Synthesis of C3-Cyanomethylated Imidazo[1,2-a]pyridines via Ultrasound-Promoted Three-Component Reaction under Catalyst- and Oxidant-Free Conditions
Jie Zhang∗
,
Yufeng Zhang
,
Jian Zhang
,
Qingguo Wu
,
Haifeng Yang∗
This work was supported by the PhD research startup foundation of Jiangsu Agri-animal Husbandry Vocational College (NSF2021CB06), the Research Innovation Program for College Students of Jiangsu Province (202112806014Y), the Animal medicine science and technology innovation team of Jiangsu Agri-animal Husbandry Vocational College (NSF2021TC02) and the Natural Science Foundation of Jiangsu Higher Education Institutions (21KJB150008).
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.
13General 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.
