Synthesis of ¹⁵ N-Pyridines and Higher Mass Isotopologs via Zincke Imine Intermediates

Abstract

Methods to incorporate stable radioisotopes are integral to pharmaceutical and agrochemical development. However, despite the prevalence of pyridines in candidate compounds, methods to incorporate 15 N atoms within their structures are limited. Here, we present a general approach to pyridine 15 N-labeling that proceeds via ring-opening to N Tf-Zincke imines and then ring-closure with commercially available 15 NH 4 Cl salts. This process functions on a range of substituted pyridines, from simple building block-type compounds to late-stage labeling of complex pharmaceuticals, and 15 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.