Structural and Thermal Characterization of Halogenated Azidopyridines: Under-Reported Synthons for Medicinal Chemistry

Owing to their participation in Click
reactions, bifunctional azides
are valuable intermediates in the preparation of medicines and biochemical
tool compounds. Despite the privileged nature of pyridines among pharmaceutical
scaffolds, reports of the synthesis and characterization of azidopyridines
bearing a halogen substituent for further elaboration are almost completely
unknown in the literature. As azidopyridines carry nearly equal numbers
of nitrogen and carbon atoms, we hypothesized that safety concerns
limited the application of these useful bifunctional building blocks
in medicinal and biological chemistry. To address this concern, we
prepared and characterized nine azidopyridines bearing a single fluorine,
chlorine, or bromine atom. All were examined by differential scanning
calorimetry (DSC), in which they demonstrated exotherms of 228–326
kJ/mol and onset temperatures between 119 and 135 °C. Selected
azidopyridines were advanced to mechanical stress testing, in which
impact sensitivity was noted for one regioisomer of C5H3FN4. The utility of these versatile intermediates
was demonstrated through their use in a variety of Click reactions
and the diversification of the halogen handles.