CN112645895B - Isoxazoline derivative with olefin side chain and synthesis method thereof - Google Patents

Isoxazoline derivative with olefin side chain and synthesis method thereof Download PDF

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CN112645895B
CN112645895B CN202011487288.1A CN202011487288A CN112645895B CN 112645895 B CN112645895 B CN 112645895B CN 202011487288 A CN202011487288 A CN 202011487288A CN 112645895 B CN112645895 B CN 112645895B
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isoxazoline derivative
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李小青
何小雪
许响生
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Zhejiang University of Technology ZJUT
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    • 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
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • 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
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Abstract

The invention relates to the technical field of organic synthesis, and aims to solve the problem of high synthesis cost of an isoxazoline derivative with an olefin side chain in the prior art, and discloses an isoxazoline derivative with an olefin side chain and a synthesis method thereof, (1) under the protection of inert gas, allyl oxime and allyl sulfone are mixed and dissolved in a solvent, and react under the action of a catalyst and alkali to obtain isoxazoline with a structure shown in a formula I; (2) and carrying out post-treatment on the reaction product to obtain a finished product. The invention has the following beneficial effects: (1) the cheap and easily obtained trifluoromethanesulfonic acid ketone is used as a catalyst, so that a large amount of oxidant is avoided; (2) the reaction only needs catalytic amount of alkali, and meanwhile, the reaction condition is mild, the operation is simple, and the compatibility of substrate functional groups is strong; (3) the direct bifunctional functionalization of olefin by using cheap metal copper as a catalyst provides an efficient and simple method.

Description

Isoxazoline derivative with olefin side chain and synthesis method thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an isoxazoline derivative with an olefin side chain and a synthesis method thereof.
Background
Isoxazole compounds, particularly isoxazoline and analogues thereof, as chiral ligands are widely applied to the fields of biological natural products, pesticides, medicines, asymmetric catalysis and the like. Over the last few years, a great deal of research has been conducted on the synthesis of isoxazolines, including transition metal catalysis and metal-free strategies. Oxime compounds containing inactive C ═ C, particularly those compounds that are likely to form isoxazolines, are of greater interest to researchers. Most cyclization reactions are severely limited by the coordination capability of the hydroxyl group, the sensitivity to oxygen (air), and the amount of metal catalyst or the need for additional additives. In addition, the late conversion of the product in the cyclization reaction is of paramount importance, but in most cases is not easily accomplished.
Direct bifunctional functionalization of olefins is a valuable reaction which is one of the effective strategies to increase the complexity of synthesizing organic chemical molecules. The oxidative allylation of olefins is a very practical reaction because the parent product in the olefin produced offers abundant possibilities for synthetic operations. Despite significant advances in the oxygen functionalization of olefins, few researchers have explored the oxygen allylation of olefins.
The direct bifunctional synthesis of olefins by the catalytic synthesis of isoxazolines with inexpensive metallic copper has not been fully investigated, and it is therefore still necessary to explore methods for efficiently constructing structurally diverse isoxazolines and the like under environmentally friendly conditions.
Patent No. CN2018116295434, the patent name "preparation method of diastereomer 4-substituted isoxazoline", preparation method of diastereomer 4-substituted isoxazoline, relates to a preparation method of 4-substituted isoxazoline. The method aims to solve the problem that the existing method is difficult to simultaneously prepare two diastereoisomer 4-substituted isoxazolines with completely opposite configurations. The method comprises the following steps: chiral bisoxazoline is taken as a catalyst ligand, and Cu (OTf) is respectively taken 2 Or Ni (OTf) 2 As a metal center, bis-oxazoline derived from indenol is used as a chiral ligand to catalyze the reaction of acryloyl oxazolidinone, acryloyl-3, 5-dimethylpyrazole and diaryl nitrone to prepare 4-substituted isoxazoline with completely opposite configuration. 100 percent of cis-isoxazoline and trans-isoxazoline with optical activity are obtained, and the enantioselectivity of the product is respectively up to more than 92 percent and 91 percent. Alcoholysis is carried out on the cis-4-substituted product and the trans-4-substituted product respectively to obtain a pair of optically pure diastereoisomers. The invention is used for preparing diastereoisomer 4-position substituted isoxazoline. The disadvantages of the synthesis include long synthesis period and high synthesis cost.
Disclosure of Invention
The invention aims to overcome the problem of high synthesis cost of the isoxazoline derivative with the olefin side chain in the prior art, and provides the isoxazoline derivative with the olefin side chain and the synthesis method thereof, wherein the method has the advantages of simple operation, mild reaction conditions, cheap and easily obtained raw materials and good yield; the obtained isoxazoline compound has important significance in drug development and active molecule modification.
In order to achieve the purpose, the invention adopts the following technical scheme:
an isoxazoline derivative with an olefin side chain, which has a structure represented by formula I:
Figure BDA0002839690800000021
wherein R is aryl; r 1 、R 2 、R 3 Are each hydrogen or methyl; r is 4 Benzene, methyl formate, ethyl formate, tert-butyl formate, cyano and benzoyl.
A synthetic method of the isoxazoline derivative with the olefin side chain comprises the following synthetic steps:
(1) under the protection of inert gas, mixing allyl oxime and allyl sulfone, dissolving in a solvent, and reacting under the action of a catalyst and alkali to obtain isoxazoline with a structure shown in formula I;
(2) and carrying out post-treatment on the reaction product to obtain a finished product.
Under the action of alkali, allyl oxime loses hydrogen ions to form imine oxygen anions, the imine oxygen anions are oxidized by catalyst copper to form imine oxygen free radicals, carbon-center free radicals are generated through self free radical cyclization, the carbon-center free radicals are added to double bonds of allyl sulfone, and then a desulfonation reaction is carried out to obtain an isoxazoline product with an olefin side chain. The target product is unknown, and the method reports the compound for the first time.
Preferably, the allylic oxime has the structure shown in formula II:
Figure BDA0002839690800000022
wherein R is aryl; r 1 、R 2 、R 3 Are each hydrogen or methyl.
Preferably, the allyl sulfone has a structure represented by formula iii:
Figure BDA0002839690800000023
wherein R is 4 Benzene, methyl formate, ethyl formate, tert-butyl formate, cyano and benzoyl.
Preferably, the catalyst in the step (1) is Cu (OTf) 2 、CuO、Cu(acac) 2 Or CuCl 2 At least one of (a).
The copper catalyst is cheap and easy to obtain, a large amount of oxidant can be avoided, and the method only uses the catalytic amount of copper salt, is high in economy and is relatively environment-friendly.
Preferably, the base in step (1) is at least one of potassium carbonate, sodium bicarbonate or sodium carbonate.
Preferably, the solvent in step (1) is at least one of acetonitrile, tetrahydrofuran, toluene, acetone, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane, ethanol, ethyl acetate or N, N-dimethylformamide.
Preferably, in step (1), the ratio of the amounts of the substance selected from the group consisting of allyl oxime, allyl sulfone, catalyst and base is 1: 1-4: 0.05-0.15: 0.5-2.
The components are in the proportion range, the conversion rate of raw materials is high, the selectivity of products is good, and the content of byproducts is low; when the ratio is out of the range, the selectivity of the product is reduced, and by-products with unknown structures are increased, thereby reducing the purity of the isoxazoline derivative with olefin side chains.
Preferably, in step (1), the reaction temperature is 55-65 ℃.
The temperature range can ensure the smooth synthesis reaction, the reaction is incomplete when the temperature is too low, and energy is wasted when the temperature is too high.
Preferably, the post-treatment in step (2) is: extracting with ethyl acetate for 3-5 times after the reaction is finished, combining the ethyl acetate, washing with saturated saline solution for 1-2 times, drying the washed ethyl acetate solution with anhydrous sodium sulfate, drying, then concentrating under reduced pressure to obtain a crude product, carrying out column chromatography separation on the crude product, collecting and combining eluent containing the target compound by taking petroleum ether/ethyl acetate mixed solution with the volume ratio of 10-50:1 as eluent, evaporating the solvent, and drying.
The treatment process can effectively remove impurities generated except reaction products, and the target product is obtained through purification.
Therefore, the invention has the following beneficial effects:
the invention has the following beneficial effects:
(1) the cheap and easily obtained trifluoromethanesulfonic acid ketone is used as a catalyst, so that a large amount of oxidant is avoided;
(2) the reaction only needs catalytic amount of alkali, and meanwhile, the reaction condition is mild, the operation is simple, and the compatibility of substrate functional groups is strong;
(3) the direct bifunctional functionalization of olefin by using cheap metal copper as a catalyst provides an efficient and simple method.
Drawings
FIG. 1 is a schematic representation of the product, Compound 1, prepared in example 1 1 H NMR spectrum.
FIG. 2 is the product of Compound 2 prepared in example 2 1 H NMR spectrum.
FIG. 3 is the product of Compound 3 prepared in example 3 1 H NMR spectrum.
FIG. 4 is a photograph of Compound 4, the product of example 4 1 H NMR spectrum.
FIG. 5 is the product of Compound 5 prepared in example 5 1 H NMR spectrum.
FIG. 6 is the product of Compound 6 prepared in example 6 1 H NMR spectrum.
FIG. 7 is a photograph of the product, Compound 7, prepared in example 7 1 H NMR spectrum.
FIG. 8 is the product of Compound 8 prepared in example 8 1 H NMR spectrum.
FIG. 9 is the product of Compound 9 prepared in example 9 1 H NMR spectrum.
FIG. 10 is the product of Compound 10 prepared in example 10 1 H NMR spectrum.
FIG. 11 is the product of Compound 11 prepared in example 11 1 H NMR spectrum.
FIG. 12 is a photograph of the product, Compound 12, prepared in example 12 1 H NMR spectrum.
FIG. 13 is the product of Compound 13 prepared in example 13 1 H NMR spectrum.
FIG. 14 is a photograph of the product, Compound 14, prepared in example 14 1 H NMR spectrum.
FIG. 15 is a drawing showing a production process of example 15Preparation of product Compound 15 1 H NMR spectrum.
FIG. 16 is the product of Compound 16 prepared in example 16 1 H NMR spectrum.
FIG. 17 is a photograph of the product, Compound 17, prepared in example 17 1 H NMR spectrum.
FIG. 18 is a photograph of compound 18, the product of preparation of example 18 1 H NMR spectrum.
FIG. 19 is a photograph of the product, Compound 19, prepared in example 19 1 H NMR spectrum.
FIG. 20 is a photograph of Compound 20, a product of preparation of example 20 1 H NMR spectrum.
FIG. 21 is a photograph of the product, Compound 21, prepared in example 21 1 H NMR spectrum.
Detailed Description
The invention is further described with reference to specific embodiments.
General examples
An isoxazoline derivative with an olefin side chain, which has a structure represented by formula I:
Figure BDA0002839690800000041
wherein R is aryl; r is 1 、R 2 、R 3 Are each hydrogen or methyl; r 4 Benzene, methyl formate, ethyl formate, tert-butyl formate, cyano and benzoyl.
A synthetic method of the isoxazoline derivative with the olefin side chain comprises the following synthetic steps:
(1) under the protection of inert gas, mixing allyl oxime and allyl sulfone, dissolving in a solvent, and heating to 55-65 ℃ under the action of a catalyst and alkali to react to obtain isoxazoline with a structure shown in formula I; the ratio of the amounts of the allyl oxime, allyl sulfone, catalyst, base is 1: 1-4: 0.05-0.15: 0.5-2. The catalyst is Cu (OTf) 2 、CuO、Cu(acac) 2 Or CuCl 2 At least one of; the solvent is acetonitrile or tetrahydrofuranAt least one of toluene, acetone, 1, 4-dioxane, dichloromethane, 1, 2-dichloroethane, ethanol, ethyl acetate or N, N-dimethylformamide; the alkali is at least one of potassium carbonate, sodium bicarbonate or sodium carbonate.
The allylic oxime has the structure shown in formula II:
Figure BDA0002839690800000051
wherein R is aryl; r is 1 、R 2 、R 3 Are each hydrogen or methyl.
The allyl sulfone has a structure shown in a formula III:
Figure BDA0002839690800000052
wherein R is 4 Benzene, methyl formate, ethyl formate, tert-butyl formate, cyano and benzoyl.
(2) And carrying out post-treatment on the reaction product to obtain a finished product.
Example 1
Figure BDA0002839690800000053
Adding (E) -1-phenylbut-3-en-1-one oxime (32.2mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) into an argon-protected reaction flask, finally adding acetonitrile (2.0mL), reacting at 60 ℃ for 12h, and after the reaction is finished, separating by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) to obtain 44.6mg with a yield of 80%.
As shown in fig. 1, product characterization: a colorless liquid; 1 H NMR(500MHz，CDCl 3 )δ7.60-7.56(m，2H)，7.42(m，2H)，7.39-7.32(m，4H)，7.30-7.26(m，1H)，5.33(d，J＝0.8Hz，1H)，5.13(d，J＝1.2Hz，1H)，4.78(dtd，J＝10.4，7.9，5.3Hz，1H)，3.36(dd，J＝16.4，10.4Hz，1H)，2.92(dd，J＝16.4，8.1Hz，1H)，2.77(m，1H)，2.65(m，1H)，2.00-1.85(m，1H)，1.87-1.70(m，1H)。
example 2
Figure BDA0002839690800000054
Adding (E) -1- (p-tolyl) but-3-en-1-oxime (35.0mg, 0.2mmol), (155.0mg, 0.6mmol) of ((2-phenylallyl) sulfonyl) benzene, 3.1mg, 0.01mmol of trifluoromethanesulfonic ketone, 3.6mg, 0.02mmol of bipyridine and sodium carbonate (31.8mg, 0.3mmol) into an argon-protected reaction flask, finally adding acetonitrile (2.0mL), reacting at 60 ℃ for 12h, and separating by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) after the reaction is finished to obtain 50mg, wherein the yield is 85%.
As shown in fig. 2, product characterization: a white solid; m.p. 45-47 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.55(d，J＝8.2Hz，2H)，7.44(d，J＝7.5Hz，2H)，7.35(dd，J＝10.2，4.8Hz，2H)，7.29(m，1H)，7.20(d，J＝8.0Hz，2H)，5.33(s，1H)，5.14(d，J＝1.1Hz，1H)，4.75(dtd，J＝10.3，7.8，5.3Hz，1H)，3.38(dd，J＝16.4，10.3Hz，1H)，2.94(dd，J＝16.4，8.0Hz，1H)，2.77(m，1H)，2.71-2.59(m，1H)，2.38(s，3H)，1.99-1.90(m，1H)，1.83-1.74(m，1H)。
example 3
Figure BDA0002839690800000061
Adding (E) -1- (4-methoxyphenyl) but-3-en-1-one oxime (38.2mg, 0.2mmol), ((2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) into an argon-protected reaction flask, finally adding acetonitrile (2.0mL), reacting at 60 ℃ for 12h, and separating by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio is 30:1) after the reaction is finished to obtain 50mg, wherein the yield is 86%.
As shown in fig. 3, product characterization: a white solid; mp is 72-74 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.63-7.54(m，2H)，7.43(m，2H)，7.36-7.31(m，2H)，7.28(m，1H)，6.93-6.89(m，2H)，5.32(d，J＝0.9Hz，1H)，5.13(d，J＝1.2Hz，1H)，4.73(dtd，J＝10.3，7.8，5.3Hz，1H)，3.83(s，3H)，3.36(dd，J＝16.3，10.3Hz，1H)，2.93(dd，J＝16.4，8.0Hz，1H)，2.76(m，1H)，2.65(m，1H)，2.00-1.86(m，1H)，1.84-1.70(m，1H)。
example 4
Figure BDA0002839690800000062
(E) -1- (4-fluorophenyl) but-3-en-1-one oxime (35.8mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, and acetonitrile (2.0mL) was finally added, followed by reaction at 60 ℃ for 12 hours, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to 50mg, yield 85%.
As shown in fig. 4, product characterization: a white solid; m.p.79-80 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.55-7.49(m，4H)，7.44-7.40(m，2H)，7.37-7.31(m，2H)，7.30-7.26(m，1H)，5.33(d，J＝0.9Hz，1H)，5.13(d，J＝1.2Hz，1H)，4.78(dtd，J＝10.4，7.9，5.3Hz，1H)，3.36(dd，J＝16.4，10.4Hz，1H)，2.92(dd，J＝16.5，8.1Hz，1H)，2.76(m，1H)，2.65(m，1H)，2.01-1.85(m，1H)，1.86-1.70(m，1H)。
example 5
Figure BDA0002839690800000071
(E) -1- (4-chlorophenyl) but-3-en-1-one oxime (39.1mg, 0.3mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, and finally acetonitrile (2.0mL) was added, followed by reaction at 60 ℃ for 12 hours, after which column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to 55mg, yield 87%.
As shown in fig. 5, product characterization: a white solid; m.p.82-84 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.60-7.56(m，2H)，7.42(m，2H)，7.39-7.31(m，4H)，7.30-7.26(m，1H)，5.33(d，J＝0.8Hz，1H)，5.13(d，J＝1.2Hz，1H)，4.78(dtd，J＝10.4，7.9，5.3Hz，1H)，3.36(dd，J＝16.4，10.4Hz，1H)，2.92(dd，J＝16.4，8.1Hz，1H)，2.77(m，1H)，2.65(m，1H)，2.00-1.89(m，1H)，1.85-1.71(m，1H)。
example 6
Figure BDA0002839690800000072
(E) -1- (4-bromophenyl) but-3-en-1-one oxime (48.0mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, and the reaction was further carried out at 60 ℃ for 12 hours, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) gave 62mg, 88% yield.
As shown in fig. 6, product characterization: a white solid; m.p.94-95 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.55-7.49(m，4H)，7.44-7.40(m，2H)，7.37-7.31(m，2H)，7.30-7.26(m，1H)，5.33(d，J＝0.9Hz，1H)，5.13(d，J＝1.2Hz，1H)，4.78(dtd，J＝10.4，7.9，5.3Hz，1H)，3.36(dd，J＝16.4，10.4Hz，1H)，2.92(dd，J＝16.5，8.1Hz，1H)，2.76(m，1H)，2.65(m，1H)，2.01-1.85(m，1H)，1.86-1.70(m，1H)。
example 7
Figure BDA0002839690800000081
(E) -1- (4- (trifluoromethyl) phenyl) but-3-en-1-one oxime (45.8mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, the reaction was further carried out at 60 ℃ for 12 hours, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) gave 60mg, 86% yield.
As shown in fig. 7, product characterization: a white solid; m.p.99-100 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.78(d，J＝8.1Hz，2H)，7.67(d，J＝8.3Hz，2H)，7.63-7.26(m，5H)，5.35(d，J＝1.0Hz，1H)，5.16(d，J＝1.2Hz，1H)，4.82(dtd，J＝10.5，7.9，5.3Hz，1H).，3.40(dd，J＝16.5，10.5Hz，1H)，2.96(dd，J＝16.5，8.1Hz，1H).，2.78(m，1H)，2.67(m，1H)，2.04-1.92(m，1H)，1.88-1.76(m，1H)。
example 8
Figure BDA0002839690800000082
(E) -1- (4-nitrophenyl) but-3-en-1-one oxime (41.2mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, and reaction was further carried out at 60 ℃ for 12 hours, after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) gave 55mg, 87% yield.
As shown in fig. 8, product characterization: a yellow solid; m.p.73-75 ℃; 1 H NMR(500MHz，CDCl 3 )δ8.28-8.21(m，2H)，7.85-7.75(m，2H)，7.46-7.38(m，2H)，7.37-7.32(m，2H)，7.31-7.26(m，1H)，5.34(d，J＝1.1Hz，1H)，5.14(d，J＝1.2Hz，1H)，4.86(dtd，J＝10.6，8.0，5.3Hz，1H)，3.41(dd，J＝16.5，10.6Hz，1H)，2.97(dd，J＝16.5，8.2Hz，1H)，2.83-2.72(m，1H)，2.71-2.61(m，1H)，2.02-1.90(m，1H)，1.89-1.76(m，1H)。
example 9
Figure BDA0002839690800000091
Methyl (E)4- (1- (hydroxyimino) but-3-en-1-yl) benzoate (43, 8mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, the reaction was further carried out at 60 ℃ for 12 hours, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to 36mg, yield 74%.
As shown in fig. 9, product characterization: a white solid; m.p.103-105 ℃; 1 H NMR(500MHz，CDCl 3 )δ8.09-8.03(m，2H)，7.73-7.69(m，2H)，7.42(m，2H)，7.37-7.31(m，2H)，7.28(m，1H)，5.33(d，J＝1.0Hz，1H)，5.13(d，J＝1.2Hz，1H)，4.81(dtd，J＝10.5，7.9，5.4Hz，1H)，3.93(s，3H)，3.40(dd，J＝16.5，10.5Hz，1H)，2.96(dd，J＝16.5，8.1Hz，1H)，2.77(m，1H)，2.66(m，1H)，2.01-1.88(m，1H)，1.87-1.73(m，1H)。
example 10
Figure BDA0002839690800000092
(E) -1- (3-nitrophenyl) but-3-en-1-one oxime (41.2mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, and reaction was further carried out at 60 ℃ for 12 hours, after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to yield 32mg, 80% yield.
As shown in fig. 10, product characterization: a yellow oil; 1 H NMR(500MHz，CDCl 3 )δ8.39(t，J＝1.9Hz，1H)，8.25(m，1H)，8.10-8.04(m，1H)，7.59(t，J＝8.0Hz，1H)，7.46-7.40(m，2H)，7.37-7.32(m，2H)，7.30-7.26(m，1H)，5.33(d，J＝1.0Hz，1H)，5.14(d，J＝1.2Hz，1H)，4.86(dtd，J＝10.5，7.9，5.4Hz，1H)，3.43(dd，J＝16.5，10.5Hz，1H)，3.00(dd，J＝16.5，8.1Hz，1H)，2.82-2.73(m，1H)，2.67(m，1H)，2.02-1.92(m，1H)，1.87-1.76(m，1H)。
example 11
Figure BDA0002839690800000101
(E) -1- (thien-2-yl) but-3-en-1-one oxime (33.4mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, the reaction was further carried out at 60 ℃ for 12 hours, and after completion of the reaction, the mixture was purified by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to 43mg, yield 80%.
As shown in fig. 11, product characterization: a tan oil; 1 H NMR(500MHz，CDCl 3 )δ7.44-7.39(m，2H)，7.39-7.30(m，3H)，7.28(d，J＝7.4Hz，1H)，7.16(d，J＝3.6Hz，1H)，7.05(dd，J＝5.0，3.7Hz，1H)，5.32(s，1H)，5.13(d，J＝1.0Hz，1H)，4.76(dtd，J＝10.3，7.8，5.4Hz，1H)，3.40(dd，J＝16.3，10.3Hz，1H)，2.96(dd，J＝16.3，8.0Hz，1H)，2.76(m，1H)，2.69-2.58(m，1H)，2.05-1.86(m，1H)，1.83-1.70(m，1H)。
example 12
Figure BDA0002839690800000102
(E) -1- (naphthalen-2-yl) but-3-en-1-oxime (42.2mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, reaction was carried out at 60 ℃ for 12h, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to give 48mg, 81% yield.
As shown in fig. 12, product characterization: a white solid; m.p.114 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.98(dd，J＝8.7，1.6Hz，1H)，7.85(m，4H)，7.57-7.47(m，2H)，7.47-7.41(m，2H)，7.36(dd，J＝10.2，4.8Hz，2H)，7.32-7.27(m，1H)，5.35(s，1H)，5.16(d，J＝1.1Hz，1H)，4.83(dtd，J＝10.4，7.8，5.4Hz，1H)，3.51(dd，J＝16.3，10.4Hz，1H)，3.08(dd，J＝16.3，8.0Hz，1H)，2.80(m，1H)，2.73-2.63(m，1H)，2.07-1.91(m，1H)，1.91-1.76(m，1H)。
example 13
Figure BDA0002839690800000111
((2-phenylallyl) sulfonyl) benzene (37.8mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, and the reaction was further carried out at 60 ℃ for 12 hours, after which the reaction was completed, purified by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) gave 58mg with a yield of 76%.
As shown in fig. 13, product characterization: a yellow oil; 1 H NMR(500MHz，CDCl 3 )δ7.40(m，2H)，7.36-7.32(m，2H)，7.31-7.27(m，3H)，7.21(m，3H)，5.31(d，J＝1.2Hz，1H)，5.09(d，J＝1.3Hz，1H)，4.54(dtd，J＝10.2，7.7，5.4Hz，1H)，2.98-2.86(m，3H)，2.67(m，3H)，2.60-2.51(m，1H)，2.47(m，1H)，1.81(m，1H)，1.67-1.61(m，1H)。
example 14
Figure BDA0002839690800000112
(E) -2, 2-dimethyl-1-phenylbut-3-en-1-one oxime (53.6mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was added at the end, the reaction was further carried out at 60 ℃ for 12 hours, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to give 63mg, 84% yield.
As shown in fig. 14, product characterization: a pink oil; 1 H NMR(500MHz，CDCl 3 )δ7.55-7.50(m，4H)，7.46-7.43(m，2H)，7.37-7.33(m，2H)，7.31-7.27(m，1H)，5.35(s，1H)，5.17(d，J＝1.1Hz，1H)，4.14(dd，J＝10.4，2.6Hz，1H)，2.95(m，1H)，2.68-2.60(m，1H)，1.92-1.82(m，1H)，1.72-1.63(m，1H)，1.28(s，3H)，1.15(s，3H)。
example 15
Figure BDA0002839690800000121
(E) -3-methyl-1-phenylbut-3-en-1-one oxime (35.0mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was finally added, the reaction was carried out at 60 ℃ for 12 hours, and after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to 47mg, 80% yield.
As shown in fig. 15, product characterization: a colorless oil; 1 H NMR(500MHz，CDCl 3 )δ7.69-7.64(m，2H)，7.45-7.38(m，5H)，7.37-7.31(m，2H)，7.30-7.25(m，1H)，5.30(d，J＝0.9Hz，1H)，5.12(d，J＝1.2Hz，1H)，3.19(d，J＝16.5Hz，1H)，3.06(d，J＝16.5Hz，1H)，2.71-2.62(m，2H)，1.95-1.86(m，2H)，1.49(d，J＝7.0Hz，3H)。
example 16
Figure BDA0002839690800000122
(E) -cyclohex-2-en-1-yl (phenyl) ketoxime (40.2mg, 0.2mmol), (2-phenylallyl) sulfonyl) benzene (155.0mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, and finally acetonitrile (2.0mL) was added, followed by reaction at 60 ℃ for 12 hours, after which column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) was isolated to 36mg, 74% yield.
As shown in fig. 16, product characterization: a white solid; m.p.114 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.67-7.62(m，2H)，7.48-7.43(m，2H)，7.39(dd，J＝6.7，3.6Hz，3H)，7.35(dd，J＝10.4，4.8Hz，2H)，7.31-7.27(m，1H)，5.36(d，J＝1.3Hz，1H)，5.10(d，J＝0.7Hz，1H)，4.34(dd，J＝8.0，5.2Hz，1H)，3.46(dd，J＝15.9，7.8Hz，1H)，3.00-2.90(m，1H)，2.46(dd，J＝14.2，9.3Hz，1H)，2.16-2.04(m，1H)，1.90(m，1H)，1.66(m，1H)，1.52-1.42(m，2H)，1.35(m，1H)，1.30-1.22(m，1H)。
example 17
Figure BDA0002839690800000123
The (E) -1-phenylbut-3-en-1-one oxime (32.2mg, 0.2mmol), (2- ((benzenesulfonyl) methyl) acrylate (144.2mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, and acetonitrile (2.0mL) was added, followed by reaction at 60 ℃ for 12 hours, after completion of the reaction, column chromatography (eluent: petroleum ether/ethyl acetate volume ratio 30:1) was used to isolate 46mg, with a yield of 81%.
As shown in fig. 17, product characterization: a yellow oil; 1 H NMR(500MHz，CDCl 3 )δ7.69-7.62(m，2H)，7.42-7.37(m，3H)，6.20(s，1H)，5.63(d，J＝1.0Hz，1H)，4.82-4.68(m，1H)，3.76(s，3H)，3.42(dd，J＝16.5，10.4Hz，1H)，3.01(dd，J＝16.5，7.9Hz，1H)，2.57-2.49(m，1H)，2.49-2.41(m，1H)，1.98-1.89(m，1H)，1.84(m，1H)。
example 18
Figure BDA0002839690800000131
The (E) -1-phenylbut-3-en-1-one oxime (32.2mg, 0.2mmol), (2- ((benzenesulfonyl) methyl) ethyl acrylate (152.6mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol), and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, and acetonitrile (2.0mL) was added, followed by reaction at 60 ℃ for 12 hours, after completion of the reaction, 45mg was isolated by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) to yield 82%.
As shown in fig. 18, product characterization: a colorless oil; 1 H NMR(500MHz，CDCl 3 )δ7.68-7.64(m，2H)，7.42-7.37(m，3H)，6.19(d，J＝0.4Hz，1H)，5.61(d，J＝1.2Hz，1H)，4.81-4.71(m，1H)，4.21(q，J＝7.1Hz，2H)，3.42(dd，J＝16.5，10.4Hz，1H)，3.01(dd，J＝16.5，7.9Hz，1H)，2.56-2.48(m，1H)，2.48-2.40(m，1H)，1.94(m，1H)，1.84(m，1H)，1.30(t，J＝7.1Hz，3H)。
example 19
Figure BDA0002839690800000132
Adding (E) -1-phenylbut-3-en-1-one oxime (32.2mg, 0.2mmol), tert-butyl 2- ((benzenesulfonyl) methyl) acrylate (169.4mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) into an argon-protected reaction flask, finally adding acetonitrile (2.0mL), reacting at 60 ℃ for 12h, and after the reaction is finished, separating by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) to obtain 49mg with a yield of 81%.
As shown in fig. 19, product characterization: a yellow oil; 1 H NMR(500MHz，CDCl 3 )δ7.69-7.64(m，2H)，7.44-7.34(m，3H)，6.09(d，J＝1.3Hz，1H)，5.54(d，J＝1.3Hz，1H)，4.76(dtd，J＝10.4，7.4，5.9Hz，1H)，3.42(dd，J＝16.5，10.4Hz，1H)，3.01(dd，J＝16.5，7.9Hz，1H)，2.53-2.34(m，2H)，1.94(m，1H)，1.83(m，1H)，1.49(s，9H)。
example 20
Figure BDA0002839690800000141
Adding (E) -1-phenylbut-3-en-1-one oxime (32.2mg, 0.2mmol), 2- ((benzenesulfonyl) methyl) acrylonitrile (124.4mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) into an argon-protected reaction bottle, finally adding acetonitrile (2.0mL), reacting at 60 ℃ for 12h, and after the reaction is finished, separating by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) to obtain 38mg with a yield of 82%.
As shown in fig. 20, product characterization: an orange solid; m.p.44-45 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.72-7.61(m，2H)，7.46-7.36(m，3H)，5.90(s，1H)，5.82(s，1H)，4.76(dtd，J＝10.5，7.7，4.9Hz，1H)，3.48(dd，J＝16.5，10.4Hz，1H)，3.02(dd，J＝16.5，7.5Hz，1H)，2.57-2.39(m，2H)，2.03-1.86(m，2H)。
example 21
Figure BDA0002839690800000142
(E) -1-phenylbut-3-en-1-one oxime (32.2mg, 0.2mmol), 1-phenyl-2- ((benzenesulfonyl) methyl) propan-2-en-1-one (171.78mg, 0.6mmol), trifluoromethanesulfonic acid ketone (3.1mg, 0.01mmol), bipyridine (3.6mg, 0.02mmol) and sodium carbonate (31.8mg, 0.3mmol) were added to an argon-protected reaction flask, acetonitrile (2.0mL) was added, the reaction was further carried out at 60 ℃ for 12 hours, and after the reaction was completed, 20mg was isolated by column chromatography (eluent: petroleum ether/ethyl acetate volume ratio of 30:1) with a yield of 32%.
As shown in fig. 21, product characterization: a white solid; m.p.87-88 ℃; 1 H NMR(500MHz，CDCl 3 )δ7.75(m，2H)，7.70-7.64(m，2H)，7.57-7.52(m，1H)，7.47-7.37(m，5H)，5.95(s，1H)，5.68(s，1H)，4.86-4.76(m，1H)，3.45(dd，J＝16.5，10.4Hz，1H)，3.05(dd，J＝16.5，7.9Hz，1H)，2.72-2.58(m，2H)，2.03-1.85(m，2H)。
from the data of examples 1-21, it can be seen that the above requirements can be met in all respects only by the scheme within the scope of the claims of the present invention, an optimized scheme can be obtained, and the isoxazoline derivative with olefin side chain can be obtained, and the material utilization and recovery rate can be maximized by each process parameter. The change of the mixture ratio, the replacement/addition/subtraction of raw materials or the change of the feeding sequence can bring corresponding negative effects.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.

Claims (4)

1. A synthetic method of an isoxazoline derivative with an olefin side chain is characterized in that the isoxazoline derivative with the olefin side chain has a structure shown in a formula I:
Figure FDA0003645122900000011
wherein R is aryl; r 1 、R 2 、R 3 Are each hydrogen or methyl; r 4 Benzene, methyl formate, ethyl formate, tert-butyl formate, cyano, benzoyl;
the synthesis method of the isoxazoline derivative with the olefin side chain comprises the following synthesis steps:
(1) under the protection of inert gas, mixing allyl oxime with a structure shown in a formula II and allyl sulfone with a structure shown in a formula III, dissolving the mixture in a solvent, and reacting under the action of a catalyst, bipyridine and alkali to obtain the isoxazoline derivative with the olefin side chain and with the structure shown in the formula I; the catalyst is Cu (OTf) 2 The alkali is sodium carbonate, and the solvent is acetonitrile;
Figure FDA0003645122900000012
wherein R is aryl; r 1 、R 2 、R 3 Are each hydrogen or methyl;
Figure FDA0003645122900000013
wherein R is 4 Benzene, methyl formate, ethyl formate, tert-butyl formate, cyano, benzoyl;
(2) and carrying out post-treatment on the reaction product to obtain a finished product.
2. The method for synthesizing an isoxazoline derivative having an olefin side chain according to claim 1, wherein in the step (1), the ratio of the amounts of allyl oxime, allyl sulfone, catalyst, and base is 1: 1-4: 0.05-0.15: 0.5-2.
3. The method for synthesizing an isoxazoline derivative having an olefin side chain according to claim 1, wherein the reaction temperature in the step (1) is 55 to 65 ℃.
4. The method for synthesizing an isoxazoline derivative having an olefin side chain according to claim 1, wherein the post-treatment in the step (2) is: extracting with ethyl acetate for 3-5 times after the reaction is finished, combining ethyl acetate, washing with saturated saline solution for 1-2 times, drying the washed ethyl acetate solution with anhydrous sodium sulfate, drying, then concentrating under reduced pressure to obtain a crude product, carrying out column chromatography separation on the crude product, collecting and combining eluent containing the target compound by taking petroleum ether/ethyl acetate mixed liquor with the volume ratio of 10-50:1 as an eluent, evaporating the solvent, and drying.
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