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

The discovery and optimization of a reaction between 2-chloropyridines and 2-azirines producing imidazo[1,2-]pyridines is described. The treatment of 2-azirines with triflic anhydride (TfO) forms an electrophilic 1-trifloyl-aziridin-2-yl triflate species which, when reacted with 2-halopyridines, generates transient pyridinium salts. These salts were treated in the same pot with triethylamine (EtN), leading to the selective formation of C3-substituted imidazo[1,2-]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.