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Copper-Catalyzed Three-Component Cascade Annulation for Divergent Syntheses of Imidazoles and Dihydroimidazoles

Gaochen Xu, Chenglong Jia, Xuemei Wang, Huan Yan, Sai Zhang, Qinghuan Wu, Ning Zhu, Jindian Duan* and Kai Guo*

*College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China, Email: duanjdnjtech.edu.cn, guoknjtech.edu.cn

G. Xu, C. Jia, X. Wang, H. Yan, S. Zhang, Q. Wu, N. Zhu, J. Duan, K. Guo, Org. Lett., 2022, 24, 1060-1065.

DOI: 10.1021/acs.orglett.1c04308



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Abstract

A copper-catalyzed three-component reaction of α,β-unsaturated ketoximes, paraformaldehyde, and amines provides imidazoles and dihydroimidazoles depending on the reaction conditions in good yields with a broad substrate scope.

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proposed mechanism



General procedure for the synthesis of imidazoles

Ketoxime-enoate (0.3 mmol, 1.5 equiv), paraformaldehyde (1 mmol, 5.0 equiv), amine (0.2 mmol, 1.0 equiv), CuBr (10 mol%), DABCO (80 mol%) and H2O (80 μL) in THF: DMSO = 1:1 (2 mL, 0.1 M), were stirred at 130C (oil bath) in a 10 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar under N2 atmosphere for 12 h. When the reaction was completed (detected by TLC), the mixture was cooled to room temperature. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 10 mL). The combined organic layers were dried with anhydrous sodium sulfate and then concentrated under vacuum. The crude residue was purified by column chromatography (petroleum ether/ethyl acetate) on silica gel to give the corresponding product.


Key Words

imidazoles, multicomponent reactions


ID: J54-Y2022