Synthesis of N-Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates.

Methods to incorporate stable radioisotopes are integral to pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods to incorporate N atoms within their structures are limited. Here, we present a general approach to pyridine N-labeling that proceeds via ring-opening to Tf-Zincke imines and then ring-closure with commercially available NHCl salts. This process functions on a range of substituted pyridines, from simple building block-type compounds to late-stage labeling of complex pharmaceuticals, and N-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.