Iridium‐Catalysed C(sp³)−H Activation and Hydrogen Isotope Exchange via Nitrogen‐Based Carbonyl Directing Groups

Abstract

Abstract. Growing interest in improved structural diversity within the pharmaceutical industry has led to a focus on more sp3‐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 a an iridium catalyzed C(sp3)−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.

Studies of Anticancer Activities In Vitro and In Vivo for Butyltin(IV)–Iridium(III) Imidazole–Phenanthroline Complexes with Aggregation-Induced Emission Properties

“…Cancer remains a devastating disease, and continuous research and improvement of treatment strategies are urgently necessary. − Metallic anticancer drugs have attracted extensive attention in the biological field, including biocatalysis, biological probes, and biopharmaceuticals. − Among these, platinum-based drugs have been widely employed in the treatment of cancer, however, toxic side effects and drug resistance have prompted the exploration for alternatives with different anticancer mechanisms. , Recently, iridium­(III) (Ir III ) complexes have drawn wide concern because of their unique chemical properties and their distinct anticancer mechanisms in comparison to platinum-based drugs. − Ye et al designed and synthesized mitochondria-targeting coumarin-derived cyclometalated Ir III complexes, possessing rich photophysical properties and higher antiproliferative activity against various cancer cells, including cisplatin-resistant cancer cells . Guan et al obtained two phenylbenzoxazole-modified Ir III complexes (NecroIr1 and NecroIr2) as necroptosis inducers in cisplatin-resistant lung cancer (A549/DDP) cells.…”