Chemoenzymatic Triazolopyridine Synthesis Enabled by Cryptic Diazo Formation by Vanadium-Dependent Haloperoxidases

Triazolopyridines are an important class of heterocycles in the pharmaceutical industry and materials sciences. In particular, [1,2,3]triazolo[1,5a]pyridines have emerged as stable and versatile diazo compound precursors for performing carbene-mediated transformations. Despite their wide range of applications in chemical synthesis, their preparation is often reliant on oxidative cyclization methods using stoichiometric oxidants in organic solvent, limiting their application in chemoenzymatic synthesis. We have recently discovered that vanadium-dependent haloperoxidase (VHPO) enzymes are effective catalysts for performing the oxidative cyclization of 2-pyridyl ketone hydrazones to give [1,2,3]triazolo[1,5a]pyridines through cryptic diazo formation. Herein, we have developed a chemoenzymatic protocol for conversion of 2-pyridyl ketones to [1,2,3]triazolo[1,5a]pyridines in a single vessel through the in situ generation of 2-pyridyl ketone hydrazones followed by VHPO-catalyzed oxidative cyclization to give [1,2,3]triazolo[1,5a]pyridines in high yield and chemoselectivity.