Iridium-catalysed C(sp3)−H activation and hydrogen isotope exchange via nitrogen-based carbonyl directing groups

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Knight, Nathan M. L. and Thompson, James D. F. and Parkinson, John A. and Lindsay, David and Tuttle, Tell and Kerr, William J. (2024) Iridium-catalysed C(sp3)−H activation and hydrogen isotope exchange via nitrogen-based carbonyl directing groups. Advanced Synthesis and Catalysis, 366 (11). pp. 2577-2586. ISSN 1615-4150 (https://doi.org/10.1002/adsc.202400156)

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Abstract

Growing interest in improved structural diversity within the pharmaceutical industry has led to a focus on more sp 3-rich drug frameworks. Meanwhile, spiralling pharmaceutical research and development costs continue to require expedited adsorption, distribution, metabolism, excretion, and toxicity studies, which are heavily reliant on the use of molecules incorporating deuterium and tritium. Herein, we report an iridium catalyzed C(sp 3)−H activation and hydrogen isotope exchange (HIE) methodology capable of utilizing pharmaceutically ubiquitous nitrogen-based carbonyl directing groups. High levels of deuterium incorporation (>80% in 37 of the examples) are demonstrated across a range of substrates (5-, 6-, and 7-membered lactams, cyclic carbamates and ureas, acyclic amides), with tolerance of a range of common functional groups (aryl, alkoxy, halogen, ester, alcohol, sulfonamide) and predictable regioselectivity. The applicability of this methodology was demonstrated with up to 98% deuterium incorporation observed in a range of challenging bioactive molecules such as Nefiracetam, Praziquantel, and Unifiram. Density functional theory has provided mechanistic insight into the C−H activation and HIE at both the expected site of incorporation and an unexpected aryl labelling via a 7-membered metallocyclic intermediate.

ORCID iDs

Knight, Nathan M. L., Thompson, James D. F., Parkinson, John A. ORCID logoORCID: https://orcid.org/0000-0003-4270-6135, Lindsay, David ORCID logoORCID: https://orcid.org/0000-0003-4498-5094, Tuttle, Tell and Kerr, William J. ORCID logoORCID: https://orcid.org/0000-0002-1332-785X;
CORE (COnnecting REpositories)