Nitrile-tolerant iridium-catalysed hydrogen isotope exchange

Isotopically labelled molecules are vital tools within drug discovery and are used extensively to assess a given candidate's absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. Related to this, transition metal-catalyzed hydrogen isotope exchange (HIE) has become a prominent technique for the rapid and selective late-stage installation of a deuterium or tritium label. Despite having a generally wide applicability, the current state-of-the-art in this specific field is limited when particularly co-ordinating motifs are present within a given molecule to be labelled. For example, the exceptional binding strength and sterically unencumbered nature of the nitrile functionality leads to inhibition of catalyst turnover, and has hindered the development of efficient methods for the HIE of nitrile-containing molecules. Herein, in silico solvent binding energy parameter approaches have been disclosed which have facilitated the discovery of uniquely tolerant neutral iridium catalyst species that demonstrate a significantly lower binding strength with nitrile functionality. In turn, we describe the first effective nitrile-tolerant HIE methodology enabled via ortho-directed C(sp ²)−H activation using air- and moisture-stable iridium pre-catalysts of the type Ir(COD)(NHC)Cl under an atmosphere of deuterium gas. This methodology proceeds under mild and practically accessible reaction conditions with a range of directing groups, including heterocycles, ketones, and amines, with this class of catalyst also shown to be applicable towards bioactive molecules, resulting in products with high levels of isotopic labelling.