Synthesis of C3-Cyanomethylated Imidazo[1,2-a]pyridines via Ultrasound-Promoted Three-Component Reaction under Catalyst- and Oxidant-Free Conditions

Abstract

An efficient synthesis of C3-cyanomethylated imidazo[1,2-a]pyridines via ultrasound-promoted three-component reaction under catalyst-free, oxidant-free, and mild conditions has been developed. A series of C3-cyanomethylated imidazo[1,2-a]pyridines were rapidly prepared with satisfactory yields and good functional group compatibility. This strategy cloud also be applied to the synthesis of zolpidem and alpidem in short steps.

Key words

ultrasonic irradiation - three-component reaction - cyanomethylation - imidazopyridines - catalyst- and oxidant-free

Publication History

Received: 09 November 2021

Accepted after revision: 23 November 2021

Accepted Manuscript online:
23 November 2021

Article published online:
14 January 2022

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• 13 General Procedure for the Preparation of Representative Compound 2-(2-Phenylimidazo[1,2-a]pyridin-3-yl)acetonitrile (3a) To a sealed tube were added 2-aminopyridine (1a, 18.8 mg, 0.2 mmol), α-bromoacetophenone (1b, 39.8 mg, 0.2 mmol, 1.0 equiv), bromoacetonitrile (48.0 mg, 0.4 mmol, 2.0 equiv), K₂CO₃ (55.3 mg, 0.4 mmol, 2.0 equiv), and DMF (2 mL). The reaction mixture was stirred at r.t. under ultrasound irradiation for 30 min. After the reaction was completed, the resulting residue was diluted with EtOAc (10 mL). The organic layer was washed with water (15 mL) in sequence. The aqueous phase was extracted with EtOAc (5 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (2:1) as eluent to afford the desired product 3a. White solid (39.6 mg, 85% yield); mp 101–103 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.04 (dt, J = 6.9, 1.2 Hz, 1 H), 7.71–7.67 (m, 3 H), 7.50 (t, J = 7.4 Hz, 2 H), 7.44–7.40 (m, 1 H), 7.33–7.29 (m, 1 H), 7.00–6.96 (m, 1 H), 4.14 (s, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 145.8, 145.5, 133.5, 129.4, 129.0, 128.9, 125.8, 123.3, 118.4, 115.4, 113.8, 108.2, 14.3 ppm.