CN113698359B - Method for synthesizing 3,5-disubstituted isoxazole compound based on three-component reaction - Google Patents

Abstract

The invention provides a method for synthesizing 3,5-disubstituted isoxazole compounds based on three-component reaction, which comprises the step of mixing aldehyde, olefin and nitrite, heating and reacting to generate 3,5-disubstituted isoxazole compounds. The safety of the scheme of the invention is greatly improved; the raw materials can be purchased commercially, advanced preparation is not needed, the reaction is easier to implement, and the reaction operation is simpler and more convenient; the application range of the substrate is wider, and substrates such as aliphatic hydrocarbon, aromatic hydrocarbon, fused ring and the like can be suitable for the reaction system; the reaction can be carried out in both acidic and alkaline environments; the reaction can be carried out under the air condition without the protection of inert gas.

Description

A method for synthesizing 3,5-disubstituted isoxazoles based on three-component reaction

technical field

The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction.

Background technique

As early as 1888, Claisen et al. used the cyclization reaction of β-ketoester and hydroxylamine to generate 3-hydroxyisoxazole. Since then, a large number of scholars have continuously enriched the research on the synthesis methodology of isoxazoles through [3+2] cycloaddition reactions, cycloisomerization reactions, and condensation reactions (shown in Figure 1). The synthesis method of isoxazole is now classified as follows by type:

1. Synthesis of isoxazole (Cycloaddition) by [3+2] cycloaddition reaction: the most commonly used method for synthesizing isoxazole is the 1,3-dipolar cycloaddition reaction of chloroxime acetate with alkynes or alkenes . First, react aromatic aldehyde with hydroxylamine hydrochloride to obtain aldoxime, which is reacted with chlorosuccinimide (NCS) to obtain chloroxime, and chloroxime is reacted with triethylamine to obtain nitrile oxide, and then reacted with alkyne or alkene , 3-dipolar plus cycloaddition reaction to obtain the target isoxazole (Figure 2A). The synthesis conditions are relatively mild, and various types of isoxazole compounds can be prepared. Compounds containing active groups such as amino, hydroxyl, and active halogens can be directly prepared, and this method also has important applications in synthetic methodology, such as the development of metal catalysis, Catalyst loading and other methods, but the disadvantage is that the substrate needs a compound containing terminal alkyne bonds, which adds certain restrictions and difficulties to the synthesis. Zhu Min et al. developed the [3+2] ring closure reaction of terminal alkynes and aldoximes by using catalytic amounts of organic hypervalent iodine reagents, and synthesized a series of 3,5-disubstituted isoxazole compounds. This reaction is simple, convenient, and regioselective, and realizes the synthesis of isoxazole under alkali-free conditions (as shown in Figure 2B).

2. Synthesis of isoxazole through cycloisomerization (Cycloisomerization): Intramolecular ring formation through the substrate acetylene ketone oxime is also a commonly used synthesis method of isoxazole. In 1970, when Sisido et al. studied the cyclization of acetylene ketone oxime, they found that the acidity and alkalinity of the reaction system had a significant decisive effect on the cyclization (as shown in Figure 3A). After the alkynyl ketoester and hydroxylamine hydrochloride react to form an oxime, if the ring closure is performed under acidic conditions, 5-substituted isoxazole-3-formic acid ethyl ester (I) is obtained if the ring closure is performed under weakly alkaline conditions. Ethyl isoxazoline-3-carboxylate (II). There are many reports on the formation of isoxazoles from alkyne oximes, while the formation of isoxazole rings from enoximes is relatively rare. In 2009, She Xuegong’s research group at Lanzhou University used α, β-unsaturated ketoesters and TsNHOH to synthesize a series of 3,5-disubstituted isoxazole compounds in one pot, and synthesized 3 with a yield of 65%. - Ethyl phenylisoxazole-5-carboxylate (shown in Figure 3B). The possible ring-forming mechanism is that TsNHOH first undergoes addition reaction to the α-unsaturated ethylenic bond of the carbonyl group, and then removes benzenesulfinic acid to obtain α-carbonyl oxime, which is dehydrated to form an isoxazole ring.

Since then, in 2011, Miyata's research group developed the synthesis of isoxazole using phenol as a proton source and Ag ⁺ catalysis (shown in Figure 3C). The authors deduce that the mechanism of the catalyzed ring formation is the binding of Ag ⁺ to the electron-deficient alkyne bond, thereby activating the alkyne bond. The electron cloud density increases due to the connection of the electron-donating group benzyl to the oxime oxygen atom, and the lone pair of electrons of the oxime oxygen attack the activated alkyne bond, and then an addition reaction occurs to form an isoxazole ring. ⁺ detachment, Ag ⁺ cyclically catalyzes the reaction. But the overall reaction yield is low, and the reaction time is long.

In 2014, Zhu's group reported a new method for palladium/silver synergistic catalysis (shown in Figure 3D). In order to reflect the applicability of the method, they successfully applied the method to the synthesis of drugs Valdecoxib and Oxacillin. However, the use of noble metals reduces the possibility of industrial application of this method.

Recently, Chang's group synthesized a series of mono-, di-, and tri-substituted (aryl, alkyl, and/or alkenyl) oximes from readily available α,β-unsaturated oximes via iodine-mediated oxidative C–O bond formation reactions. Isoxazole compounds (shown in Figure 3E). The synthesis method has the advantages of not using transition metals, simple operation, mild reaction conditions, short reaction time, wide application range of substrates and the like.

3. Synthesis of isoxazole through condensation reaction (Condensation): In 1888, Claisen et al. used β-ketoester and hydroxylamine to react cyclization to generate 3-hydroxyisoxazole (shown in Figure 4A). The reaction can realize the one-pot synthesis of isoxazole under metal-free conditions, but the by-product 5-isoxazolone will be generated in this system, which reduces the yield of the main product. In order to clarify the mechanism of side reaction generation, Cocivera et al. carried out NMR research in 1976 and believed that 5-isoxazolone was transformed from a thermodynamically unstable cis-isomer. In 2000, Larsen et al. improved the method to avoid the formation of by-product 5-isoxazolone (shown in Figure 4B). In the reaction, 3-hydroxyl 5-methylisoxazole derivatives were synthesized by three-step method through N,O protection of raw materials.

In summary, since Claisen et al. first developed the synthesis method of isoxazole in 1888, researchers have enriched the synthesis of isoxazole through new strategies such as [3+2] cycloaddition reaction, cycloisomerization reaction, and condensation reaction. A new method for the synthesis of isoxazoles.

In the [3+2] cycloaddition reaction strategy, the raw material aldoxime or ketoxime is not easy to obtain commercially and needs to be prepared in advance; in addition, in the cycloisomerization reaction and condensation reaction strategy, it is necessary to use hydroxylamine hydrochloride Reagents, which have constraints such as safety when used on a large scale. With the increasingly prominent environmental problems, the development of efficient, green and convenient synthetic methodologies will be the development direction of synthetic chemistry in the future.

Contents of the invention

In view of the above problems, the present invention provides a method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction.

In order to achieve the above purpose, the following technical solutions are adopted:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, in which aldehydes, olefins and nitrites are mixed and heated for reaction to generate 3,5-disubstituted isoxazole compounds.

Preferably, the reaction is carried out in water.

Preferably, the reaction is carried out in an organic solvent.

Preferably, the organic solvent is any one of tetrahydrofuran, chlorobenzene, acetone, N,N-dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethylsulfoxide, methanol or ethanol.

Preferably, persulfate is added as oxidant to the reaction.

Preferably, an acidic or basic substance is added to the reaction.

Preferably, sodium sulfate is added to the reaction.

Preferably, the aldehyde is selected from aliphatic aldehydes, aromatic aldehydes or fused ring aldehydes. The olefin is selected from aromatic olefins or condensed ring olefins; the nitrite is selected from alkyl nitrite.

Preferably, the organic solvent contains water, and the volume ratio of the organic solvent to water is 5:1.

Preferably, the persulfate is any one or more of sodium persulfate, potassium persulfate or ammonium persulfate.

Preferably, the acidic substance is formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrofluoric acid, boron trifluoride ether or fluoroboric acid; the basic substance is imidazole, potassium tert-butoxide, sodium carbonate, 4-di Aminopyridine, sodium acetate, piperazine, potassium phosphate, triethylamine, sodium bicarbonate, 1,4-diazabicyclo[2.2.2]octane, cesium carbonate or 1,8-diazabicyclo Undec-7-ene.

Preferably, the molar ratio of the aldehyde, olefin and nitrite is: 1-5:1-10:1-20.

Preferably, the heating temperature of the reaction is 20-140°C, and the reaction time is 0.5-24h.

Preferably, the heating temperature of the reaction is 100° C., and the reaction time is 8 hours.

The invention has the following beneficial effects: 1. The nitrogen atom in the isoxazole molecule is derived from nitrite instead of hydroxylamine hydrochloride, and the safety of the reaction is greatly improved; 2. The raw materials used can be purchased commercially without preparation in advance, and the reaction It is easier to implement, and the reaction operation is more convenient; 3. The scope of application of the substrate is wider, such as aliphatic hydrocarbons, aromatic hydrocarbons, fused rings and other substrates can be applied to our reaction system; 4. The reaction is in acidic environment and alkaline It can be carried out in any environment; 5. The reaction can be carried out under air conditions without inert gas protection.

Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure pointed out in the written description, claims hereof as well as the appended drawings.

Description of drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description These are some embodiments of the present invention. Those skilled in the art can also obtain other drawings based on these drawings without creative work.

Fig. 1 is the synthesizing method schematic diagram of isoxazole in the prior art;

Fig. 2 is the schematic diagram of the method for synthesizing isoxazole by [3+2] cycloaddition method;

Fig. 3 is the synthesizing method schematic diagram of isoxazole by cycloisomerization reaction;

Fig. 4 is the schematic diagram of the method for synthesizing isoxazole by condensation reaction;

Figure 5 is a schematic diagram of the reaction formula of the product 3,5-diphenylisoxazole in Example 1 of the present invention;

Figure 6 exemplifies the different products obtained by changing the substrate of the present invention;

Fig. 7 is a schematic diagram of the reaction mechanism of the present invention;

Fig. 8 is a graph showing the reaction conditions and yield results of various embodiments of the present invention.

Detailed ways

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments It is a part of embodiments of the present invention, but not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Example 1:

A method for synthesizing 3,5-disubstituted isoxazoles based on a three-component reaction, using 0.5mmol styrene, 0.25mmol p-bromobenzaldehyde, 0.5mmol tert-butyl nitrite (TBN), in 0.6mL solvent The reaction was carried out under heating in water at 100° C. for 8 hours, and the white transparent crystal 3aa was obtained by column chromatography with a yield of 5%.

Example 2:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 1 is that the solvent used is DMF, and the yield is 15%.

Example 3:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 1 is that the solvent used is a mixed solution of DMF and water, and the ratio of DMF and water is 5:1, The yield is 35%.

Example 4:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 3 is that 0.125 mmol K ₂ S ₂ O ₈ is added as an oxidant during the reaction, and the yield is 47%.

Example 5:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 4 is that 0.625 mmol of acetic acid is added during the reaction, and the yield is 51%.

Embodiment 6:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 5 is that 0.25 mmol of sodium sulfate is also added during the reaction, and the yield is 58%.

Embodiment 7:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 6 is that 0.5 mmol of sodium sulfate is added during the reaction, and the yield is 61%.

Embodiment 8:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 6 is that the reaction temperature is 80° C., and the yield is 52%.

Embodiment 9:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 6 is that the reaction temperature is 110° C., and the yield is 61%.

Example 10:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 6 is that the reaction temperature is 120° C., and the yield is 40%.

Example 11:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 6 is that 0.25 mmol of styrene is used, and the yield is 22%.

Example 12:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction, the difference from Example 6 is that 0.75 mmol of styrene is used, and the yield is 71%.

Example 13:

A method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction. First, 2mmol styrene, 1mmol benzaldehyde, and 2mmol tert-butyl nitrite are used to react in 2mL solvent DMF at 30°C for 3 Hours, column chromatography gave white transparent crystals 4a with a yield of 5%. The prepared compound was subjected to NMR analysis, and the result showed that 4a was 3,5-diphenylisoxazole, and the reaction formula was shown in FIG. 5 . The reaction conditions and yield results of the above examples are shown in Figure 8.

Further, the method of the present invention is not limited to the above-mentioned reaction substrates, and aldehyde substrates such as aliphatic aldehydes, aryl aldehyde groups and fused ring aldehydes are suitable for this reaction, as shown in Figure 6, corresponding reactants 1 and Reactant 2 uses different substrates to obtain different products 4, for example, compounds 4a, 4b...4u or 5a, 5b...5f, etc.

The method used in the present invention passes through the following reaction route, as shown in Figure 7: promptly adopt aldehyde A and olefin B and nitrite E to make reactant, in reaction system, the aldehyde free radical C that aldehyde A produces under the action of oxidizing agent is to olefin Addition is performed to generate free radical D. At this time, the radical coupling reaction between the free radical D and the nitroso radical F generated by the heating of the nitrite E can generate compound G, which is rapidly isomerized into 1,3-dicarbonyl ketoxime intermediate H, Subsequently, an intramolecular ring-closing reaction occurs to generate compound I, and the target isoxazole compound J is generated by losing one molecule of water. As shown in Figure 6, in this reaction system, aldehyde substrates such as aliphatic aldehyde cyclohexanaldehyde (reaction produces product 4u), aromatic aldehyde benzaldehyde (reaction produces product 4a), heterocyclic aldehyde 4-pyridine Formaldehyde (product 4r after reaction) etc. can be applied, olefinic substrates such as aliphatic olefin 1-hexene (product 5f after reaction), aromatic olefin 4-bromostyrene (product 5a after reaction), thick Cycloalkene 2-naphthene (generate product 5d after reaction) etc. all can be applicable; Nitrite ester substrate such as isobutyl nitrite, n-butyl nitrite, isoamyl nitrite etc. all can be applicable; React in It can be carried out in both acidic environment and alkaline environment.

To sum up, the nitrogen atom in the isoxazole molecule in the present invention is derived from TBN molecule instead of hydroxylamine hydrochloride. Hydroxylamine hydrochloride is used as the source. Usually, it is necessary to prepare aldoxime or ketoxime by reacting substrate aldehyde or ketone in advance, and the operation is cumbersome. , and hydroxylamine hydrochloride has safety problems during large-scale reactions. When TBN is used as the raw material, the raw material does not need to be prepared in advance, and it can be completed in one pot, and the safety is better than that of hydroxylamine hydrochloride.

Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: they can still modify the technical solutions described in the aforementioned embodiments, or perform equivalent replacements for some of the technical features; and these The modification or replacement does not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims (7)

1. A method for synthesizing 3,5-disubstituted isoxazoles based on a three-component reaction, characterized in that aldehydes, olefins and nitrites are mixed and heated for reaction to generate 3,5-disubstituted isoxazoles compound; Wherein, the aldehyde is an aromatic aldehyde; the olefin is an aromatic olefin; the nitrite is tert-butyl nitrite; the molar ratio of the aldehyde, olefin and nitrite is 1 to 5:1 to 10 :1～20; The reaction is carried out in an organic solvent. The organic solvent is N,N-dimethylformamide, the organic solvent contains water, and the volume ratio of the organic solvent to water is 5:1. 2. The method for synthesizing 3,5-disubstituted isoxazoles based on the three-component reaction according to claim 1, characterized in that, adding persulfate as an oxidizing agent in the reaction. 3. The method for synthesizing 3,5-disubstituted isoxazoles based on a three-component reaction according to claim 1, characterized in that an acidic or basic substance is added to the reaction. 4. The method for synthesizing 3,5-disubstituted isoxazoles based on the three-component reaction according to claim 1, characterized in that sodium sulfate is added to the reaction. 5. the method for synthesizing 3,5-disubstituted isoxazoles based on three-component reaction according to claim 2, is characterized in that, described persulfate is sodium persulfate, potassium persulfate or ammonium persulfate any one or more of them. 6. the method for synthesizing 3,5-disubstituted isoxazoles based on three-component reaction according to claim 3, is characterized in that, described acidic substance is formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrofluoric acid Acid, boron trifluoride ether or fluoboric acid; the basic substance is imidazole, potassium tert-butoxide, sodium carbonate, 4-dimethylaminopyridine, sodium acetate, piperazine, potassium phosphate, triethylamine, sodium bicarbonate , 1,4-diazabicyclo[2.2.2]octane, cesium carbonate or 1,8-diazabicycloundec-7-ene. 7. The method for synthesizing 3,5-disubstituted isoxazole compounds based on a three-component reaction according to any one of claims 1-6, characterized in that, the heating temperature of the reaction is 20-140°C, and the reaction The time is 0.5-24h.

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