Synthesis of ¹⁵N-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 NTf-Zincke imines and then ringclosure 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.

15NRORC: An Azine Labeling Protocol

“…This revealed that, while mildly effective at displacing triflamide, transfer of triflate to the alkyl amine was equally viable, reducing the overall likelihood for high 15 N isotopic enrichment through ANRORC displacement. It is worth noting that other groups concurrently investigated this mode of activation and were able to elegantly engineer its successful utilization for a similar 15 N isotopic labeling strategy. ,, In parallel, however, after much surveying of activation methods, a modified Zincke-type activation with tosylate 13 (see Scheme ) proved most effective in our hands across a relatively broad range of azine substrates …”

Combining Umpolung and Carbon Isotope Exchange Strategies for Accessing Isotopically Labeled α-Keto Acids

“…Traditional early stage methods for introducing diverse isotopes often prove time-consuming and resource-intensive, encompassing multiple synthesis steps, harsh conditions, and expensive materials, presenting a significant challenge. However, recent advancements in late-stage approaches, − particularly isotope exchange reactions involving hydrogen, − carbon, − fluorine, nitrogen, − and sulfur, now allow for the direct labeling of the desired compound in a single step, effectively addressing challenges inherent in traditional methodologies.…”