The investigation of pharmacokinetics and pharmacodynamics is an essential component of the development of novel pharmaceutical candidates. These studies are highly reliant on isotopically-labelled drug analogues and, as such, late-stage hydrogen isotope exchange (HIE) reactions have become important methods for their synthesis. The Kerr group has performed extensive work in this area, with our iridium(I) pre-catalysts of type 1 and 2 exceptionally active in facilitating the mild and selective ortho-labelling of aromatic compounds, mediated by a wide variety of directing groups (DGs) (Figure 1, Top). With N-heteroaromatic ring systems ubiquitous in drug molecules, we subsequently investigated their labelling using our Ir(I) pre-catalysts, and uncovered α-deuteration in a wide range substrates (Figure 1, Bottom). After extensive optimisation and catalyst screening, high deuterium incorporations were observed in over 25 pyridine examples, with C-2, -3 and -4 substituted pyridine ring systems. Further studies discovered that, in some C-2 substituted cases, selective C-6 labelling could be achieved through careful control of the reaction time, and sterically hindered derivatives could be deuterated using alternate conditions. Expansion of this methodology revealed that other heterocycles, such as pyrimidines, quinolines and quinoxalines, also displayed high incorporations adjacent to the heteroatom, and drug examples exemplify the utility of this methodology. In addition, the reaction can be performed at very mild temperatures, with low deuterium pressure and employs a green solvent. This methodology is currently undergoing mechanistic study within our laboratory and extensive DFT calculations have been utilised to further develop our mechanistic insights into this new and effective labelling methodology.

Iridium-catalysed hydrogen isotope exchange of N-heteroaromatics

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