Core-Regenerating Atom-Pair Exchange Enables Skeletal Carbon Isotope Incorporation into Pyridines

Abstract We report a core-regenerating atom pair exchange strategy for skeletal carbon isotope incorporation into pyridines. The two-step sequence proceeds through pyridine dearomatization followed by a [4 + 2]/retro-[4 + 2] cycloaddition cascade with an isotope-labeled sulfonyl cyanide reagent, enabling selective replacement of a pyridine carbon atom with an isotopically labeled counterpart. This transformation addresses a longstanding challenge in the preparation of carbon-isotope-labeled pyridines, which are valuable for medicinal chemistry and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies. The method exhibits high regioselectivity and broad tolerance of diverse pyridine substitution patterns, providing rapid access to a wide range of 13C-labeled pyridine building blocks and bioactive molecules.