7 Hz), 152.7 (d, J = 3.0 Hz), 132.1 (d, J = 8.6 Hz), 129.1 (d, J = 3.0 Hz), 124.4 (d, J = 3.4 Hz), 116.6 (d, J = 11.5 Hz), 116.3 (d, J = 22.0 Hz), 78.1 (d, J = 2.3 Hz), 61.8, 40.4 (d, J = 7.7 Hz), 14.0; 19 F NMR (376 MHz, CDCl 3 ) δ -112.5; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 FNNaO 3 + : 260.0693, Found: 260.0684; IR (neat , cm -1 ): υ 2983, 2929, 2854, 1736, 1454, 1203, 1027, 898, 758.
Figure 924329dest_path_image019
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Figure 924329dest_path_image019
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产率：83%; 1H NMR (400 MHz, CDCl 3) δ 7.62 (dd, J = 7.6, 1.3 Hz, 1H), 7.53 (dd, J = 7.6, 1.8 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.31 – 7.26 (m, 1H), 5.20 (dd, J = 11.0, 7.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.83 (dd, J = 17.3, 11.0 Hz, 1H), 3.76 (dd, J = 17.3, 7.0 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.9, 156.9, 133.6, 131.2, 130.9, 130.1, 127.5, 121.7, 78.4, 61.8, 41.2, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12H 12 79BrNNaO 3 +: 319.9893, C 12H 12 81BrNNaO 3 +: 321.9872, Found: 319.9874, 321.9912; IR (neat, cm -1): υ 2982, 2938, 1736, 1341, 1200, 1026, 1016, 852, 756。 Yield: 83%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (dd, J = 7.6, 1.3 Hz, 1H), 7.53 (dd, J = 7.6, 1.8 Hz, 1H), 7.38 – 7.33 (m , 1H), 7.31 – 7.26 (m, 1H), 5.20 (dd, J = 11.0, 7.0 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.83 (dd, J = 17.3, 11.0 Hz, 1H), 3.76 (dd, J = 17.3, 7.0 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.9, 156.9, 133.6, 131.2, 130.9, 130.1, 127.5, 121.7, 78.4, 61.8, 41.2, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 79 BrNNaO 3 + : 319.9893, C 12 H 12 81 BrNNaO 3 + : 321.9872, Found: 319.9874, 321.9912; IR (neat, cm -1 ): υ 2982, 2938, 1736, 1341, 1200, 1026, 1016, 852, 756.
Figure 96684dest_path_image020
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Figure 96684dest_path_image020
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产率：87%; 1H NMR (400 MHz, CDCl 3) δ 7.35 – 7.20 (m, 4H), 5.10 (t, J = 9.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 9.0 Hz, 2H), 2.55 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.2, 156.7, 138.1, 131.5, 129.6, 128.8, 127.6, 125.7, 77.0, 61.8, 41.3, 22.8, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13H 15NNaO 3 +: 256.0944, Found: 256.0940; IR (neat, cm -1): υ 2981, 2928, 1735, 1336, 1200, 1030, 889, 852, 758。 Yield: 87%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 – 7.20 (m, 4H), 5.10 (t, J = 9.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 9.0 Hz, 2H), 2.55 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.2, 156.7, 138.1, 131.5, 129.6, 128.8, 127.6, 125.7, 77.0, 61.8, 41.3, 22.8, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 3 + : 256.0944, Found: 256.0940; IR (neat, cm - 1 ): υ 2981, 2928, 1735, 1336, 1200, 1030, 889, 852, 758.
Figure 314039dest_path_image021
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Figure 314039dest_path_image021
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产率：67%; 1H NMR (400 MHz, CDCl 3) δ7.74 (dd, J = 7.7, 1.8 Hz, 1H), 7.36 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 6.99 – 6.88 (m, 2H), 5.08 (dd, J = 11.3, 7.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.74 (d, J = 11.3 Hz, 1H), 3.70 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.5, 157.4, 155.4, 131.6, 129.4, 120.7, 117.6, 111.3, 77.9, 61.6, 55.4, 41.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13H 15NNaO 4 +: 272.0893, Found: 272.0891; IR (neat, cm -1): υ 2981, 2940, 2840, 1735, 1600, 1462, 1248, 1199, 1026, 891, 853, 754。 Yield: 67%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (dd, J = 7.7, 1.8 Hz, 1H), 7.36 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 6.99 – 6.88 (m, 2H), 5.08 (dd, J = 11.3, 7.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 3.74 (d, J = 11.3 Hz, 1H) ), 3.70 (d, J = 7.2 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.5, 157.4, 155.4, 131.6, 129.4, 120.7, 117.6 , 111.3, 77.9, 61.6, 55.4, 41.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 15 NNaO 4 + : 272.0893, Found: 272.0891; IR (neat, cm -1 ): υ 2981 , 2940, 2840, 1735, 1600, 1462, 1248, 1199, 1026, 891, 853, 754.
Figure 521029dest_path_image022
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Figure 521029dest_path_image022
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产率：69%; 1H NMR (400 MHz, CDCl 3) δ7.77 (dd, J = 7.8, 1.7 Hz, 1H), 7.38 – 7.33 (m, 1H), 6.98 – 6.88 (m, 2H), 5.10 (dd, J = 11.0, 7.2 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.86 – 3.68 (m, 2H), 1.43 (t, J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.6, 156.8, 155.6, 131.5, 129.4, 120.6, 117.6, 112.0, 78.0, 63.9, 61.6, 41.5, 14.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14H 17NNaO 4 +: 286.1050, Found: 286.1063; IR (neat, cm -1): υ 2983, 2950, 2939, 2890, 1730, 1453, 1282, 1255, 1030, 888, 760。 Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (dd, J = 7.8, 1.7 Hz, 1H), 7.38 – 7.33 (m, 1H), 6.98 – 6.88 (m, 2H), 5.10 (dd, J = 11.0, 7.2 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.86 – 3.68 (m, 2H), 1.43 (t , J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.6, 156.8, 155.6, 131.5, 129.4, 120.6, 117.6, 112.0, 78.0, 63.9, 61.6, 41.5, 14.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 17 NNaO 4 + : 286.1050, Found: 286.1063; IR (neat, cm -1 ): υ 2983, 2950, 2939, 2890, 1730, 1453, 1282, 1255, 1030, 888, 760.
Figure 41004dest_path_image023
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Figure 41004dest_path_image023
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产率：51%; 1H NMR (400 MHz, CDCl 3) δ 9.54 (s, 1H), 7.37 – 7.30 (m, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.95 – 6.89 (m, 1H), 5.13 (dd, J = 10.8, 7.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.79 – 3.68 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.6, 157.8, 157.3, 132.1, 128.5, 119.6, 117.1, 113.0, 76.7, 62.2, 39.0, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 12H 13NNaO 4 +: 258.0737, Found: 258.0730; IR (neat, cm -1): υ 3211, 3057, 2984, 2939, 1737, 1494, 1258, 1201, 1157, 754, 655。 Yield: 51%; 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (s, 1H), 7.37 – 7.30 (m, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.95 – 6.89 (m, 1H), 5.13 (dd, J = 10.8, 7.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.79 – 3.68 (m, 2H) , 1.32 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.6, 157.8, 157.3, 132.1, 128.5, 119.6, 117.1, 113.0, 76.7, 62.2, 39.0, 14.0; HRMS ( ESI-TOF): Anal. Calcd. For C 12 H 13 NNaO 4 + : 258.0737, Found: 258.0730; IR (neat, cm -1 ): υ 3211, 3057, 2984, 2939, 1737, 1494, 1258, 1201, 1157, 754, 655.
Figure 700655dest_path_image024
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Figure 700655dest_path_image024
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产率：77%; 1H NMR (400 MHz, CDCl 3) δ 7.55 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.09 (dd, J = 9.8, 8.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.09 – 4.04 (m, 2H), 3.94 (t, J = 4.5 Hz, 2H), 3.67 – 3.45 (m, 2H), 2.65 (s, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.2, 160.3, 155.4, 128.4, 121.2, 114.6, 77.7, 69.2, 61.8, 61.0, 38.9, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14H 17NNaO 5 +: 302.0999, Found: 302.0989; IR (neat, cm -1): υ 3412, 2993, 2944, 1742, 1257, 1210, 1169, 1076, 1026, 890, 837, 818。 Yield: 77%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.09 (dd, J = 9.8, 8.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.09 – 4.04 (m, 2H), 3.94 (t, J = 4.5 Hz, 2H), 3.67 – 3.45 (m, 2H), 2.65 (s , 1H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.2, 160.3, 155.4, 128.4, 121.2, 114.6, 77.7, 69.2, 61.8, 61.0, 38.9, 14.0 ; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 17 NNaO 5 + : 302.0999, Found: 302.0989; IR (neat, cm -1 ): υ 3412, 2993, 2944, 1742, 1257, 1210, 1169 , 1076, 1026, 890, 837, 818.
Figure 721701dest_path_image025
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Figure 721701dest_path_image025
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产率：74%; 1H NMR (400 MHz, CDCl 3) δ7.76 – 7.71 (m, 1H), 7.33 – 7.26 (m, 2H), 5.15 (t, J = 9.3 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.68 (d, J = 9.3 Hz, 1H), 3.67 (d, J = 9.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.8, 159.8 (d, J = 257.1 Hz), 152.0 (d, J = 3.3 Hz), 130.0 (d, J = 3.6 Hz), 128.0 (d, J = 3.4 Hz), 124.9 (d, J = 9.8 Hz), 120.0 (d, J = 25.4 Hz), 115.8 (d, J = 11.7 Hz), 78.3 (d, J = 2.5 Hz), 61.9, 40.1 (d, J = 7.7 Hz), 14.0; 19F NMR (376 MHz, CDCl 3) δ -100.3; HRMS (ESI-TOF): Anal. Calcd. For C 12H 11 79BrFNNaO 3 +: 337.9799, C 12H 11 81BrFNNaO 3 +: 339.9778, Found: 337.9795, 339.9771; IR (neat, cm -1): υ 3072, 2985, 2929, 2855, 1726, 1594, 1203, 1170, 908, 878, 869, 823。 Yield: 74%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 – 7.71 (m, 1H), 7.33 – 7.26 (m, 2H), 5.15 (t, J = 9.3 Hz, 1H), 4.25 ( q, J = 7.1 Hz, 2H), 3.68 (d, J = 9.3 Hz, 1H), 3.67 (d, J = 9.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR ( 100 MHz, CDCl 3 ) δ 169.8, 159.8 (d, J = 257.1 Hz), 152.0 (d, J = 3.3 Hz), 130.0 (d, J = 3.6 Hz), 128.0 (d, J = 3.4 Hz), 124.9 (d, J = 9.8 Hz), 120.0 (d, J = 25.4 Hz), 115.8 (d, J = 11.7 Hz), 78.3 (d, J = 2.5 Hz), 61.9, 40.1 (d, J = 7.7 Hz) , 14.0; 19 F NMR (376 MHz, CDCl 3 ) δ -100.3; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 11 79 BrFNNaO 3 + : 337.9799, C 12 H 11 81 BrFNNaO 3 + : 339.9778 , Found: 337.9795, 339.9771; IR (neat, cm -1 ): υ 3072, 2985, 2929, 2855, 1726, 1594, 1203, 1170, 908, 878, 869, 823.
Figure 783198dest_path_image026
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Figure 783198dest_path_image026
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产率：62%; 1H NMR (400 MHz, CDCl 3) δ 9.55 (s, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 5.16 (dd, J = 11.0, 7.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.81 – 3.61 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.3, 156.9, 155.9, 131.9, 127.7, 124.3, 118.6, 114.3, 77.0, 62.4, 38.8, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C 12H 12 35ClNNaO 4 +: 292.0347, Found: 292.0329; IR (neat, cm -1): υ 3072, 2996, 2967, 2930, 2911, 1751, 1384, 1204, 1193, 1170, 812, 667。 Yield: 62%; 1 H NMR (400 MHz, CDCl 3 ) δ 9.55 (s, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 5.16 (dd, J = 11.0, 7.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.81 – 3.61 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H) ); 13 C NMR (100 MHz, CDCl 3 ) δ 169.3, 156.9, 155.9, 131.9, 127.7, 124.3, 118.6, 114.3, 77.0, 62.4, 38.8, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 35 ClNNaO 4 + : 292.0347, Found: 292.0329; IR (neat, cm -1 ): υ 3072, 2996, 2967, 2930, 2911, 1751, 1384, 1204, 1193, 1170, 812, 667.
Figure 487455dest_path_image027
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Figure 487455dest_path_image027
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产率：76%; 1H NMR (400 MHz, CDCl 3) δ8.99 (d, J = 8.6 Hz, 1H), 7.91 – 7.85 (m, 2H), 7.62 – 7.57 (m, 1H), 7.56 – 7.50 (m, 2H), 7.45 (dd, J = 8.1, 7.3 Hz, 1H), 5.17 (dd, J = 9.8, 8.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.85 – 3.78 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.1, 156.4, 133.8, 131.1, 130.4, 128.4, 127.8, 127.5, 126.9, 126.3, 125.4, 124.6, 77.0, 61.9, 41.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 16H 15NNaO 3 +: 292.0944, Found: 292.0934; IR (neat, cm -1): υ 3050, 2982, 2938, 1735, 1318, 1202, 1024, 891, 801, 773。 Yield: 76%; 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (d, J = 8.6 Hz, 1H), 7.91 – 7.85 (m, 2H), 7.62 – 7.57 (m, 1H), 7.56 – 7.50 (m, 2H), 7.45 (dd, J = 8.1, 7.3 Hz, 1H), 5.17 (dd, J = 9.8, 8.2 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.85 – 3.78 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.1, 156.4, 133.8, 131.1, 130.4, 128.4, 127.8, 127.5, 126.9, 126.3, 125.4 , 124.6, 77.0, 61.9, 41.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 15 NNaO 3 + : 292.0944, Found: 292.0934; IR (neat, cm -1 ): υ 3050, 2982 , 2938, 1735, 1318, 1202, 1024, 891, 801, 773.
Figure 634403dest_path_image028
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Figure 634403dest_path_image028
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产率：77%; 1H NMR (400 MHz, CDCl 3) δ7.31 (s, 1H), 6.45 (s, 1H), 5.02 (dd, J = 11.2, 7.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 – 3.63 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.6, 154.9, 152.5, 151.7, 143.0, 111.1, 108.6, 96.9, 77.8, 61.5, 56.14, 56.11, 55.8, 41.4, 13.9; HRMS (ESI-TOF): Anal. Calcd. For C 15H 19NNaO 6 +: 332.1105, Found: 332.1104; IR (neat, cm -1): υ 3003, 2978, 2939, 2839, 1715, 1462, 1271, 1207, 1162, 1025, 797。 Yield: 77%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 1H), 6.45 (s, 1H), 5.02 (dd, J = 11.2, 7.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.75 – 3.63 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.6, 154.9, 152.5, 151.7, 143.0, 111.1, 108.6, 96.9, 77.8, 61.5, 56.14, 56.11, 55.8, 41.4, 13.9; HRMS (ESI-TOF) Anal. Calcd. For C 15 H 19 NNaO 6 + : 332.1105, Found: 332.1104; IR (neat, cm -1 ): υ 3003, 2978, 2939, 2839, 1715, 1462, 1271, 1207, 1162, 1025, 797.
Figure 193560dest_path_image029
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Figure 193560dest_path_image029
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产率：69%; 1H NMR (400 MHz, CDCl 3) δ 7.83 – 7.74 (m, 2H), 7.42 – 7.32 (m, 3H), 5.20 (dd, J = 11.2, 7.2 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.80 – 3.62 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.7, 152.3, 140.5, 138.8, 131.0, 126.14, 126.12, 124.7, 124.2, 122.4, 78.6, 62.1, 39.0, 14.0; HRMS (EI-TOF): Anal. Calcd. For C 14H 13NO 3S: 275.0616, Found: 275.0614; IR (neat, cm -1): υ 2983, 2961, 2922, 1747, 1193, 1163, 1153, 898, 832, 749, 727。 Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 - 7.74 (m, 2H), 7.42 - 7.32 (m, 3H), 5.20 (dd, J = 11.2, 7.2 Hz, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.80 – 3.62 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.7, 152.3, 140.5, 138.8 , 131.0, 126.14, 126.12, 124.7, 124.2, 122.4, 78.6, 62.1, 39.0, 14.0; HRMS (EI-TOF): Anal. Calcd. For C 14 H 13 NO 3 S: 275.0616, Found: 275.0614; IR (neat , cm -1 ): υ 2983, 2961, 2922, 1747, 1193, 1163, 1153, 898, 832, 749, 727.
Figure 109563dest_path_image030
。
Figure 109563dest_path_image030
.
产率：69%; 1H NMR (400 MHz, CDCl 3) δ7.94 (dd, J = 8.7, 1.8 Hz, 1H), 7.88 (s, 1H), 7.85 – 7.78 (m, 3H), 7.54 – 7.46 (m, 2H), 5.20 (dd, J = 11.3, 7.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.76 (dd, J = 16.8, 7.1 Hz, 1H), 3.69 (dd, J = 16.8, 11.3 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.1, 156.0, 134.0, 132.7, 128.4, 128.3, 127.7, 127.2, 127.1, 126.6, 126.0, 123.4, 78.1, 61.9, 38.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 16H 15NNaO 3 +: 292.0944, Found: 292.0940; IR (neat, cm -1): υ 3062, 2983, 2955, 1743, 1200, 1191, 1162, 898, 821, 749。 Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (dd, J = 8.7, 1.8 Hz, 1H), 7.88 (s, 1H), 7.85 – 7.78 (m, 3H), 7.54 – 7.46 (m, 2H), 5.20 (dd, J = 11.3, 7.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.76 (dd, J = 16.8, 7.1 Hz, 1H), 3.69 (dd , J = 16.8, 11.3 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.1, 156.0, 134.0, 132.7, 128.4, 128.3, 127.7, 127.2, 127.1, 126.6, 126.0, 123.4, 78.1, 61.9, 38.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 15 NNaO 3 + : 292.0944, Found: 292.0940; IR (neat, cm -1 ) : υ 3062, 2983, 2955, 1743, 1200, 1191, 1162, 898, 821, 749.
Figure 236919dest_path_image031
。
Figure 236919dest_path_image031
.
产率：75%; 1H NMR (400 MHz, CDCl 3) δ 8.46 (s, 1H), 8.16 (dd, J = 8.1, 1.7 Hz, 1H), 7.67 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.48 – 7.37 (m, 2H), 5.10 (dd, J = 11.8, 6.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.90 (dd, J = 18.1, 11.8 Hz, 1H), 3.75 (dd, J = 18.1, 6.9 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 175.0, 170.0, 155.8, 154.9, 151.7, 134.2, 125.9, 125.8, 123.9, 118.2, 114.4, 77.9, 61.7, 40.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 15H 13NNaO 5 +: 310.0686, Found: 310.0690; IR (neat, cm -1): υ 2977, 2924, 1754, 1650, 1615, 1465, 1189, 1034, 813, 759。 Yield: 75%; 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.16 (dd, J = 8.1, 1.7 Hz, 1H), 7.67 (ddd, J = 8.7, 7.1, 1.7 Hz , 1H), 7.48 – 7.37 (m, 2H), 5.10 (dd, J = 11.8, 6.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.90 (dd, J = 18.1, 11.8 Hz, 1H), 3.75 (dd, J = 18.1, 6.9 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 175.0, 170.0, 155.8, 154.9, 151.7, 134.2, 125.9, 125.8, 123.9, 118.2, 114.4, 77.9, 61.7, 40.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 13 NNaO 5 + : 310.0686, Found: 310.0690; IR ( cm -1 ): υ 2977, 2924, 1754, 1650, 1615, 1465, 1189, 1034, 813, 759.
Figure 871163dest_path_image032
。
Figure 871163dest_path_image032
.
产率：58%; 1H NMR (400 MHz, CDCl 3) δ 7.49 – 7.42 (m, 2H), 7.39 – 7.29 (m, 3H), 7.06 (d, J = 16.5 Hz, 1H), 6.77 (d, J = 16.5 Hz, 1H), 5.10 (dd, J = 10.8, 7.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.49 (d, J = 7.5 Hz, 1H), 3.48 (d, J = 10.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.0, 156.9, 137.4, 135.4, 129.1, 128.8, 127.0, 116.8, 78.0, 61.9, 37.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14H 15NNaO 3 +: 268.0944, Found: 268.0936; IR (neat, cm -1): υ 3069, 2978, 2924, 1737, 1589, 1362, 1340, 1162, 1073, 894, 882, 785, 691。 Yield: 58%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 – 7.42 (m, 2H), 7.39 – 7.29 (m, 3H), 7.06 (d, J = 16.5 Hz, 1H), 6.77 (d , J = 16.5 Hz, 1H), 5.10 (dd, J = 10.8, 7.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.49 (d, J = 7.5 Hz, 1H), 3.48 (d , J = 10.8 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.0, 156.9, 137.4, 135.4, 129.1, 128.8, 127.0, 116.8, 78.0, 61.9, 37.4, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 15 NNaO 3 + : 268.0944, Found: 268.0936; IR (neat, cm -1 ): υ 3069, 2978, 2924, 1737, 1589, 1362, 1340, 1162, 1073, 894, 882, 785, 691.
Figure 234011dest_path_image033
。
Figure 234011dest_path_image033
.
产率：87%; 1H NMR (400 MHz, CDCl 3) δ 7.48 – 7.42 (m, 2H), 7.36 – 7.27 (m, 3H), 4.96 (dd, J = 10.5, 7.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.85 – 3.76 (m, 2H), 3.23 (s, 3H), 2.56 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.6, 163.6, 153.4, 151.3, 134.1, 129.3, 127.7, 125.3, 97.0, 76.2, 61.5, 40.7, 34.5, 14.0, 13.1; HRMS (ESI-TOF): Anal. Calcd. For C 17H 20N 3O 4 +: 330.1448, Found: 330.1468; IR (neat, cm -1): υ 2988, 2918, 2852, 1738, 1650, 1548, 1310, 1281, 1089, 1032, 976, 854, 751。 Yield: 87%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 - 7.42 (m, 2H), 7.36 - 7.27 (m, 3H), 4.96 (dd, J = 10.5, 7.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.85 – 3.76 (m, 2H), 3.23 (s, 3H), 2.56 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13 C NMR ( 100 MHz, CDCl 3 ) δ 170.6, 163.6, 153.4, 151.3, 134.1, 129.3, 127.7, 125.3, 97.0, 76.2, 61.5, 40.7, 34.5, 14.0, 13.1; HRMS (ESI-TOF): Anal. Calcd 17 H 20 N 3 O 4 + : 330.1448, Found: 330.1468; IR (neat, cm -1 ): υ 2988, 2918, 2852, 1738, 1650, 1548, 1310, 1281, 1089, 1032, 976, 854, 75 .
Figure 4521dest_path_image034
。
Figure 4521dest_path_image034
.
产率：73%; 1H NMR (400 MHz, CDCl 3) δ5.02 (dd, J = 10.7, 7.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.65 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 10.7 Hz, 1H), 2.36 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.1, 149.5, 148.3, 127.1, 106.3, 76.9, 61.8, 40.0, 36.1, 15.1, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 11H 14 35ClN 3NaO 3 +: 294.0616, C 11H 14 37ClN 3NaO 3 +: 296.0586, Found: 294.0625, 296.0592; IR (neat, cm -1): υ 2996, 2937, 2851, 1729, 1529, 1367, 1275, 1028, 892, 808。 Yield: 73%; 1 H NMR (400 MHz, CDCl 3 ) δ 5.02 (dd, J = 10.7, 7.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H) , 3.65 (d, J = 7.5 Hz, 1H), 3.64 (d, J = 10.7 Hz, 1H), 2.36 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz) , CDCl 3 ) δ 170.1, 149.5, 148.3, 127.1, 106.3, 76.9, 61.8, 40.0, 36.1, 15.1, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C 11 H 14 35 ClN 3 NaO 3 + : 294.0616, C 11 H 14 37 ClN 3 NaO 3 + : 296.0586, Found: 294.0625, 296.0592; IR (neat, cm -1 ): υ 2996, 2937, 2851, 1729, 1529, 1367, 1275, 8028 .
实施例五。Example five.
Figure 552046dest_path_image035
。
Figure 552046dest_path_image035
.
以丙烯酸丁酯为例，向具有磁力搅拌子的试管中，添加对溴苯甲醛（0.65 mmol），对甲苯磺酰肼（0.7 mmol）和MeOH（1 mL），将混合物在60 ℃下搅拌30分钟。 真空除去溶剂后，依次加入CuCl 2（0.05 mmol），THF（2.0 mL），丙烯酸丁酯（0.5 mmol），TMEDA（0.75 mmol），TBN（2.0 mmol）和THF（2.0 mL）。将试管用封口膜密封，并在65 ℃下搅拌24 h。用饱和氯化钠溶液淬灭，再用乙酸乙酯萃取后，利用旋转蒸发仪除去溶剂、硅胶吸附，最后用乙酸乙酯和石油醚的混合溶剂进行柱层析即可得产物异噁唑啉 4aj。产率：88%; 1H NMR (400 MHz, CDCl 3) δ 7.52 (s, 4H), 5.16 (dd, J = 10.4, 8.0 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 3.63 – 3.56 (m, 2H), 1.70 – 1.61 (m, 2H), 1.43– 1.32 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl 3) δ 169.9, 155.1, 131.9, 128.2, 127.5, 124.7, 78.2, 65.8, 38.5, 30.4, 18.9, 13.6; 1HRMS (ESI-TOF): Anal. Calcd. For C 14H 16 79BrNNaO 3 +: 348.0206, C 14H 16 81BrNNaO 3 +: 350.0185, Found: 348.0188, 350.0204; IR (neat, cm -1): υ 2958, 2931, 2872, 1738, 1210, 1058, 1006, 888, 861, 819. 产物4aj如下：
Figure 673586dest_path_image036
。 Taking butyl acrylate as an example, to a test tube with a magnetic stirring bar, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), and the mixture was stirred at 60 °C for 30 minute. After the solvent was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), butyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially. The test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4aj . Yield: 88%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (s, 4H), 5.16 (dd, J = 10.4, 8.0 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 3.63 – 3.56 (m, 2H), 1.70 – 1.61 (m, 2H), 1.43 – 1.32 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.9, 155.1, 131.9, 128.2, 127.5, 124.7, 78.2, 65.8, 38.5, 30.4, 18.9, 13.6; 1 HRMS (ESI-TOF): Anal. Calcd. For C 14 H 16 79 BrNNaO 3 + 6 C : 348.02 H 16 81 BrNNaO 3 + : 350.0185, Found: 348.0188, 350.0204; IR (neat, cm -1 ): υ 2958, 2931, 2872, 1738, 1210, 1058, 1006, 888, 861, 819. The product 4aj is as follows:
Figure 673586dest_path_image036
.
  保持反应条件不变，仅仅更换烯烃化合物2，得到的产物以及表征如下： 
Figure 574546dest_path_image037
。 Keeping the reaction conditions unchanged, only replacing the olefin compound 2, the obtained products and their characterizations are as follows:
Figure 574546dest_path_image037
.
产率：80%; 1H NMR (400 MHz, CDCl 3) δ 7.50 (s, 4H), 5.03 (t, J = 9.4 Hz, 1H), 3.53 (d, J = 9.4 Hz, 2H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl 3) δ 168.8, 154.9, 131.8, 128.2, 127.6, 124.5, 82.7, 78.9, 38.3, 27.8; 1HRMS (ESI-TOF): Anal. Calcd. For C 14H 16 79BrNNaO 3 +: 348.0206, C 14H 16 81BrNNaO 3 +: 350.0185, Found: 348.0195, 350.0200; IR (neat, cm -1): υ 2976, 2935, 1733, 1590, 1346, 1149, 1007, 894, 866, 834, 820。 Yield: 80%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (s, 4H), 5.03 (t, J = 9.4 Hz, 1H), 3.53 (d, J = 9.4 Hz, 2H), 1.48 ( s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.8, 154.9, 131.8, 128.2, 127.6, 124.5, 82.7, 78.9, 38.3, 27.8; 1 HRMS (ESI-TOF): Anal. Calcd. For C 14 H 16 79 BrNNaO 3 + : 348.0206, C 14 H 16 81 BrNNaO 3 + : 350.0185, Found: 348.0195, 350.0200; IR (neat, cm -1 ): υ 2976, 2935, 1733, 1590, 0179 , 894, 866, 834, 820.
Figure 465141dest_path_image038
。
Figure 465141dest_path_image038
.
产率：83%; 1H NMR (400 MHz, CDCl 3) δ 7.51 (s, 4H), 7.39 – 7.32 (m, 5H), 5.24 – 5.17 (m, 3H), 3.59 (d, J = 7.7 Hz, 1H), 3.58 (d, J = 10.7 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 169.6, 155.1, 134.8, 131.8, 128.5, 128.4, 128.2, 127.3, 124.7, 78.1, 67.4, 38.4; 1HRMS (ESI-TOF): Anal. Calcd. For C 17H 14 79BrNNaO 3 +: 382.0049, C 17H 14 81BrNNaO 3 +: 384.0029, Found: 382.0042, 384.0030; IR (neat, cm -1): υ 3068, 3037, 2955, 1755, 1174, 1162, 881, 825, 734, 693。 Yield: 83%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 4H), 7.39 – 7.32 (m, 5H), 5.24 – 5.17 (m, 3H), 3.59 (d, J = 7.7 Hz , 1H), 3.58 (d, J = 10.7 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.6, 155.1, 134.8, 131.8, 128.5, 128.4, 128.2, 127.3, 124.7, 78.1, 67.4, 38 ; 1 HRMS (ESI-TOF): Anal. Calcd. For C 17 H 14 79 BrNNaO 3 + : 382.0049, C 17 H 14 81 BrNNaO 3 + : 384.0029, Found: 382.0042, 384.0030; IR (neat, cm -1 ) : υ 3068, 3037, 2955, 1755, 1174, 1162, 881, 825, 734, 693.
Figure 934300dest_path_image039
。
Figure 934300dest_path_image039
.
产率：67%; 1H NMR (400 MHz, CDCl 3) δ 7.59 – 7.50 (m, 4H), 7.43 – 7.33 (m, 2H), 7.28 – 7.21 (m, 1H), 7.16 – 7.10 (m, 2H), 5.41 (dd, J = 11.3, 7.0 Hz, 1H), 3.77 (dd, J = 17.0, 7.0 Hz, 1H), 3.70 (dd, J = 17.0, 11.3 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 168.3, 155.2, 150.1, 131.9, 129.4, 128.3, 126.2, 124.8, 121.0, 78.1, 38.5; 1HRMS (ESI-TOF): Anal. Calcd. For C 16H 12 79BrNNaO 3 +: 367.9893, C 16H 12 81BrNNaO 3 +: 369.9872, Found: 367.9881, 369.9859; IR (neat, cm -1): υ 3070, 3043, 2976, 2927, 1773, 1589, 1489, 1193, 1162, 1069, 818, 748。 Yield: 67%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 – 7.50 (m, 4H), 7.43 – 7.33 (m, 2H), 7.28 – 7.21 (m, 1H), 7.16 – 7.10 (m, 2H), 5.41 (dd, J = 11.3, 7.0 Hz, 1H), 3.77 (dd, J = 17.0, 7.0 Hz, 1H), 3.70 (dd, J = 17.0, 11.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.3, 155.2, 150.1, 131.9, 129.4, 128.3, 126.2, 124.8, 121.0, 78.1, 38.5; 1 HRMS (ESI-TOF): Anal. Calcd. For C 16 H 12 79 BrNNaO 3 + : 367.9893, C 16 H 12 81 BrNNaO 3 + : 369.9872, Found: 367.9881, 369.9859; IR (neat, cm -1 ): υ 3070, 3043, 2976, 2927, 1773, 1589, 1168, 109, 83, , 748.
Figure 277556dest_path_image040
。
Figure 277556dest_path_image040
.
产率：60%; 1H NMR (400 MHz, CDCl 3) δ 7.58 – 7.52 (m, 4H), 5.28 (dd, J = 11.1, 7.0 Hz, 1H), 4.65 (dq, J = 12.6, 8.3 Hz, 1H), 4.53 (dq, J = 12.6, 8.3 Hz, 1H), 3.76 – 3.56 (m, 2H); 13C NMR (100 MHz, CDCl 3) δ 168.4, 155.1, 132.1, 128.4, 127.1, 125.1, 122.5 (q, J = 277.2 Hz), 77.5, 61.2 (q, J = 37.1 Hz), 38.7; 19F NMR (376 MHz, CDCl 3) δ -73.7; HRMS (ESI-TOF): Anal. Calcd. For C 12H 9 79BrF 3NNaO 3 +: 373.9610, C 12H 9 81BrF 3NNaO 3 +: 375.9590, Found: 373.9605, 375.9593; IR (neat, cm -1): υ 2991, 2977, 2923, 1772, 1274, 1176, 1161, 1054, 971, 894, 824。 Yield: 60%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 – 7.52 (m, 4H), 5.28 (dd, J = 11.1, 7.0 Hz, 1H), 4.65 (dq, J = 12.6, 8.3 Hz) , 1H), 4.53 (dq, J = 12.6, 8.3 Hz, 1H), 3.76 – 3.56 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 168.4, 155.1, 132.1, 128.4, 127.1, 125.1, 122.5 (q, J = 277.2 Hz), 77.5, 61.2 (q, J = 37.1 Hz), 38.7; 19 F NMR (376 MHz, CDCl 3 ) δ -73.7; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 9 79 BrF 3 NNaO 3 + : 373.9610, C 12 H 9 81 BrF 3 NNaO 3 + : 375.9590, Found: 373.9605, 375.9593; IR (neat, cm -1 ): υ 2991, 2977, 2923, 1772 1274, 1176, 1161, 1054, 971, 894, 824.
Figure 247787dest_path_image041
。
Figure 247787dest_path_image041
.
产率：60%; 1H NMR (400 MHz, CDCl 3) δ 7.51 (s, 4H), 5.21 (t, J = 9.2 Hz, 1H), 4.81 (dd, J = 15.5, 2.5 Hz, 1H), 4.75 (dd, J = 15.5, 2.5 Hz, 1H), 3.62 (d, J = 9.2 Hz, 2H), 2.52 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 169.1, 155.1, 132.0, 128.3, 127.2, 124.8, 77.8, 76.6, 75.8, 53.2, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C 13H 10 79BrNNaO 3 +: 329.9736, C 13H 10 81BrNNaO 3 +: 331.9716, Found: 329.9721, 331.9710; IR (neat, cm -1): υ 3277, 2977, 2945, 1742, 1219, 1204, 1069, 1021, 895, 884, 821, 638。 Yield: 60%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 4H), 5.21 (t, J = 9.2 Hz, 1H), 4.81 (dd, J = 15.5, 2.5 Hz, 1H), 4.75 (dd, J = 15.5, 2.5 Hz, 1H), 3.62 (d, J = 9.2 Hz, 2H), 2.52 (t, J = 2.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 169.1 , 155.1, 132.0, 128.3, 127.2, 124.8, 77.8, 76.6, 75.8, 53.2, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C 13 H 10 79 BrNNaO 3 + : 329.9736, C 13 H BrNNaO 10 8 3 + : 331.9716, Found: 329.9721, 331.9710; IR (neat, cm -1 ): υ 3277, 2977, 2945, 1742, 1219, 1204, 1069, 1021, 895, 884, 821, 638.
Figure 992889dest_path_image042
。
Figure 992889dest_path_image042
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产率：81%; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 5.60 (dd, J = 11.3, 7.2 Hz, 1H), 3.78 (dd, J = 17.0, 7.2 Hz, 1H), 3.54 (dd, J = 17.0, 11.3 Hz, 1H), 3.11 (s, 3H), 2.88 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 167.4, 156.1, 131.9, 128.7, 128.1, 123.7, 77.4, 36.72, 36.70, 35.4; HRMS (ESI-TOF): Anal. Calcd. For C 12H 13 79BrN 2NaO 2 +: 319.0053, C 12H 13 81BrN 2NaO 2 +: 321.0032, Found: 319.0041, 321.0030; IR (neat, cm -1): υ 2925, 2860, 1649, 1396, 1151, 1003, 897, 824。 Yield: 81%; 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 5.60 (dd, J = 11.3, 7.2 Hz, 1H), 3.78 (dd, J = 17.0, 7.2 Hz, 1H), 3.54 (dd, J = 17.0, 11.3 Hz, 1H), 3.11 (s, 3H), 2.88 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 167.4, 156.1, 131.9, 128.7, 128.1, 123.7, 77.4, 36.72, 36.70, 35.4; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 13 79 BrN 2 NaO 2 + : 319.0053, C 12 H 13 81 BrN 2 NaO 2 + : 321.0032, Found: 319.0041, 321.0030; IR (neat, cm -1 ): υ 2925, 2860, 1649, 1396, 1151, 1003, 897.
Figure 383681dest_path_image043
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Figure 383681dest_path_image043
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产率：85% yield (137.9 mg); mp: 114-116 oC; 1H NMR (400 MHz, Benzene-d6) δ 7.22 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.78 (dd, J = 11.2, 7.7 Hz, 1H), 4.11 (dd, J = 16.6, 7.7 Hz, 1H), 3.18 – 3.07 (m, 3H), 3.00 (dq, J = 14.4, 7.1 Hz, 1H), 2.63 (dd, J = 16.6, 11.2 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Benzene-d6) δ 166.3, 156.3, 132.0, 128.7, 128.6, 124.3, 78.8, 41.8, 40.7, 36.7, 14.4, 12.8; HRMS (ESI-TOF): Anal. Calcd. For C 14H 17 79BrN 2NaO 2 +: 347.0366, C 14H 17 81BrN 2NaO 2 +: 349.0345, Found: 347.0332, 349.0329; IR (neat, cm -1): υ 2968, 2930, 2871, 1633, 1261, 1068, 1005, 895, 830。 Yield: 85% yield (137.9 mg); mp: 114-116 oC ; 1 H NMR (400 MHz, Benzene-d6) δ 7.22 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz , 2H), 4.78 (dd, J = 11.2, 7.7 Hz, 1H), 4.11 (dd, J = 16.6, 7.7 Hz, 1H), 3.18 – 3.07 (m, 3H), 3.00 (dq, J = 14.4, 7.1 Hz, 1H), 2.63 (dd, J = 16.6, 11.2 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, Benzene-d6) δ 166.3, 156.3, 132.0, 128.7, 128.6, 124.3, 78.8, 41.8, 40.7, 36.7, 14.4, 12.8; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 17 79 BrN 2 NaO 2 + : 347.0366, C 14 H 17 81 BrN 2 NaO 2 + : 349.0345, Found: 347.0332, 349.0329; IR (neat, cm -1 ): υ 2968, 2930, 2871, 1633, 1261, 1068, 1005, 8 .
Figure 214234dest_path_image044
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Figure 214234dest_path_image044
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产率：45%; 1H NMR (400 MHz, DMSO-d6) δ 8.14 (t, J = 5.7 Hz, 1H), 7.68 – 7.60 (m, 4H), 5.12 (dd, J = 11.6, 7.0 Hz, 1H), 4.71 (t, J = 5.5 Hz, 1H), 3.68 (dd, J = 17.2, 11.6 Hz, 1H), 3.54 (dd, J = 17.2, 7.0 Hz, 1H), 3.45 – 3.40 (m, 2H), 3.26 – 3.10 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.7, 156.0, 131.9, 128.8, 128.0, 123.8, 79.4, 59.6, 41.6, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C 12H 13 79BrN 2NaO 3 +: 335.0002, C 12H 13 81BrN 2NaO 3 +: 336.9981, Found: 334.9983, 336.9962; IR (neat, cm -1): υ 3240, 2950, 2924, 2887, 1641, 1535, 1204, 1058, 1038, 902, 825。 Yield: 45%; 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (t, J = 5.7 Hz, 1H), 7.68 – 7.60 (m, 4H), 5.12 (dd, J = 11.6, 7.0 Hz, 1H), 4.71 (t, J = 5.5 Hz, 1H), 3.68 (dd, J = 17.2, 11.6 Hz, 1H), 3.54 (dd, J = 17.2, 7.0 Hz, 1H), 3.45 – 3.40 (m, 2H) ), 3.26 – 3.10 (m, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 169.7, 156.0, 131.9, 128.8, 128.0, 123.8, 79.4, 59.6, 41.6, 38.5; HRMS (ESI-TOF): Anal. Calcd. For C 12 H 13 79 BrN 2 NaO 3 + : 335.0002, C 12 H 13 81 BrN 2 NaO 3 + : 336.9981, Found: 334.9983, 336.9962; IR (neat, cm -1 ): υ 3240, 2950 , 2924, 2887, 1641, 1535, 1204, 1058, 1038, 902, 825.
Figure 456996dest_path_image045
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Figure 456996dest_path_image045
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产率：75%; 1H NMR (400 MHz, DMSO-d6) δ 7.73 – 7.59 (m, 4H), 5.62 (dd, J = 11.4, 7.2 Hz, 1H), 3.83 (dd, J = 17.0, 7.2 Hz, 1H), 3.73 – 3.43 (m, 9H); 13C NMR (100 MHz, DMSO-d6) δ 166.2, 156.2, 131.9, 128.8, 128.0, 123.8, 77.2, 66.2, 66.1, 45.8, 42.3, 36.6; HRMS (ESI-TOF): Anal. Calcd. For C 14H 15 79BrN 2NaO 3 +: 361.0158, C 14H 15 81BrN 2NaO 3 +: 363.0138, Found: 361.0139, 363.0139; IR (neat, cm -1): υ 2969, 2930, 2860, 1637, 1422, 1234, 1113, 1024, 891, 826。 Yield: 75%; 1 H NMR (400 MHz, DMSO-d6) δ 7.73 - 7.59 (m, 4H), 5.62 (dd, J = 11.4, 7.2 Hz, 1H), 3.83 (dd, J = 17.0, 7.2 Hz, 1H), 3.73 – 3.43 (m, 9H); 13 C NMR (100 MHz, DMSO-d6) δ 166.2, 156.2, 131.9, 128.8, 128.0, 123.8, 77.2, 66.2, 66.1, 45.8, 42.3, 36.6; HRMS (ESI-TOF): Anal. Calcd. For C 14 H 15 79 BrN 2 NaO 3 + : 361.0158, C 14 H 15 81 BrN 2 NaO 3 + : 363.0138, Found: 361.0139, 363.0139; IR (neat, cm - 1 ): υ 2969, 2930, 2860, 1637, 1422, 1234, 1113, 1024, 891, 826.
Figure 322184dest_path_image046
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Figure 322184dest_path_image046
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产率：53%; 1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.58 (s, 5H), 7.44 (s, 1H), 5.07 (dd, J = 11.6, 7.0 Hz, 1H), 3.66 (dd, J = 17.3, 11.7 Hz, 1H), 3.53 (dd, J = 17.3, 7.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 171.9, 155.8, 131.9, 128.8, 128.0, 123.8, 79.3, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C 10H 9 79BrN 2NaO 2 +: 290.9740, C 10H 9 81BrN 2NaO 2 +: 292.9719, Found: 290.9724, 292.9711; IR (neat, cm -1): υ 3410, 3185, 2969, 2928, 1650, 1591, 1401, 1010, 896, 820。 Yield: 53%; 1 H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.58 (s, 5H), 7.44 (s, 1H), 5.07 (dd, J = 11.6, 7.0 Hz, 1H), 3.66 ( dd, J = 17.3, 11.7 Hz, 1H), 3.53 (dd, J = 17.3, 7.0 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 171.9, 155.8, 131.9, 128.8, 128.0, 123.8, 79.3, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C 10 H 9 79 BrN 2 NaO 2 + : 290.9740, C 10 H 9 81 BrN 2 NaO 2 + : 292.9719, Found: 290.9724, 292.9711; IR ( neat, cm -1 ): υ 3410, 3185, 2969, 2928, 1650, 1591, 1401, 1010, 896, 820.
Figure 133145dest_path_image047
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Figure 133145dest_path_image047
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产率：56%; 1H NMR (400 MHz, CDCl 3) δ 7.58 – 7.51 (m, 4H), 7.41 – 7.30 (m, 5H), 5.75 (dd, J = 11.0, 8.3 Hz, 1H), 3.75 (dd, J = 16.6, 11.0 Hz, 1H), 3.31 (dd, J = 16.6, 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 155.3, 140.6, 131.9, 128.8, 128.4, 128.3, 128.1, 125.8, 124.4, 82.8, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15H 12 79BrNNaO +: 323.9994, C 15H 12 81BrNNaO +: 325.9974, Found: 323.9984, 325.9967; IR (neat, cm -1): υ 3068, 3041, 2968, 2921, 2851, 1587, 1335, 1159, 1007, 901, 830, 757, 697, 671。 Yield: 56%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 - 7.51 (m, 4H), 7.41 - 7.30 (m, 5H), 5.75 (dd, J = 11.0, 8.3 Hz, 1H), 3.75 (dd, J = 16.6, 11.0 Hz, 1H), 3.31 (dd, J = 16.6, 8.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.3, 140.6, 131.9, 128.8, 128.4, 128.3, 128.1 , 125.8 , 124.4 , 82.8 , 42.9 ; HRMS ( ESI - TOF): Anal. Calcd. neat, cm -1 ): υ 3068, 3041, 2968, 2921, 2851, 1587, 1335, 1159, 1007, 901, 830, 757, 697, 671.
Figure 450994dest_path_image048
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Figure 450994dest_path_image048
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产率：52%; 1H NMR (400 MHz, CDCl 3) δ 7.55 (s, 4H), 7.40 – 7.32 (m, 2H), 7.10 – 7.02 (m, 2H), 5.73 (dd, J = 11.0, 8.3 Hz, 1H), 3.74 (dd, J = 16.6, 11.0 Hz, 1H), 3.27 (dd, J = 16.6, 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 162.6 (d, J = 247.0 Hz), 155.3, 136.4 (d, J = 3.2 Hz), 132.0, 128.3, 128.1, 127.7 (d, J = 8.2 Hz), 124.5, 115.7 (d, J = 21.6 Hz), 82.2, 42.9; 19F NMR (376 MHz, CDCl 3) δ -113.6; HRMS (ESI-TOF): Anal. Calcd. For C 15H 11 79BrFNNaO +: 341.9900, C 15H 11 81BrFNNaO +: 343.9880, Found: 341.9896, 343.9894; IR (neat, cm -1): υ 2975, 2927, 1591, 1347, 1193, 1161, 1009, 889, 820。 Yield: 52%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 4H), 7.40 – 7.32 (m, 2H), 7.10 – 7.02 (m, 2H), 5.73 (dd, J = 11.0, 8.3 Hz, 1H), 3.74 (dd, J = 16.6, 11.0 Hz, 1H), 3.27 (dd, J = 16.6, 8.3 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 162.6 (d, J = 247.0 Hz), 155.3, 136.4 (d, J = 3.2 Hz), 132.0, 128.3, 128.1, 127.7 (d, J = 8.2 Hz), 124.5, 115.7 (d, J = 21.6 Hz), 82.2, 42.9; 19 F NMR (376 MHz, CDCl 3 ) δ -113.6; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 11 79 BrFNNaO + : 341.9900, C 15 H 11 81 BrFNNaO + : 343.9880, Found: 341.9896, 343.9894 ; IR (neat, cm -1 ): υ 2975, 2927, 1591, 1347, 1193, 1161, 1009, 889, 820.
Figure 497447dest_path_image049
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Figure 497447dest_path_image049
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产率：46%; 1H NMR (400 MHz, CDCl 3) δ 7.53 (s, 4H), 7.37 – 7.28 (m, 4H), 5.71 (dd, J = 11.0, 8.2 Hz, 1H), 3.74 (dd, J = 16.6, 11.0 Hz, 1H), 3.25 (dd, J = 16.6, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 155.2, 139.1, 134.1, 131.9, 128.9, 128.1, 127.2, 124.5, 82.0, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15H 12 79BrClNO +: 335.9785, C 15H 12 81BrClNO +: 337.9765, Found: 335.9819, 337.9777; IR (neat, cm -1): υ 3068, 2959, 2922, 1589, 1488, 1348, 1093, 1009, 908, 837, 823。 Yield: 46%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 4H), 7.37 - 7.28 (m, 4H), 5.71 (dd, J = 11.0, 8.2 Hz, 1H), 3.74 (dd , J = 16.6, 11.0 Hz, 1H), 3.25 (dd, J = 16.6, 8.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 139.1, 134.1, 131.9, 128.9, 128.1, 127.2, 124.5, 82.0, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 12 79 BrClNO + : 335.9785, C 15 H 12 81 BrClNO + : 337.9765, Found: 335.9819, 337.9777; IR (neat, cm - 1 ): υ 3068, 2959, 2922, 1589, 1488, 1348, 1093, 1009, 908, 837, 823.
Figure 217142dest_path_image050
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Figure 217142dest_path_image050
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产率：50%; 1H NMR (400 MHz, CDCl 3) δ 7.52 (s, 4H), 7.48 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.68 (dd, J = 11.0, 8.1 Hz, 1H), 3.74 (dd, J = 16.7, 11.0 Hz, 1H), 3.24 (dd, J = 16.7, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 155.2, 139.6, 131.9, 131.8, 128.09, 128.07, 127.5, 124.5, 122.2, 82.0, 42.8; HRMS (ESI-TOF): Anal. Calcd. For C 15H 12 79Br 79Br NO +: 379.9280, C 15H 12 79Br 81Br NO +: 381.9260, C 15H 12 81Br 81Br NO +: 383.9239, Found: 379.9261, 381.9252, 383.9222; IR (neat, cm -1): υ 3062, 2969, 2917, 1589, 1488, 1348, 1071, 1008, 909, 837, 820。 Yield: 50%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 (s, 4H), 7.48 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.68 ( dd, J = 11.0, 8.1 Hz, 1H), 3.74 (dd, J = 16.7, 11.0 Hz, 1H), 3.24 (dd, J = 16.7, 8.1 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 139.6, 131.9, 131.8, 128.09, 128.07, 127.5, 124.5, 122.2, 82.0, 42.8; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 12 79 Br 79 Br NO + : 159.928 H 12 79 Br 81 Br NO + : 381.9260, C 15 H 12 81 Br 81 Br NO + : 383.9239, Found: 379.9261, 381.9252, 383.9222; IR (neat, cm -1 ): υ 3062, 2969, 5917, 1488, 1348, 1071, 1008, 909, 837, 820.
Figure 448272dest_path_image051
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Figure 448272dest_path_image051
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产率：55%; 1H NMR (400 MHz, CDCl 3) δ 7.60 – 7.48 (m, 4H), 7.26 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.70 (dd, J = 11.0, 8.5 Hz, 1H), 3.70 (dd, J = 16.7, 11.0 Hz, 1H), 3.28 (dd, J = 16.7, 8.5 Hz, 1H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl 3) δ 155.3, 138.1, 137.5, 131.9, 129.4, 128.5, 128.1, 125.8, 124.3, 82.9, 42.7, 21.1; HRMS (ESI-TOF): Anal. Calcd. For C 16H 14 79BrNNaO +: 338.0151, C 16H 14 81BrNNaO +: 340.0131, Found: 338.0157, 340.0122; IR (neat, cm -1): υ 2977, 2917, 2860, 1587, 1397, 1344, 1070, 1006, 905, 831, 813。 Yield: 55%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 – 7.48 (m, 4H), 7.26 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.70 (dd, J = 11.0, 8.5 Hz, 1H), 3.70 (dd, J = 16.7, 11.0 Hz, 1H), 3.28 (dd, J = 16.7, 8.5 Hz, 1H), 2.34 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.3, 138.1, 137.5, 131.9, 129.4, 128.5, 128.1, 125.8, 124.3, 82.9, 42.7, 21.1; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 14 79 BrNNaO + : 338.0151, C 16 H 14 81 BrNNaO + : 340.0131, Found: 338.0157, 340.0122; IR (neat, cm -1 ): υ 2977, 2917, 2860, 1587, 1397, 1344, 9010 831, 813.
Figure 253417dest_path_image052
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Figure 253417dest_path_image052
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产率：57%; 1H NMR (400 MHz, CDCl 3) δ 7.54 (s, 4H), 7.37 – 7.31 (m, 1H), 7.18 – 7.07 (m, 2H), 7.04 – 6.98 (m, 1H), 5.74 (dd, J = 11.1, 8.0 Hz, 1H), 3.77 (dd, J = 16.6, 11.1 Hz, 1H), 3.28 (dd, J = 16.6, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 163.0 (d, J = 246.7 Hz), 155.2, 143.3 (d, J = 6.9 Hz), 132.0 , 130.4 (d, J = 8.1 Hz), 128.14 , 128.10 , 124.5, 121.3 (d, J = 3.0 Hz), 115.2 (d, J = 21.2 Hz), 112.8 (d, J = 22.4 Hz), 81.9 (d, J = 1.8 Hz), 42.9; 19F NMR (376 MHz, CDCl 3) δ -112.0; HRMS (ESI-TOF): Anal. Calcd. For C 15H 11 79BrFNNaO +: 341.9900, C 15H 11 81BrFNNaO +: 343.9880, Found: 341.9906, 343.9900; IR (neat, cm -1): υ 2974, 2925, 2891, 1588, 1485, 1454, 1251, 1143, 1071, 1053, 897, 873, 830, 784, 692。 Yield: 57%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (s, 4H), 7.37 – 7.31 (m, 1H), 7.18 – 7.07 (m, 2H), 7.04 – 6.98 (m, 1H) , 5.74 (dd, J = 11.1, 8.0 Hz, 1H), 3.77 (dd, J = 16.6, 11.1 Hz, 1H), 3.28 (dd, J = 16.6, 8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 163.0 (d, J = 246.7 Hz), 155.2, 143.3 (d, J = 6.9 Hz), 132.0 , 130.4 (d, J = 8.1 Hz), 128.14 , 128.10 , 124.5, 121.3 (d, J = 8.1 Hz) 3.0 Hz), 115.2 (d, J = 21.2 Hz), 112.8 (d, J = 22.4 Hz), 81.9 (d, J = 1.8 Hz), 42.9; 19 F NMR (376 MHz, CDCl 3 ) δ -112.0; HRMS (ESI-TOF): Anal. Calcd. For C 15 H 11 79 BrFNNaO + : 341.9900, C 15 H 11 81 BrFNNaO + : 343.9880, Found: 341.9906, 343.9900; IR (neat, cm -1 ): υ 2974, 2925, 2891, 1588, 1485, 1454, 1251, 1143, 1071, 1053, 897, 873, 830, 784, 692.
Figure 103561dest_path_image053
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Figure 103561dest_path_image053
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产率：57%; 1H NMR (400 MHz, CDCl 3) δ 7.53 (s, 5H), 7.46 – 7.42 (m, 1H), 7.32 – 7.28 (m, 1H), 7.26 – 7.21 (m, 1H), 5.70 (dd, J = 11.1, 8.0 Hz, 1H), 3.75 (dd, J = 16.7, 11.1 Hz, 1H), 3.27 (dd, J = 16.7, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 155.2, 143.0, 131.9, 131.3, 130.3, 128.8, 128.1, 128.0, 124.5, 124.3, 122.8, 81.8, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15H 12 79Br 79Br NO +: 379.9280, C 15H 12 79Br 81Br NO +: 381.9260, C 15H 12 81Br 81Br NO +: 383.9239, Found: 379.9266, 381.9236, 383.9210; IR (neat, cm -1): υ 3093, 3071, 2974, 2919, 1589, 1569, 1340, 1161, 1072, 894, 881, 830, 818, 785, 691, 661。 Yield: 57%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (s, 5H), 7.46 – 7.42 (m, 1H), 7.32 – 7.28 (m, 1H), 7.26 – 7.21 (m, 1H) , 5.70 (dd, J = 11.1, 8.0 Hz, 1H), 3.75 (dd, J = 16.7, 11.1 Hz, 1H), 3.27 (dd, J = 16.7, 8.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 143.0, 131.9 , 131.3, 130.3, 128.8, 128.1, 128.0, 124.5, 124.3, 122.8, 81.8, 42.9; HRMS (ESI-TOF): Anal. Calcd. For C 15 HBr 12 79 NO + : 379.9280, C 15 H 12 79 Br 81 Br NO + : 381.9260, C 15 H 12 81 Br 81 Br NO + : 383.9239, Found: 379.9266, 381.9236, 383.9210; IR (neat, cm -1 ): υ30 , 3071, 2974, 2919, 1589, 1569, 1340, 1161, 1072, 894, 881, 830, 818, 785, 691, 661.
Figure 677762dest_path_image054
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Figure 677762dest_path_image054
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产率：56%; 1H NMR (400 MHz, CDCl 3) δ 7.65 (s, 1H), 7.60 – 7.47 (m, 7H), 5.80 (dd, J = 11.1, 8.1 Hz, 1H), 3.81 (dd, J = 16.7, 11.1 Hz, 1H), 3.30 (dd, J = 16.7, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 155.2, 141.7, 132.0, 131.1 (q, J = 32.5 Hz), 129.3, 129.1, 128.1, 128.0, 125.1 (q, J = 3.7 Hz), 124.6, 122.6 (q, J = 4.0 Hz), 81.9, 43.0; 19F NMR (376 MHz, CDCl 3) δ -62.6; HRMS (ESI-TOF): Anal. Calcd. For C 16H 11 79BrF 3NNaO +: 391.9868, C 16H 11 81BrF 3NNaO +: 393.9848, Found: 391.9885, 393.9844; IR (neat, cm -1): υ 3062, 3006, 2949, 1324, 1171, 1117, 1072, 905, 895, 837, 802, 701, 661。 Yield: 56%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.60 - 7.47 (m, 7H), 5.80 (dd, J = 11.1, 8.1 Hz, 1H), 3.81 (dd , J = 16.7, 11.1 Hz, 1H), 3.30 (dd, J = 16.7, 8.1 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 155.2, 141.7, 132.0, 131.1 (q, J = 32.5 Hz ), 129.3, 129.1, 128.1, 128.0, 125.1 (q, J = 3.7 Hz), 124.6, 122.6 (q, J = 4.0 Hz), 81.9, 43.0; 19 F NMR (376 MHz, CDCl 3 ) δ -62.6; HRMS (ESI-TOF): Anal. Calcd. For C 16 H 11 79 BrF 3 NNaO + : 391.9868, C 16 H 11 81 BrF 3 NNaO + : 393.9848, Found: 391.9885, 393.9844; IR (neat, cm -1 ) : υ 3062, 3006, 2949, 1324, 1171, 1117, 1072, 905, 895, 837, 802, 701, 661.
Figure 564947dest_path_image055
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Figure 564947dest_path_image055
.
产率：60%; 1H NMR (400 MHz, CDCl 3) δ 7.55 (s, 4H), 6.03 (dd, J = 12.0, 8.5 Hz, 1H), 3.78 (dd, J = 16.8, 12.0 Hz, 1H), 3.50 (dd, J = 16.8, 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl 3) δ 154.9, 132.0, 128.2, 127.6, 124.8, 72.4, 40.6; 19F NMR (376 MHz, CDCl 3) δ -141.35 – -142.79 (m, 2F), -152.46 – -152.70 (m, 1F), -160.98 – -161.22 (m, 2F); HRMS (ESI-TOF): Anal. Calcd. For C 15H 7 79BrF 5NNaO +: 413.9523, C 15H 7 81BrF 5NNaO +: 415.9503, Found: 413.9508, 415.9506; IR (neat, cm -1): υ 3061, 2977, 2930, 1523, 1503, 1130, 1012, 964, 894, 840, 824。 Yield: 60%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 4H), 6.03 (dd, J = 12.0, 8.5 Hz, 1H), 3.78 (dd, J = 16.8, 12.0 Hz, 1H) ), 3.50 (dd, J = 16.8, 8.5 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 154.9, 132.0, 128.2, 127.6, 124.8, 72.4, 40.6; 19 F NMR (376 MHz, CDCl 3 ) ) δ -141.35 – -142.79 (m, 2F), -152.46 – -152.70 (m, 1F), -160.98 – -161.22 (m, 2F); HRMS (ESI-TOF): Anal. Calcd. For C 15 H 7 79 BrF 5 NNaO + : 413.9523, C 15 H 7 81 BrF 5 NNaO + : 415.9503, Found: 413.9508, 415.9506; IR (neat, cm -1 ): υ 3061, 2977, 2930, 1523, 10503, 1 , 964, 894, 840, 824.
实施例六：在实施例四的基础上，更换化合物1与化合物2，其余不变，得到如下产物。Embodiment 6: On the basis of Embodiment 4, compound 1 and compound 2 are replaced, and the rest remain unchanged to obtain the following product.
Figure 654125dest_path_image056
Figure 245644dest_path_image057
。
Figure 654125dest_path_image056
Figure 245644dest_path_image057
.
产率：60%; 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.6 Hz, 1H), 8.16 – 7.95 (m, 3H), 7.60 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 5.10 – 5.01 (m, 1H), 3.97 (dd, J = 15.1, 7.4 Hz, 1H), 3.89 – 3.76 (m, 4H), 3.56 (dd, J = 17.1, 10.5 Hz, 1H), 3.37 – 3.29 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 160.8, 159.0, 156.2, 136.8, 136.0, 135.4, 128.3, 126.3, 125.3, 121.7, 121.6, 114.3, 77.1, 55.4, 41.7, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C 18H 17N 2O 5S +: 373.0853, Found: 373.0859; IR (neat, cm -1): υ 3069, 2963, 2920, 2848, 1739, 1321, 1300, 1248, 1178, 1162, 1018, 839, 747, 671. 4bz 产率：36%; 1H NMR (400 MHz, CDCl 3) δ 7.57 – 7.45 (m, 1H), 7.34 – 7.28 (m, 1H), 7.21 – 7.13 (m, 1H), 6.14 (s, 1H), 4.91 – 4.83 (m, 1H), 3.63 – 3.46 (m, 2H), 3.34 (dd, J = 16.9, 10.7 Hz, 1H), 3.07 (dd, J = 16.9, 7.5 Hz, 1H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl 3) δ 170.8, 155.4, 151.5 (dd, J = 253.5, 12.6 Hz), 150.3 (dd, J = 249.8, 13.2 Hz), 126.2 (dd, J = 6.3, 4.0 Hz), 123.2 (dd, J = 6.7, 3.7 Hz), 117.7 (d, J = 17.9 Hz), 115.6 (d, J = 18.8 Hz), 80.3, 42.2, 37.3, 23.1; 19F NMR (376 MHz, CDCl 3) δ -134.0 (d, J = 22.0 Hz, 1F), -136.2 (d, J = 22.0 Hz, 1F); HRMS (ESI-TOF): Anal. Calcd. For C 12H 12F 2N 2NaO 2 +: 277.0759, Found: 277.0756; IR (neat, cm -1): υ 3294, 2988, 2942, 2926, 1738, 1651, 1225, 1192, 1026, 1009, 822。 Yield: 60%; 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 7.6 Hz, 1H), 8.16 - 7.95 (m, 3H), 7.60 (d, J = 8.8 Hz, 2H) , 7.00 (d, J = 8.8 Hz, 2H), 5.10 – 5.01 (m, 1H), 3.97 (dd, J = 15.1, 7.4 Hz, 1H), 3.89 – 3.76 (m, 4H), 3.56 (dd, J = 17.1, 10.5 Hz, 1H), 3.37 – 3.29 (m, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 160.8, 159.0, 156.2, 136.8, 136.0, 135.4, 128.3, 126.3, 125.3, 121.7, 121.6, 114.3, 77.1, 55.4, 41.7, 38.3; HRMS (ESI-TOF): Anal. Calcd. For C 18 H 17 N 2 O 5 S + : 373.0853, Found: 373.0859; IR (neat, cm -1 ): υ 3069, 2963, 2920, 2848, 1739, 1321, 1300, 1248, 1178, 1162, 1018, 839, 747, 671. 4bz yield: 36%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.57 – 7.45 (m, 1H), 7.34 – 7.28 (m, 1H), 7.21 – 7.13 (m, 1H), 6.14 (s, 1H), 4.91 – 4.83 (m, 1H), 3.63 – 3.46 (m, 2H), 3.34 (dd, J = 16.9, 10.7 Hz, 1H), 3.07 (dd, J = 16.9, 7.5 Hz, 1H), 1.97 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 170.8, 155.4, 151.5 (dd, J = 253.5, 12.6 Hz), 150.3 (dd, J = 249.8, 13.2 Hz), 126.2 (dd, J = 6.3, 4.0 Hz), 123.2 (dd, J = 6.7, 3.7 Hz), 11 7.7 (d, J = 17.9 Hz), 115.6 (d, J = 18.8 Hz), 80.3, 42.2, 37.3, 23.1; 19 F NMR (376 MHz, CDCl 3 ) δ -134.0 (d, J = 22.0 Hz, 1F ), -136.2 (d, J = 22.0 Hz, 1F); HRMS (ESI-TOF): Anal. Calcd. For C 12 H 12 F 2 N 2 NaO 2 + : 277.0759, Found: 277.0756; IR (neat, cm -1 ): υ 3294, 2988, 2942, 2926, 1738, 1651, 1225, 1192, 1026, 1009, 822.

Claims (10)

  1. 一种异噁唑啉的简单制备方法，其特征在于：以醛、对甲苯磺酰肼、烯烃和亚硝酸酯为反应底物，在碱与铜催化剂存在下，在有机溶剂中反应得到异噁唑啉；A simple preparation method of isoxazoline is characterized in that: taking aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst, reacting in an organic solvent to obtain isoxazoline oxazoline;
    其中，所述醛的化学结构通式为：
    Figure 441574dest_path_image001
    ；式中，R 1选自芳基、取代芳基、杂芳香基、萘基或者烯基；     Wherein, the general chemical structure of the aldehyde is:
    Figure 441574dest_path_image001
    ; In the formula, R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl;
    所述烯烃的化学结构通式为：
    Figure 827556dest_path_image002
    ；式中R 4、R 5独立的选自氢、烷基、芳基、酯基、醚、酰胺基、羰基、硅基、羟基、缩醛、氰基、卤素、炔基、羧基或者磷酸酯基；     The general chemical structure of the alkene is:
    Figure 827556dest_path_image002
    In the formula, R 4 and R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl or phosphate base;
    所述亚硝酸酯的化学结构通式为：
    Figure 669610dest_path_image003
    ；式中R 6选自叔丁基、正丁基、异丁基或者异丙基；     The general formula of the chemical structure of the nitrite is:
    Figure 669610dest_path_image003
    ; R in the formula is selected from tert-butyl, n-butyl, isobutyl or isopropyl;
    所述异噁唑啉的化学结构式为：
    Figure 799240dest_path_image004
    。     The chemical structural formula of the isoxazoline is:
    Figure 799240dest_path_image004
    .
  2. 根据权利要求1所述异噁唑啉的简单制备方法，其特征在于：所述反应的反应温度为25～80℃，时间为12～48小时。The simple preparation method of isoxazoline according to claim 1 is characterized in that: the reaction temperature of the reaction is 25-80 DEG C, and the time is 12-48 hours.
  3. 根据权利要求1所述异噁唑啉的简单制备方法，其特征在于：碱的用量为烯烃摩尔量的1～1.8倍；所述铜催化剂用量为烯烃摩尔量的5～20%。The simple preparation method of isoxazoline according to claim 1 is characterized in that: the consumption of alkali is 1-1.8 times of the mole of olefin; the consumption of the copper catalyst is 5-20% of the mole of olefin.
  4. 根据权利要求1所述异噁唑啉的简单制备方法，其特征在于：所述有机溶剂为乙酸乙酯、四氢呋喃、乙腈、丙酮、氯仿或者 N, N-二甲基甲酰胺；所述铜催化剂为氯化铜、氯化亚铜、溴化亚铜或者碘化亚铜。 The simple preparation method of isoxazoline according to claim 1, characterized in that: the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform or N , N -dimethylformamide; the copper catalyst It is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide.
  5. 根据权利要求1所述异噁唑啉的简单制备方法，其特征在于：所述醛化合物用量为烯烃摩尔量的1～1.5倍；对甲苯磺酰肼用量为烯烃摩尔量的1～1.5倍，亚硝酸酯用量为烯烃摩尔量的3～5倍。The simple preparation method of isoxazoline according to claim 1 is characterized in that: the amount of the aldehyde compound is 1-1.5 times the molar amount of the olefin; the amount of p-toluenesulfonyl hydrazide is 1-1.5 times the molar amount of the olefin, The amount of nitrite is 3 to 5 times the molar amount of olefin.
  6. 根据权利要求5所述异噁唑啉的简单制备方法，其特征在于：所述醛化合物用量为烯烃摩尔量的1.3倍；对甲苯磺酰肼用量为烯烃摩尔量的1.4倍，亚硝酸酯用量为烯烃摩尔量的4倍。The simple preparation method of isoxazoline according to claim 5 is characterized in that: the amount of the aldehyde compound is 1.3 times the molar amount of olefin; the amount of p-toluenesulfonyl hydrazide is 1.4 times the molar amount of olefin, and the amount of nitrite is It is 4 times the molar amount of olefin.
  7. 根据权利要求1所述异噁唑啉的简单制备方法，其特征在于：芳基或者取代芳基的化学结构通式为：
    Figure 269405dest_path_image005
    ，其中，R 2、R 3独立的选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基。     The simple preparation method of isoxazoline according to claim 1, is characterized in that: the general formula of chemical structure of aryl or substituted aryl is:
    Figure 269405dest_path_image005
    , wherein R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester , hydroxyl or sulfone group.
  8. 一种无金属催化剂制备异噁唑啉的方法，其特征在于：将苯甲醛化合物、对甲苯磺酰肼在甲醇溶剂中混合后，再加入烯烃、亚硝酸酯、有机溶剂、碱，反应得到异噁唑啉；A method for preparing isoxazoline without metal catalyst, which is characterized in that: after mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, then adding olefin, nitrite, organic solvent and alkali, and reacting to obtain isoxazoline oxazoline;
    其中，所述苯甲醛化合物的化学结构通式如下：Wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows:
    Figure 91867dest_path_image006
    Figure 91867dest_path_image006
    所述烯烃的化学结构通式为R 2-CH 2CH 2； The general chemical structure of the alkene is R 2 -CH 2 CH 2 ;
    所述亚硝酸酯的化学结构通式为O=N-OR 6； The general chemical structure of the nitrite is O=N-OR 6 ;
    所述异噁唑啉的化学结构通式如下：The general formula of the chemical structure of the isoxazoline is as follows:
    Figure 155638dest_path_image007
    Figure 155638dest_path_image007
    式中，R 1选自氢、烷基、氟、氯、溴、羧酸、酰胺、硫醚、氨基、烷氧基、三氟甲基、硝基、氰基、酯基、羟基或者砜基；R 2选自烷基、芳基、酯基、羰基、醚、酰胺基、硅基、羟基、缩苯甲醛化合物、氰基、卤素、炔基、羧基或者磷酸酯基；R 6选自叔丁基、正丁基、异丁基或者异丙基。 In the formula, R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ; R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group; R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl.
  9. 铜催化剂在催化醛、对甲苯磺酰肼、烯烃和亚硝酸酯为反应底物制备异噁唑啉中的应用。Application of copper catalyst in catalyzing aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates to prepare isoxazoline.
  10. 根据权利要求1所述异噁唑啉的简单制备方法制备的异噁唑啉。The isoxazoline prepared by the simple preparation method of isoxazoline according to claim 1.
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