Multicomponent one-pot synthesis of imidazo[1,2-a]pyridine functionalized with azides

Imidazo[1,2-a]pyridine are nitrogen fused heterocycles which are acknowledged as privileged molecules due their wide range of properties in medicinal chemistry, including anti-diabetic, anti-cancer, anti-viral, anti-ulcer, anti-microbial, anti-IHV, hypnotic, analgesic and antipyretic activities. These scaffolds are also valuable for other fields like bioimaging, probes or chemosensors, due to their optoelectronic properties, which include high quantum yields, large Stokes shifts, and good stability. One-pot processes that include multicomponent reactions are the most efficient, robust, and sustainable synthetic tools for the synthesis of valuable molecules. Among these, isocyanide-based multicomponent reactions stand out as the most versatile and effective tools for the synthesis of heterocyclic molecules directly or via post-transformation. Specifically, the Groebke-Blackburn-Bienaymé (GBB) reaction is the most effective tool for accessing imidazo[1,2-a]pyridine. This reaction involves an aldehyde or ketone, an amidine and an isocyanide, with Lewis or Bronsted acid catalysis. The reactivity of the endocyclic nitrogen in the amidine component allows the intramolecular nitrilium ion trapping, leading to the formation of the heterocyclic scaffold, whereas the acid component is not incorporated in the final products as in classical Ugi reaction. Herein we developed the one-pot synthesis under mild conditions to access functionalized imidazo[1,2-a]pyridine using ammonium chlorine as a catalyst. The resulting GBB products could serve as synthetic platforms for further post-transformations.