Metal‐catalysed hydrogen isotope exchange labelling: a brief overview

Abstract

An overview is given of this Special Issue of the Journal of Labelled Compounds and Radiopharmaceuticals dealing with the subject of metal‐catalysed hydrogen isotope exchange labelling. In addition to summarizing the areas covered by the contributed papers, the overview also adds some historical information and gives short reviews of those areas and metals, not specifically covered by the contributed papers. Copyright © 2010 John Wiley & Sons, Ltd.

Palladium(II)‐Mediated C−H Tritiation of Complex Pharmaceuticals

“…We envisioned that such chemistry, if developed, could offer novel tritiation scope compared to previous methods. Electrophilic C−H metalation is distinct from the likely mechanisms of C−H cleavage in previous methods involving low‐valent metals and metal tritides (e.g., oxidative addition or β‐hydride elimination). A conceptual challenge for the development of such chemistry is that electrophilic transition metals are unlikely to persist in the presence of T 2 gas, due to facile reduction.…”

“…Molecules labeled with tritium (T, 3 H, half‐life: 12.3 years) are in perpetually high demand for the study of protein receptor‐ligand interactions, autoradiographic imaging of molecular interactions in biological tissue, and the investigation of molecular absorption, distribution, metabolism and excretion (ADME) . To enable such applications quickly and with low cost, particularly in academic and industrial settings with rapid turnover cycles for evaluation of candidate pharmaceuticals and imaging tracers, direct C−H tritiation on the final molecule of interest is a desired synthetic approach . The preferred source of tritium is tritium gas (T 2 ), because T 2 is the low cost synthetic precursor of other tritium building blocks, and is practical to handle on micromole scale with commercially available manifolds.…”

“…Iridium complexes such as Crabtree's catalyst, [Ir(COD)(PCy 3 )(py)]PF 6 , are regarded as state of the art for aromatic H/T exchange (Figure A), but have a limited scope of useful directing groups, and are poisoned by common coordinating groups in bioactive compounds that do not direct C−H activation, such as 4‐pyridyl substituents . Heterogeneous catalysts such as rhodium and palladium metal are generally limited to tritiation at activated N‐heterocycle, benzylic, and anomeric C−H bonds in reactions with T 2 . A molecular iron(0) catalyst exhibits excellent reactivity for tritiation with T 2 at unhindered aromatic C−H bonds without directing groups, but does not tolerate common protic functionality in pharmaceuticals such as alcohols or trace water and oxygen .…”

“…In conclusion, we report C−H tritiation of complex pharmaceuticals with T 2 based on electrophilic C−H palladation. The substrate scope includes C−H bonds adjacent to directing groups that have not been utilized with previous tritiation methods . Furthermore, a wide range of functional groups are tolerated, including protic and Lewis basic functional groups that are not tolerated by previous state of the art methods.…”

Tritiodefluorination of alkyl C–F groups

“…Tritium is the most versatile radioisotope used for identifying organic compounds in biochemical research . Most frequently, tritiations are carried out using carrier‐free tritium gas in the presence of a noble metal catalyst in order to reduce double or triple bonds, tritiodehalogenation of appropriate synthetic precursors or to carry out 1 H/ 3 H exchanges on the desired molecule . Catalytic dehalogenations of organic halides, using tritium gas, provide a state‐of‐the‐art approach of site‐selective labeling, while yielding high specific activity (SA) of the labeled material (Figure ) .…”