Synthesis of Imidazo[1,2‑a]pyridine-Fused 1,3-Benzodiazepine Derivatives with Anticancer Activity via a One-Pot Cascade GBB-3CR/Pd(II)-Catalyzed Azide-Isocyanide Coupling/Cyclization Process

• Published in: Journal of organic chemistry 2023-09, Vol.88 (18), p.13125-13134
• Main Authors: Zhong, Cheng-Ran, Zhang, Yang-Hong, Yao, Gang, Zhu, Hai-Li, Hu, Yin-Di, Zeng, Zhi-Gang, Liao, Chang-Zhou, He, Hui-Ting, Luo, Ya-Ting, Xiong, Jun
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.3c01341

A new one-pot synthesis of imidazo­[1,2-a]­pyridine-fused 1,3-benzodiazepine derivatives via a sequential GBB-3CR/Pd­(II)-catalyzed azide-isocyanide coupling/cyclization process was developed. The Groebke–Blackburn–Bienaymé three-component reactions (GBB-3CR) of 2-aminopyridine, 2-azidobenzaldehydes, and isocyanides in the presence of a catalytic amount of p-toluenesulfonic acid gave azide intermediates without separation. The reaction was followed by using another molecule of isocyanides to produce imidazo­[1,2-a]­pyridine-fused 1,3-benzodiazepine derivatives in good yields by the Pd­(II)-catalyzed azide-isocyanide coupling/cyclization reaction. The synthetic approach produces novel nitrogen-fused polycyclic heterocycles under mild reaction conditions. The preliminary biological evaluation demonstrated that compound 6a inhibited glioma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.