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

The discovery and optimization of a reaction between 2-chloropyridines and 2<i>H</i>-azirines producing imidazo[1,2-<i>a</i>]pyridines is described. The treatment of 2<i>H</i>-azirines with triflic anhydride (Tf₂O) forms an electrophilic 1-trifloyl-aziridin-2-yl triflate species which, when reacted <i>in situ</i> 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-<i>a</i>]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.