Methods
to incorporate stable radioisotopes are integral to pharmaceutical
and agrochemical development. However, despite the prevalence of pyridines
in candidate compounds, methods to incorporate 15N atoms
within their structures are limited. Here, we present a general approach
to pyridine 15N-labeling that proceeds via ring-opening
to NTf-Zincke imines and then ring-closure with commercially
available 15NH4Cl salts. This process functions
on a range of substituted pyridines, from simple building block-type
compounds to late-stage labeling of complex pharmaceuticals, and 15N-incorporation is >95% in most cases. The reactivity
of
the Zincke imine intermediates also enables deuteration of the pyridine
C3- and C5-positions, resulting in higher mass isotopologs required
for LCMS analysis of biological fluids during drug development
