Synthesis of Imidazo[1,2‑a]pyridines: Triflic Anhydride-Mediated Annulation of 2H‑Azirines with 2‑Chloropyridines

The discovery and optimization of a reaction between 2-chloropyridines and 2H-azirines producing imidazo­[1,2-a]­pyridines is described. The treatment of 2H-azirines with triflic anhydride (Tf2O) forms an electrophilic 1-trifloyl-aziridin-2-yl triflate species which, when reacted in situ with 2-halopyridines, generates transient pyridinium salts. These salts were treated in the same pot with triethylamine (Et3N), leading to the selective formation of C3-substituted imidazo­[1,2-a]­pyridines, an heterocyclic moiety commonly found in medicinal chemistry leads and drugs. Thorough optimization of the activation/cyclization resulted in yields ranging from 15 to 85% for a variety of substituted heterocycles.