Preparation method and application of novel 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole
阅读说明：本技术 一种新型5-硫氰酸酯取代的1,4,5-三取代的1,2,3-***的制备方法及应用 (Preparation method and application of novel 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole ) 是由 宋汪泽 李明 董锟 郑玉斌 于 2019-09-19 设计创作，主要内容包括：本发明属于有机合成技术领域,提供了一种新型5-硫氰酸酯取代的1,4,5-三取代的1,2,3-三唑的制备方法及应用。本发明中5-硫氰酸酯取代的1,4,5-三取代的1,2,3-三唑的制备方法以及5-硫代-1,4,5-三取代的1,2,3-三唑的制备方法反应条件温和,产物收率不低于62％。该制备方法的反应条件温和、绿色、反应效率高,更适合规模化生产要求,制备得到的5-硫代-1,4,5-三取代的1,2,3-三唑类化合物具有潜在的生理活性。(The invention belongs to the technical field of organic synthesis, and provides a preparation method and application of novel 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole. The preparation method of the 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole and the preparation method of the 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole have mild reaction conditions, and the yield of the product is not lower than 62%. The preparation method has mild and green reaction conditions and high reaction efficiency, is more suitable for large-scale production requirements, and the prepared 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole compound has potential physiological activity.)
1. A preparation method of novel 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole is characterized by comprising the following steps:
in an organic solvent, under the action of a pentamethylcyclopentadienyl 1, 5-cyclooctadiene ruthenium chloride catalyst, catalyzing a reaction of a thiocyanato internal alkyne compound and an organic azide compound to prepare 5-thiocyanato substituted 1,4, 5-trisubstituted 1,2, 3-triazole, wherein the reaction formula is as follows:
wherein R is1And R2Is alkyl or aryl, R1And R2The same or different;
i is a thiocyanate radical internal alkyne compound;
the mol ratio of the thiocyanato internal alkyne compound to the organic azide compound is 1:1.5-1:3, and the concentration of the thiocyanato internal alkyne compound in the system is 0.01-0.1 mmol/ml;
the dosage of [ Cp, Ru, (COD) Cl ] is 0.5-50 mol% of the thiocyanato internal alkyne compound;
the reaction temperature is between room temperature and 80 ℃, the reaction time is between 12 and 24 hours, and the 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole with the yield not lower than 66 percent is prepared.
2. The method according to claim 1, wherein the organic solvent is one or more selected from benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane, and petroleum ether.
3. A preparation method of novel 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole is characterized by comprising the following steps:
in an organic solvent, under the action of a pentamethylcyclopentadienyl 1, 5-cyclooctadiene ruthenium chloride catalyst, a 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole is generated in situ by the reaction of a thiocyanate alkynes compound and an organic azide compound, the 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole continuously reacts with a lattice reagent or a lithium reagent to generate the novel 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole, and the reaction formula is as follows:
wherein R is1,R2And R3Is alkyl or aryl, R4Is an alkyl group;
i is a thiocyanate radical internal alkyne compound;
IV is a Grignard reagent;
VI is a lithium reagent;
the mol ratio of the thiocyanato internal alkyne compound to the organic azide compound to the Grignard reagent or the lithium reagent is 1:1.5:2-1:3:4, and the concentration of the thiocyanato internal alkyne compound in the system is 0.01-0.1 mmol/ml;
the dosage of [ Cp, Ru, (COD) Cl ] is 0.5-50 mol% of the thiocyanato internal alkyne compound;
the reaction temperature is 0-room temperature, the reaction time is 24-36 h, and the 5-sulfo-1, 4, 5-trisubstituted 1,2, 3-triazole compound with the yield not less than 62 percent is prepared.
4. The method according to claim 3, wherein the organic solvent is one or more selected from benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane, and petroleum ether.
5. The process according to claim 3 or 4, wherein the Grignard reagent is a 1.0mol/L THF solution of phenylmagnesium bromide, a 1.0mol/L THF solution of methylmagnesium bromide, a 1.0mol/L THF solution of isopropylmagnesium bromide or a 1.0mol/L THF solution of cyclopropylmagnesium bromide.
6. The method according to claim 3 or 4, wherein the lithium reagent is a 2.5mol/L n-butyllithium n-hexane solution.
7. The method according to claim 5, wherein the lithium reagent is a 2.5mol/L n-hexane solution of n-butyllithium.
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a preparation method of novel 5-sulfo-1, 4, 5-trisubstituted 1,2, 3-triazole, which comprises a preparation method of 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole and a preparation method of 5-sulfo-1, 4, 5-trisubstituted 1,2, 3-triazole.
Background
The azide-alkyne cycloaddition reaction is one of the most important methods for preparing the 1,2, 3-triazole compounds. In recent years, a series of documents and patents have reported methods for producing 1,2, 3-triazole compounds. However, no document has been reported on a method for producing 5-thiocyanate-substituted 1,4, 5-trisubstituted 1,2, 3-triazoles by cycloaddition reaction involving alkyne in azide-thiocyanate groups. How to realize cycloaddition reaction in which azide-thiocyanate group alkyne participates and improve regioselectivity of the reaction is the focus of attention. The 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazoles can in principle be converted further into 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazoles by reaction with Grignard reagents or lithium reagents. However, no relevant report is found at present. Although some methods for preparing 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazoles by azide-thio intein cycloaddition reaction have been reported (angelw. chem. int.ed.2017,56,10766 and angelw. chem. int.ed.2014,53,1877), the technology for preparing 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazoles by the "one-pot" method using thiocyanate-group intein as a raw material is still in need of further development. The 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole compound is an important compound with potential biological activity, so the research on the preparation method thereof is of great significance.
The invention adopts various thiocyanato internal alkynes and organic azide compounds as raw materials, uses 2.5mol percent [ Cp & ltRu (COD) Cl ] as a catalyst, and reacts for 12-24 hours at room temperature, and finally obtains the 5-thiocyanato substituted 1,4, 5-trisubstituted 1,2, 3-triazole compounds with the yield of 66-85 percent. Then, various thiocyanate radical internal alkyne, organic azide compounds and Grignard reagents or lithium reagents are adopted as raw materials, 2.5mol percent [ Cp & ltRu (COD) Cl ] is used as a catalyst, and the 5-sulfo-1, 4, 5-trisubstituted 1,2, 3-triazole compound is finally obtained with the yield of 62-79 percent in 24-36 hours by a three-component one-pot reaction.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method for synthesizing 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole and a preparation method for 5-sulfo-1, 4, 5-trisubstituted 1,2, 3-triazole.
The technical scheme of the invention is as follows:
a preparation method of novel 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole comprises the following steps:
in an organic solvent, under the action of a pentamethylcyclopentadienyl 1, 5-cyclooctadiene ruthenium chloride ([ Cp < Ru > (COD) Cl ]) catalyst, catalyzing the reaction of alkyne compounds in thiocyanate groups and organic azide compounds to prepare 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole, wherein the reaction formula is as follows:
wherein R is1And R2Is alkyl or aryl, R1And R2The same or different;
i is a thiocyanate radical internal alkyne compound;
the mol ratio of the thiocyanato internal alkyne compound to the organic azide compound is 1:1.5-1:3, and the concentration of the thiocyanato internal alkyne compound in the system is 0.01-0.1 mmol/ml;
the dosage of [ Cp, Ru, (COD) Cl ] is 0.5-50 mol% of the thiocyanato internal alkyne compound;
the reaction temperature is between room temperature and 80 ℃, the reaction time is between 12 and 24 hours, and 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole with the yield not lower than 66 percent is prepared;
the organic solvent is one or more of benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane and petroleum ether, and preferably the solvent is tetrahydrofuran, dichloromethane or chloroform.
A preparation method of novel 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole comprises the following steps:
in an organic solvent, under the action of pentamethylcyclopentadienyl 1, 5-cyclooctadieneyl ruthenium chloride ([ Cp < Ru > (COD) Cl ]) catalyst, the reaction of alkyne compounds in thiocyanate groups and organic azide compounds generates 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole in situ, the 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole continuously reacts with a lattice reagent or a lithium reagent to generate novel 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole, and the reaction formula is as follows:
wherein R is1,R2And R3Is alkyl or aryl, R4Is an alkyl group;
i is a thiocyanate radical internal alkyne compound;
IV is a Grignard reagent;
VI is a lithium reagent;
the mol ratio of the thiocyanato internal alkyne compound to the organic azide compound to the Grignard reagent or the lithium reagent is 1:1.5:2-1:3:4, and the concentration of the thiocyanato internal alkyne compound in the system is 0.01-0.1 mmol/ml;
the dosage of [ Cp, Ru, (COD) Cl ] is 0.5-50 mol% of the thiocyanato internal alkyne compound;
the reaction temperature is 0-room temperature, the reaction time is 24-36 h, and the 5-sulfo-1, 4, 5-trisubstituted 1,2, 3-triazole compound with the yield not less than 62 percent is prepared.
The organic solvent is one or more of benzene, toluene, diethyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, trifluorotoluene, cyclohexane and petroleum ether, and preferably the solvent is tetrahydrofuran, dichloromethane or chloroform.
The Grignard reagent is 1.0mol/L THF solution of phenylmagnesium bromide, 1.0mol/L THF solution of methylmagnesium bromide, 1.0mol/L THF solution of isopropylmagnesium bromide or 1.0mol/L THF solution of cyclopropylmagnesium bromide.
The lithium reagent is 2.5mol/L n-hexane solution of n-butyllithium.
The invention has the beneficial effects that: the preparation method of the 5-thiocyanate substituted 1,4, 5-trisubstituted 1,2, 3-triazole and the preparation method of the 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole have mild reaction conditions, and the yield of the product is not lower than 62%. The preparation method has mild and green reaction conditions and high reaction efficiency, is more suitable for large-scale production requirements, and the prepared 5-thio-1, 4, 5-trisubstituted 1,2, 3-triazole compound has potential physiological activity.
Detailed Description
The following further describes the specific embodiments of the present invention in combination with the technical solutions.