A metal-catalysed functional group metathesis approach to the carbon isotope labelling of carboxylic acids

The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs to probe these features typically requires toxic, radioactive gases such as [¹⁴C]CO and [¹⁴C]CO₂. Here we describe an approach to directly carbon-label carboxylic-acid-containing pharmaceuticals via a metal-catalysed functional group exchange reaction, forming ¹⁴C-labelled carboxylic-acid-containing drugs without radioactive gases, in one pot, using an easily available and handled carboxylic acid ¹⁴C source. To enable this process, a functional group metathesis of carbon-carbon covalent bonds in acid chloride functionalities is developed, exploiting the ability of nickel catalysts to both reversibly activate carbon-chloride bonds and exchange functionalities between organic molecules. The drug development applicability is illustrated by the direct incorporation of the ¹⁴C label or ¹³C label into an array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or a special apparatus, at ambient conditions and without loss of the radiolabel.