Method for one-step direct preparation of 3-acyl imidazole [1, 5-a] pyridine through [4 +1] ketomethyl secondary amination reaction

A ketone methyl secondary amination, acyl imidazole technology, applied in the field of chemical synthesis, can solve the problems of the process being harmful to the environment, unsatisfactory efficiency, etc., and achieve the advantages of shortening synthesis steps, good substrate scope, and improving synthesis efficiency. Effect

Active Publication Date: 2022-02-18
ANHUI SCI & TECH UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Obviously, the efficiency is not satisfactory and the process is also harmful to the environment

Method used

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  • Method for one-step direct preparation of 3-acyl imidazole [1, 5-a] pyridine through [4 +1] ketomethyl secondary amination reaction
  • Method for one-step direct preparation of 3-acyl imidazole [1, 5-a] pyridine through [4 +1] ketomethyl secondary amination reaction
  • Method for one-step direct preparation of 3-acyl imidazole [1, 5-a] pyridine through [4 +1] ketomethyl secondary amination reaction

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Embodiment 1

[0032] Experimental reagents and instruments:

[0033] In the present invention, unless otherwise stated, all reactions were carried out under air atmosphere using commercial materials and solvents without further purification. At room temperature, use CDCl 3 or DMSO-D 6 Measured as a solvent 1 H NMR (400 MHz, 500 MHz or 600MHz) and 13 C NMR (101 MHz, 126 MHz, or 151 MHz) spectra. High-resolution mass spectra (HRMS) were recorded on a BRUKERVPEXII spectrometer in ESI mode. Flash column chromatography was performed on 200-300 mesh silica gel.

[0034] Such as image 3 As shown, the method for the direct preparation of 3-acylimidazol[1,5-a]pyridine in one step by secondary amination reaction of [4+1]ketomethyl includes the following steps: Under the condition of 10 mA constant current, electrolysis Cell electrolysis of acetophenone (1a; 0.2 mmol, 1 equiv), pyridin-2-phenyl(pyridin-2-yl) formamide (2a; 0.4 mmol, 2 equiv) and NH 4 I (0.3 mmol) for 16 h afforded product 3a ...

Embodiment 2

[0042] This example evaluates the electrochemical approach by performing reactions on a 10 mmol scale. Using 25mA constant current and reacting for 20 hours, a 62% yield of 3a could be obtained ( Figure 5 ). The results demonstrate the potential of this electrochemical synthesis of imidazo[1,5-a]pyridines.

[0043] Specifically, such as Figure 5 As shown, acetophenone (1a, 10mmol), phenyl (pyridin-2-yl) formamide (2a, 20mmol), NH 4 I (15mmol), (DMSO 50mL) were placed in a 100mL reaction tube equipped with a graphite rod anode (diameter = 0.6cm) and a platinum cathode (1.0cm 2 ). The reaction was carried out at 80°C under a constant current of 25 mA for 20 hours, and the reaction process was monitored by thin layer chromatography (TLC). The system was poured into water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with saturated brine and washed with anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure. The re...

Embodiment 3

[0046] The difference between this embodiment and embodiment 1 is only that the electrolytic reaction is carried out at 78°C, the diameter of the graphite rod is 0.7cm; the area of ​​the platinum sheet is 1.2cm 2 .

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Abstract

The invention provides a method for one-step direct preparation of 3-acyl imidazole [1, 5-a] pyridine through [4 + 1] ketomethyl secondary amination reaction, and the method comprises the following steps: electrolyzing 1 equivalent of R1-ethyl ketone, 2 equivalent of pyridine-2-R2-formamide and 1.5 equivalent of NH4I for 16-20 hours in a diaphragm-free electrolytic bath under the constant current condition of 10-25 mA to obtain a product. The efficient electrochemical synthesis method of 3-acyl imidazole [1, 5-a] pyridine is developed, and the conventional multi-step reaction of synthesis of 3-acylimidazole [1, 5-a] pyridine is avoided through two times of amination of cheap ketone methyl sp3 hydrocarbon; the direct synthesis method, the cheap materials, the simple metal-free system, no additional electrolyte or oxidant and expandability enable the method to become a practical and green method for preparing 3-acyl imidazole [1, 5-a] pyridine and a large pi-system.

Description

technical field [0001] The present invention relates to a method for directly preparing 3-acyl imidazol[1,5-a]pyridine in one step by the secondary amination reaction of [4+1] ketomethyl, in particular to an electrochemically mediated [4+1] The invention relates to a method for directly preparing 3-acyl imidazol[1,5-a]pyridine in one step through secondary amination reaction of ketomethyl, belonging to the technical field of chemical synthesis. Background technique [0002] Imidazo[1,5-a]pyridines are characteristic fused N-heterocyclic compounds that have broad applications in medicinal chemistry for drug discovery. In recent years, the chemical community has developed several synthetic methods to construct these compounds, which greatly facilitated the study of drug structure-activity relationship (SAR) for this scaffold. However, these methods have limitations in the synthesis of 3-acylimidazo[1,5-a]pyridines. 3-Acylimidazo[1,5-a]pyridines are key pharmacophores widely ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王强查蒙
Owner ANHUI SCI & TECH UNIV
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