阅读说明：本技术 一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物的合成方法 (Synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate and analogue ) 是由 李洪基 杨诗超 于 2019-10-30 设计创作，主要内容包括：本发明公开了一种3-芳基-4,5-二氢异噁唑-5-基甲基对甲苯磺酸酯以及类似物的合成方法,属于有机化学技术领域。采用铁(II)催化Koser高价碘试剂(HIRs)促进I-O键裂解,促进不饱和肟基自由基环化,得到异恶唑啉骨架产物3-苯基-4,5-二氢异噁唑-5-基磺酸酯。磺酸酯基团作为离去基团,可以进一步转化为多种系列类似物。该方法为合成3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯系列提供了一种简便、廉价、高效的途径。(The invention discloses a synthesis method of 3-aryl-4, 5-dihydroisoxazole-5-methyl p-toluenesulfonate and analogues, belonging to the technical field of organic chemistry. Promoting I-O bond cleavage by using iron (II) to catalyze Koser high-valence iodine reagents (HIRs) and promoting unsaturated oximido free radical cyclization to obtain an isoxazoline skeleton product 3-phenyl-4, 5-dihydroisoxazole-5-yl sulfonate. The sulfonate group, as a leaving group, can be further converted into a variety of series of analogs. The method provides a simple, convenient, cheap and efficient way for synthesizing 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate series.)

1. A method for synthesizing 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate 3 is characterized by comprising the following operations: taking unsaturated oxime 1 and a high-iodine reagent 2 as raw materials, reacting in the presence of an iron catalyst to obtain 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate 3, wherein the reaction equation is as follows:

wherein Ar is phenyl, substituted phenyl or naphthyl; in the substituted phenyl, the substitution is one or more than two of C1-C4 alkyl, C1-C4 alkoxy or halogen; r is methyl, substituted phenyl or naphthyl; in the substituted phenyl, the substitution is dimethyl, nitro or halogen.

2. The method of synthesis according to claim 1, characterized in that: said iron catalyst is selected from the group consisting of Fe (acac)₂、FeCl₂、FeBr₂、FeSO₄、Fe(acac)₃、Fe(OAc)₃Or FeCl₃。

3. The method of synthesis according to claim 2, characterized in that: said iron catalyst is selected from the group consisting of Fe (acac)₂。

4. The method of synthesis according to claim 1, characterized in that: the reaction is carried out in a solvent selected from THF, CH₃OH、CH₃CN、CH₂Cl₂、CHCl₃、ClCH₂CH₂Cl or toluene.

5. The method of synthesis according to claim 4, characterized in that: the organic solvent is selected from THF and CH₂Cl₂、ClCH₂CH₂Cl or toluene.

6. The method of synthesis according to claim 1, characterized in that: the unsaturated oxime 1 and the high iodine reagent 2 are used as raw materials, and the molar ratio of the raw materials to the iron catalyst is 1:1-1.5: 0.03-0.05.

7. The method of synthesis according to claim 1, characterized in that: the reaction is carried out under air or an inert atmosphere.

8. The method of synthesis according to claim 1, characterized in that: the reaction temperature is selected from 0 ℃ to 30 ℃.

9. The method of synthesis according to claim 8, characterized in that: the reaction temperature is selected from room temperature.

10. A synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-ylmethyl substituent 4-9 has the following reaction equation:

the method is characterized in that: reacting the product 3 obtained in the claim 1 with phenoxy anion, thiophen anion, isothionitrile anion and halogen anion acetone at 60-90 ℃, and reacting azide anion in DMSO or DMF at 80-100 ℃ to obtain 3-aryl-4, 5-dihydroisoxazol-5-ylmethyl substituent 4-9.

Technical Field

The invention relates to a synthetic method of isoxazole heterocycle, in particular to a synthetic method of 3-aryl-4, 5-dihydroisoxazole-5-yl methyl sulfonate and analogues thereof, belonging to the technical field of organic chemistry.

Background

Isoxazoline compounds, in particular 3-aryl-4, 5-dihydroisoxazole-5-yl methyl sulfonate and analogues thereof, are widely applied to the fields of biological natural products, pesticides, medicines, asymmetric catalysis and the like as chiral ligands. 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. Oximes containing inactive C ═ C are of greater interest because of their potential to form isoxazolines. Most cyclization reactions are severely limited by the coordination capability of the hydroxyl group, the sensitivity to oxygen (air), and the large amount of metal catalyst or the need for additional additives. In addition, the late conversion of the cyclization product is of paramount importance, but in most cases is not easily accomplished.

High-valence iodine in the past decadesThe reagent is widely applied to the synthesis of complex organic molecules due to the advantages of simple preparation, strong applicability, wide synthesis application and the like. Traditionally, HIRs can act as reaction substrates, oxidants, promoters, or the like. Most reactions rely primarily on HIRs in combination with transition metal catalysts. Iron catalysis has also made some progress due to its economics and low toxicity. As Kuninobu reported the first Fe (CO)₃Promoting PhI (OAc)₂The cleavage of the I-O bond in (PIDA) generates a higher valent iodine radical which initiates the subsequent addition of an olefin radical.

However, the synthesis of isoxazolines using iron, which is a cheap metal, in combination with iodine, which is a high valence, has not been fully studied, and therefore, it is still necessary to develop a method for efficiently constructing structurally diverse 3-phenyl-4, 5-dihydroisoxazol-5-yl methanesulfonate and the like under environmentally friendly conditions.

Disclosure of Invention

In order to overcome the defects, the invention adopts iron (II) to catalyze Koser high-valent iodine reagents (HIRs) to promote I-O bond cleavage and unsaturated oximido radical cyclization to obtain an isoxazoline skeleton product 3-phenyl-4, 5-dihydroisoxazol-5-yl sulfonate. The sulfonate group, as a leaving group, can be further converted into a variety of series of analogs. The method provides a simple, convenient, cheap and efficient way for synthesizing 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate series.

A synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate comprises the following operations: taking unsaturated oxime 1 and a high-iodine reagent 2 as raw materials, reacting in the presence of an iron catalyst to obtain 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate 3, wherein the reaction equation is as follows:

wherein Ar is phenyl, substituted phenyl or naphthyl; in the substituted phenyl, the substitution is one or more than two of C1-C4 alkyl, C1-C4 alkoxy or halogen; r is methyl, substituted phenyl or naphthyl; in the substituted phenyl, the substitution is dimethyl, nitro or halogen.

Further, in the above technical scheme, the iron catalyst is selected from Fe (acac)₂、FeCl₂、FeBr₂、FeSO₄、Fe(acac)₃、Fe(OAc)₃、FeCl₃Etc., preferably Fe (acac)₂。

Further, in the above technical scheme, the organic solvent is selected from THF and CH₃OH、CH₃CN、CH₂Cl₂、CHCl₃、ClCH₂CH₂Cl, toluene, and the like. Preferred reaction solvents are THF and CH₂Cl₂、ClCH₂CH₂Cl or toluene.

Further, in the technical scheme, the unsaturated oxime 1 and the high iodine reagent 2 are used as raw materials, and the molar ratio of the raw materials to the iron catalyst is 1:1-1.5: 0.03-0.05.

Further, in the above technical scheme, the reaction can be carried out in air or under an inert atmosphere, such as a nitrogen atmosphere.

Further, in the above technical scheme, the reaction temperature is selected from 0 ℃ to 30 ℃, and room temperature reaction is preferred.

In order to expand the application range of the invention, the dihydroisoxazole 3 prepared by the method is reacted with different nucleophiles to respectively obtain sulfonate PhO^－、PhS^－、NCS^－、Br^－、I^－、N₃ ^－And various types of derivative products are 4-9 after the negative ions are substituted, so that the product types are enriched, and the practicability of the method is improved.

Wherein the sulfonate is PhO^－When in substitution, the nucleophilic reagent is PhONa, PhOLi or PhOK; sulfonate ester PhS^－When substituted, the nucleophilic reagent is PhSNa, PhSLi or PhSK; sulfonate ester by NCS^－When in substitution, the nucleophilic reagent is NaSCN or KSCN; sulfonate quilt Br^－When in substitution, the nucleophilic reagent is NaBr, LiBr or KBr; sulfonate quilt I^－When substituted, the nucleophilic reagent is NaI, LiI or KI. In the nucleophilic substitution, the reaction conditions are preferably carried out in an acetone solvent at 60 to 90 ℃ until the reaction of the starting materials is completed.

Sulfonate N₃ ^－When substituted, the nucleophile is NaN₃The solvent is preferably DMF or DMSO, and the reaction is carried out at 80-100 ℃ until the reaction of the raw materials is complete.

The following equation is used:

to further explore the reaction principle, the following comparative experiments were performed, and the reaction results were visually expressed by the following equation:

from the above results, TEMPO experiments show that the cyclization of free radicals is involved in the catalytic cycle. The model reaction, carried out under an oxygen atmosphere, showed that oxygen did not affect radical cyclization. Furthermore, in H₂Reaction in O to give a 3a/11 mixture in a ratio of 3:4, confirming that TsO-is replaced by H₂And (4) performing nucleophilic substitution on O.

Taking the example of the reaction of 1a and 2a to form 3a, the reaction is presumed to be possible by the following mechanism:

the invention has the beneficial effects that:

compared with the prior saturated carbon-hydrogen bond oxidation by using PIDA, the invention develops that the highly active sulfonyloxy free radicals formed by HIRs of Koser at room temperature are key points for enabling oxime free radicals to close rings by using an iron catalyst, and 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate is obtained after ring closing.

Wherein the sulfonate ester in the product molecule acts as a good leaving group with different nucleophiles, e.g. N₃ ^－、Br^－、I^－、SCN^－、OPh^－、SPh^－Plasma nucleophilic substitution derivatization to form a series of analogs.

Detailed Description