Tritium hydrogen-isotope exchange with electron-poor tertiary benzenesulfonamide moiety; application in late-stage labeling of T0901317.

The multifunctional radioligand [ 3 H]T0901317 ([ 3 H]1) has been employed as a powerful autoradiographic tool to target several receptors, such as liver X, farnesoid X, and retinoic acid-related orphan receptor alpha and gamma subtypes at nanomolar concentrations. Although [ 3 H]1 is commercially available and its synthesis via tritiodebromination has been reported, the market price of this radioligand and the laborious synthesis of corresponding bromo-intermediate potentially preclude its widespread use in biochemical, pharmacological, and pathological studies in research lab settings. We exploit recent reports on hydrogen-isotope exchange (HIE) reactions in tertiary benzenesulfonamides where the sulfonamide represents an ortho-directing group that facilitates CH activation in the presence of homogenous iridium(I) catalysts. Herein, we report a time- and cost-efficient method for the tritium late-stage labeling of compound 1-a remarkably electron-poor substrate owing to the tertiary trifluoroethylsulfonamide moiety. Under a straightforward HIE condition using a commercially available Kerr-type NHC Ir(I) complex, [(cod)Ir (NHC)Cl], the reaction with 1 afforded a specific activity of 10.8 Ci/mmol. Additionally, alternative HIE conditions using the heterogeneous catalyst of Ir-black provided sufficient 0.72 D-enrichment of 1 but unexpectedly failed while repeating with tritium gas.