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A late-stage 18O labeling approach of
sulfonamides that employs the corresponding unlabeled molecule as the starting
material was developed. Upon deamination of the sulfonamide, a sulfinate
intermediate was isotopically enriched using eco-friendly reagents H218O
and 15NH3(aq) to afford a M+5 isotopologue of the parent
compound. This degradation-reconstruction approach afforded isolated yields of up
to 96% for the stable isotope labeled (SIL) sulfonamides, and was compatible with
multiple marketed therapeutics, including celecoxib, on a gram scale. The SIL
products also exhibited no 18O/16O back exchange under extreme
conditions, further validating the utility of this green strategy for drug
labeling for both in vitro and in vivo use. This procedure was also
adapted to include pharmaceutically relevant methyl sulfones by using 13CH3,
affording M+5 isotopic enrichment, thereby illustrating the broad utility of