Late-Stage 18O Labeling of Primary Sulfonamides via a Degradation-Reconstruction Pathway

Abstract

A late-stage <sup>18</sup>O 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 H<sub>2</sub><sup>18</sup>O and <sup>15</sup>NH<sub>3</sub>(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 <sup>18</sup>O/<sup>16</sup>O back exchange under extreme conditions, further validating the utility of this green strategy for drug labeling for both <i>in vitro</i> and <i>in vivo</i> use. This procedure was also adapted to include pharmaceutically relevant methyl sulfones by using <sup>13</sup>CH<sub>3</sub>, affording M+5 isotopic enrichment, thereby illustrating the broad utility of this methodology.