Iridium-catalysed C-6 hydrogen isotope exchange of pyridines

Iridium-catalysed C-6 hydrogen isotope exchange of pyridines

Andrew J. Dalgleish, under the supervision of  Prof. William J. Kerr, is utilising ARCHIE-WeSt to perform DFT calculations on a wide range of iridium(III) complexes which have extensive application in hydrogen isotope exchange.

As the investigation of pharmacokinetics and pharmacodynamics is an essential component of the effective 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, Top).1, 2 With pyridine ring systems ubiquitous in drug molecules, we subsequently investigated their labelling with our Ir(I) catalysts (Figure 1, Bottom).

After extensive optimisation and catalyst screening, high deuterium incorporations were observed in over 25 pyridine examples, with reaction times as low as 4 h. Expansion of this methodology revealed that other heterocycles, such as pyrimidines, quinolines and quinoxalines, also displayed high incorporations with unusual catalyst selectivity. DFT calculations from ARCHIE-WeSt have been used to further develop our mechanistic insights into this new and effective labelling methodology.

For more information about the project contact Prof. William J. Kerr (w.kerr@strath.ac.uk) Professor at the Department of Pure and applied Chemistry at the University of Strathclyde or Andrew J. Dalgleish (andrew.dalgleish@strath.ac.uk), PhD student.

For a list of the research areas in which ARCHIE-WeSt users are active please click here.

References & Publications

  1. J. A. Brown, A. R. Cochrane, S. Irvine, W. J. Kerr, B. Mondal, J. A. Parkinson, L. C. Paterson, M. Reid, T. Tuttle, S. Andersson and G. N. Nilsson, Adv. Synth. Catal. 2014, 356, 3551–3562.
  2. J. Atzrodt, V. Derdau, W. J. Kerr and M. Reid, Angew. Chem. Int. Ed., 2018, 57, 3022–3047.