Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides

Abstract

For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a homogeneous iridium catalyst supported by a bidentate phosphine‐imidazolin‐2‐imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivatives proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chemistry, and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine. Further insights into the mechanism of the HIE reaction with catalyst 1 have been provided utilizing DFT calculations, NMR studies, and X‐ray diffraction analysis.

NHC‐Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines

“…[8] HIE has become the state-of-art strategy for the incorporation of deuterium or tritium atoms into complex organic molecules. [9,10] In life sciences, isotopically labeled compounds [11] are experiencing a renaissance owing to the highly improved mass spectrometry applications utilizing labeled mass spectrometry (MS) standards [12,13] and to the limitations of 14 C labeling, such as high cost and synthesis duration. In this context, we were interested in the synthesis of new NHC-stabilized IrNPs and the study of their catalytic properties in HIE reactions (Scheme 1).…”

Comparison of Iridium(I) Catalysts in Temperature Mediated Hydrogen Isotope Exchange Reactions

“…One interesting example for the different reactivity of iridium catalysts is described in Scheme . With catalyst 6 at 25 °C we have obtained selectively deuterium incorporation in the aromatic position A of phenylacetic amide 10 . Interestingly with catalyst 2 a we obtained no deuterium introduction at all at 25 °C.…”

“…This is a remarkable result as phenyl acetic acids derivatives are core structures in a variety of important drugs, like clopidogrel, naproxene, camylofine, etc. and labelling of these compounds is still challenging …”

Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange

“…Inspired by the results from Muri et al ., a collaborative study between the Sanofi laboratories and Tamm and co‐workers recently evaluated the use of Tamm's bidentate NHC‐P complex 20 in HIE reactions . This highly electron‐rich ligand set facilitates the labelling of a wide range of directing groups to high levels (Scheme 20); whilst ketones, heterocycles, the nitro group, and esters were shown to be suitable, perhaps the most noteworthy results were those which employed a Boc unit to direct labelling into the aryl rings of anilines or heterocycles 42a. The significant steric bulk of this Boc protecting group may usually render its use challenging; however, the chelated system present within Tamm's catalyst allows for excellent levels of incorporation under mild conditions.…”

“…Finally, and in a very recent addition to the use of bidentate iridium(I) complexes in HIE processes, Tamm and Derdau have established a catalytic protocol for the selective labelling of pharmacologically important phenylacetic acid esters and amides under mild reaction conditions . Employing Tamm's P , N ‐ligated complex 20 , >25 substrates have been labelled, via the more challenging 6‐mmi, with deuterium incorporation up to 99%.…”