CAS No.:​ 53-03-2

Chinese Name:​ Tris(dimethylphenylphosphine)(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]iridium(I) hexafluorophosphate

English Name:​ (Dimethylphenylphosphine)(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]iridium(I) hexafluorophosphate

Applications:​ Highly active iridium complex for catalyzing hydrogen isotope exchange.

Isotopic labeling plays a crucial role in drug discovery, offering unparalleled insights into the metabolic pathways of potential drug molecules. Isotopic labeling is a vital method for developing pharmaceutical and agrochemical molecules. In the pharmaceutical field, for instance, isotopically labeled active pharmaceutical ingredients are commonly prepared to understand metabolic pathways and identify specific metabolites. Deuterium atoms are the most common isotopic labels, ideal for studying the kinetic isotope effect (KIE) of cleaving C–H versus C–D bonds. Compared to unlabeled compounds, deuterated compounds have different molecular weights, allowing them to serve as internal standards in LC–MS analysis. Therefore, synthesizing deuterated organic molecules holds significant importance, especially labeling aryl/heteroaryl/alkylamine moieties, as these structural motifs are prevalent in a vast number of organic molecules.

Acid-mediated H/D exchange is the oldest method for labeling arenes. However, this reaction can only modify simple arenes through electrophilic substitution. Based on homogeneous metal-catalyzed C–H bond activation, a series of organometallic catalysts have been developed for H/D exchange at aryl and α/β-positions of alkyl amines. For example, iridium-based Crabtree or Kerr catalysts can perform isotopic labeling of C(sp²)–H bonds using D₂ gas (Figure 1).

Iridium(I) catalysts ligated with sterically hindered N-heterocyclic carbene (NHC) and phosphine ligands have been synthesized and applied in hydrogen isotope exchange processes. These Ir(I) catalysts facilitate the incorporation of isotopes into a wide range of substrates using conveniently handled deuterium and tritium gases. These active catalysts achieve exceptionally high levels of isotope incorporation while operating with low catalyst loadings, short reaction times, and displaying versatile chemoselectivity. Several industrially relevant drug molecules, such as the sulfonamide drug celecoxib, have also been labeled, as shown in Figure 2.

In 2024, Professor Kerr's group reported a C(sp³)–H activation and hydrogen isotope exchange (HIE) method catalyzed by highly active NHC-phosphine ligated Ir(I) catalysts. This method leverages pharmaceutically prevalent nitrogen-based carbonyl directing groups. High levels of deuterium incorporation (>80% in 37 examples) were demonstrated across a series of substrates (5-, 6-, and 7-membered lactams, cyclic carbamates and ureas, and acyclic amides), with tolerance for a range of common functional groups (aryl, alkoxy, halogens, esters, alcohols, sulfonamides) and predictable regioselectivity. The applicability of the method was demonstrated by achieving up to 98% deuterium incorporation in a series of challenging bioactive molecules, such as Nefiracetam, Praziquantel, and Unifiram, as shown in Figure 3.

In summary, tris(dimethylphenylphosphine)(1,5-cyclooctadiene)[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]iridium(I) hexafluorophosphate can be used for C2-deuteration of indoles, azaindoles, and pyrrole N-heterocycles. High levels of deuterium incorporation were achieved across a range of substrates by employing common directing groups as removable functional handles.

Our company can provide milligram, hectogram, and kilogram quantities of NHC-P-Ir(I) complex catalysts, with excellent pricing and high quality. Inquiries are welcome.

Suzhou Crelo New Materials Technology Co., Ltd. primarily engages in the design and development of chiral ligands and catalysts, the synthesis of chiral drugs and intermediates, and the technical development, transfer, consulting, and services related to chiral technology. The company's patented SadPhos series ligands feature unique skeletal structures and broad catalytic capabilities. The company possesses a comprehensive catalyst library and also provides other chiral technology-related services. We welcome your inquiries.