Substrate-Directed Annulative-Sulfonylation/Desulfonylation Cascade Using (E)‑β-Iodovinyl Sulfones: A Diverse Approach for the Synthesis of Imidazo[1,2‑a]pyridines with Sulfone Motifs

The 3-aryl-imidazo[1,2-a]pyridines are among the most promising molecular frameworks in drug discovery and development; however, their sulfonyl analogues remain largely underexplored. In this study, we report a base-mediated annulative-sulfonylation of 4-(pseudo)halo-2-aminopyridines using (E)-β-iodovinyl sulfones in polyethylene glycol (PEG400), resulting in the formation of 7-sulfonyl-derived imidazo[1,2-a]pyridines in good to high yields. Remarkably, the 4-(pseudo)halo-2-aminopyridines allow unexpected sulfonyl migration, leading to the first preparative synthesis of imidazo[1,2-a]pyridine-derived sulfone analogues. Conversely, other substituted 2-aminopyridines participate in a desulfonylative-annulation using (E)-β-iodovinyl sulfones to afford 3-substituted-imidazo[1,2-a]pyridines in moderate to high yields. Importantly, this metal-free protocol is versatile, accommodating a wide range of substrates while demonstrating good functional group tolerance and compatibility. Notably, the method has proven effective in synthesizing 3,7-diphenyl-imidazo[1,2-a]pyridine, a tyrosine kinase (KDR) inhibitor, as well as its isomeric analogue. Furthermore, gram-scale reactions have been successfully conducted, and potential mechanistic pathways have been rationalized based on existing experimental results.