CN-117534671-B - Method for synthesizing imidazo [1, 2-alpha ] pyridine derivative by using titanocene dichloride as catalyst

Abstract

The invention discloses a method for synthesizing imidazo [1, 2-alpha ] pyridine derivatives by using titanocene dichloride catalysis, which uses titanocene dichloride as a Lewis acid catalyst, adopts a one-pot method to react with 2-aminopyridine compounds, benzaldehyde compounds and isocyanoacetic acid ethyl ester at 40-60 ℃ under the condition of no solvent, generates imine intermediates by reacting the 2-aminopyridine compounds with the benzaldehyde compounds under the catalysis of titanocene dichloride, generates subsequent intermediates by adding the imine intermediates with isocyanoacetic acid ethyl ester, and generates imidazo [1, 2-alpha ] pyridine derivatives by [4+1] cycloaddition reaction and 1,3 proton transfer. The method has the advantages of simple operation, low synthesis cost, mild reaction conditions, short reaction time, green solvent-free catalysis and simple column chromatography separation of the product after the reaction is finished.

Inventors

• WANG YUNYUN
• LI XIAOYUE
• LU XU
• WANG TAO

Assignees

• 宁夏师范学院

Dates

Publication Date

20260512

Application Date

20231110

Claims (2)

1. 1. A method for synthesizing imidazo [1, 2-alpha ] pyridine derivatives by using titanocene dichloride catalysis is characterized in that benzaldehyde compounds shown in a formula I, 2-aminopyridine compounds shown in a formula II and ethyl isocyanoacetate shown in a formula III are added into a reaction bottle under the condition of no solvent, titanocene dichloride is added as a catalyst, and the mixture is reacted at 40-60 ℃, and after the reaction is finished, the products are separated and purified to obtain imidazo [1, 2-alpha ] pyridine derivatives shown in a formula IV; I II III IV Wherein R 1 、R 2 each independently represents any one of H, halogen, C 1 ～C 4 alkyl, C 1 ～C 4 alkoxy, and phenyl; the molar ratio of the benzaldehyde compound to the 2-aminopyridine compound to the ethyl isocyanoacetate is 1:1.1-1.3:1.1-1.3; the addition amount of the dichloro titanocene is 8% -12% of the molar amount of the benzaldehyde compound.
2. 2. The method for synthesizing imidazo [1, 2-alpha ] pyridine derivatives by using titanocene dichloride catalysis according to claim 1, wherein the reaction is carried out for 1.5-3.5 hours at 50 ℃.

Description

Method for synthesizing imidazo [1, 2-alpha ] pyridine derivative by using titanocene dichloride as catalyst Technical Field The invention belongs to the technical field of synthesis of imidazo [1, 2-alpha ] pyridine derivatives, and in particular relates to a method for synthesizing imidazo [1, 2-alpha ] pyridine derivatives by using a dichloro-titanocene-catalyzed benzaldehyde compound, a 2-aminopyridine compound and ethyl isocyanoacetate. Background N-heterocyclic compounds are widely found in natural products, drugs and functional materials with biological activity and play an important role in the fields of life sciences and material sciences. Among the numerous nitrogen-fused heterocyclic compounds, imidazo [1,2- α ] pyridine derivatives are considered as a key building block due to their wide application in the fields of optics, materials science, and organometallics, and are also considered as "drug-favored" frameworks due to their wide application in the field of medicinal chemistry. In recent decades, many synthetic methods, such as Mikhail V.il' in et al (Il'in M V,Sysoeva A A,Novikov A S,et al.Diaryliodoniums as hybrid hydrogen-and halogen-bond-donating organocatalysts for the Groebke–Blackburn–Bienayméreaction[J].The Journal of Organic Chemistry,2022,87(7):4569-4579.), have found in 2022 that dibenzoiodonium and diphenyliodonium trifluoride have high catalytic activity for a multicomponent reaction to form a series of imidazopyridines, requiring reaction in 50 ℃ chloroform, but chloroform is extremely toxic and generates phosgene and hydrogen chloride upon photodecomposition, and is lethal in large doses, not conforming to the green chemistry theme. 2022, MEENAKSHI BUDHIRAJA et al (Budhiraja M,Ali A,Tyagi V.Construction of a Bifunctional Pd (0)-CALB@SiO2 Hybrid Catalyst for the Synthesis and Arylation of Imidazo[1,2-α]pyridine in One Pot[J].European Journal of Organic Chemistry,2023,26(11):e202201426.) reported an effective strategy for constructing an enzyme-metal biohybrid catalyst [ Pd (0) -CALB@SiO 2 ] by encapsulating Candida antarctica Lipase B and Pd (0) in silica to catalyze multicomponent reactions and Linnaeus-methyl coupling to produce clinically significant imidazo [1,2- α ] pyridine derivatives, which require high temperature heating and overnight reaction time. 2022, nicolas S.Anjos et al (Anjos N S,Chapina A I,Santos A R,et al.Groebke-Blackburn-BienayméMulticomponent Reaction Catalysedby Reusable Ionic Liquids [ J ]. EuropeanJournal of Organic Chemistry,2022 (40): e 202200615.) have studiedThe application of the acidic ionic liquid (BAIL) as a catalyst in groebke-blackburn-bienaym multicomponent reaction can obtain a series of imidazole-fused heterocyclic compounds with the yield of 42-93% by heating in a sealed tube for 1-4 hours at the temperature of 150 ℃ in a microwave manner, wherein the temperature is too high and the time is as long as 24 hours. Solvent-free synthesis of imidazo [1,2-a ] pyridine compounds and their oxidation resistance [ J ]. Synthesis chemistry, 2020,28 (03)) in the year 2020 Matgao epi et al (Matgao epi, chen Zhifei, yang Jin elementary, use ethanol as solvent, catalyze Groebke-Blackburn-Bienaym e three-component reaction (GBB-3 CR) between 2-aminopyridine, ferrocenecarboxaldehyde and isocyanides with LaCl 3 under 80 ℃ heating, and synthesize 5 ferrocenylimidazo [1,2-a ] pyridine compounds at higher temperatures. 2021, mosayeb Akbari et al (Akbari M,Maleki A,Bahadorikhalili S,et al.Efficient synthesis of novel 2-(2-chloroquinolin-3-yl)imidazo[1,2-α]pyridin-3-amine derivatives[J].Journal of the Chinese Chemical Society,2021,68(7):1328-1333.) reacted in acetonitrile using 10mol% trimethylsilyl chloride as a catalyst, the acetonitrile was more polar, the post-treatment was more complicated, and it was harmful to the human body. Disclosure of Invention The invention aims to provide a method for efficiently synthesizing imidazo [1, 2-alpha ] pyridine derivatives, which has the advantages of mild reaction conditions, simple operation, short reaction time and good substrate applicability. Adding a benzaldehyde compound shown in a formula I, a 2-aminopyridine compound shown in a formula II and ethyl isocyanoacetate shown in a formula III into a reaction bottle, adding titanocene dichloride as a catalyst, reacting at 40-60 ℃, and separating and purifying a product after the reaction is finished to obtain an imidazo [1, 2-alpha ] pyridine derivative shown in a formula IV; wherein R 1、R2 independently represents any one of H, halogen, C 1～C4 alkyl, C 1～C4 alkoxy and phenyl. In the above synthesis method, the molar ratio of the benzaldehyde compound, the 2-aminopyridine compound and the ethyl isocyanoacetate is preferably 1:1.1-1.3:1.1-1.3. In the above synthetic method, the addition amount of the titanocene dichloride is preferably 8% -12% of the molar amount of the benzaldehyde compound. In the above synthesis method, the reaction is preferably carried out at 50