Expanded applicability of iridium(I) NHC/phosphine catalysts in hydrogen isotope exchange processes with pharmaceutically-relevant heterocycles

Abstract

An assessment of emerging C-H activation catalysts of the type [(COD)Ir(IMes)(PR3)]PF6 in the deuteration of N-heterocycles is divulged. Substrate scope, competition experiments, and labelling of drug type molecules have revealed PR3 = PPh3 provides a broadly more applicable and widely effective catalyst system compared to other available complexes in the present series.

Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic Esters—An Experimental and Theoretical Study on Directing Group Chemoselectivity

“…As such, any studies which evaluate our developed catalysts in the labelling of aromatic esters should also compare them against the ability of 5 to mediate the same catalytic labelling reactions under identical conditions [19,29]. To this end, and to initiate this research programme, the labelling of a series of para-substituted ethyl benzoate derivatives 6 was examined, using our standard labelling protocol (5 mol % [Ir], 1 atm D2, 1 h) with Crabtree's catalyst 5 (Scheme 2, blue bars) and our developed catalyst systems 1b and 1a (Scheme 2, red and green bars, respectively).…”

“…Over recent years, research in our laboratory has focused on the development of iridium(I) N-heterocyclic carbene (NHC)-ligated precatalysts of the type 1, and their application in HIE via ortho-directed C-H activation protocols (2→4 via 3, Scheme 1) [6,[16][17][18][19][20][21][22]. Despite the growing list of compatible directing groups, we [23] and others [24][25][26][27] have found these developed C-H activation methods less applicable in the labelling of aromatic esters under ambient conditions.…”

Tritiation of azido‐labeled diiodo cabazitaxel (Jevtana) and docetaxel (Taxotere) derivatives to generate 3H‐photoaffinity probes

“…Therefore, to test the feasibility of this approach, we performed commonly known hydrogen isotope exchange methods on cabazitaxel 1a , docetaxel 1b, and baccatine. Unfortunately, both the commercially available Crabtree‐ and Kerr‐ catalysts as well as high temperature solid state isotopic exchange resulted in specific activities less than 10 Ci/mmol. While this may be sufficient for most pharmacokinetic studies, for our labelling experiments, we required a specific activity of at least 50 Ci/mmol …”

Evaluation of a P,N‐ligated iridium(I) catalyst in hydrogen isotope exchange reactions of aryl and heteroaryl compounds

“…Thus, today, tritium tracers are widely used for ADME‐profiling of new drug candidates but also as a discovery tool for photoaffinity labelling and for radioligand, protein, and covalent binding assays. In particular, Kerr's catalysts 2 and 3 are widely applied for mild and selective ortho ‐labelling using a broad range of directing groups such as ketones, amides, esters, primary sulfonamides, and several heterocycles . Despite recent progress, a number of interesting functionalities, ubiquitous throughout drug motives, still present significant challenges for established HIE protocols.…”