Approval of new drug candidates requires documented distribution, metabolism and toxicity investigations, which are supported by specifically positioned isotope labels in the molecule of interest. Carbone isotope labeling is a powerful tool for studying these features of the molecule.

In a new paper from Troels Skrydstrups research group published in Angewandte Chemie International Edition, the team of researchers in collaboration with AstraZeneca scientists, have devised a method for the carbon isotope labeling of aliphatic ketones. Such functional groups are common constituents of numerous well-known pharmaceuticals.
The scope of substrates as well as the synthesis of pharmaceutically relevant compounds is broad, which illustrates the generality and applicability of this method.

In this paper, they report on the synthesis of an extensive range of functionalized aliphatic ketones with good functional group tolerance by a Ni(I)-promoted coupling of primary or secondary alkyl iodides with NN₂ pincer Ni(I)I-acyl complexes. The latter were easily accessed from the corresponding Ni(II)-alkyl complexes with stoichiometric CO using the COware technology and the CO releasing molecule, SilaCOgen. This Ni-mediated carbonylative coupling is adaptable to late stage carbon isotope labeling (including carbon-14), as illustrated by the preparation of isotopically labelled pharmaceuticals.