Palladium-Catalyzed Nondirected Late-Stage C–H Deuteration of Arenes

Abstract

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C–H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…In this context, a dual ligand system composed of bulky amides derived from amino acids in combination with a pyridine derivative was shown to assist the concerted metalation deprotonation (CMD) step of palladium-catalyzed C–H activation, thus facilitating this reaction . Further modification of the amino-acid-derived ligands by substituting the carboxylic acid functionality by a sulfonamide lead to highly active catalyst systems that prove its value in the HIE of a broad range of aromatic substrates using deuterium oxide as deuterium source . While the exchange proceeds slower at more sterically hindered positions, high deuterium incorporations could generally be achieved (Scheme d).…”

Bringing Vibrational Imaging to Chemical Biology with Molecular Probes

“…The versatile applications of Raman-tagged cellular imaging are still expanding and would benefit from facile synthesis of new vibrationally tagged molecules. Toward this front, we envision that the recent synthetic advances in late-stage functionalization − could provide convenient synthetic routes to deuterium or triple-bond tagged molecular targets beyond currently available pools.…”

Superacid‐Mediated Late‐Stage Aromatic Polydeuteration of Pharmaceuticals

“…On the other hand, the use of iron or manganese nanoparticles with D 2 O under hydrogen pressure allows for the labeling of electron‐rich (hetero)arenes with substantially higher degree of deuteration (Figure 1A) [5h,i] . Multisite homogeneous Pd‐catalyzed H/D exchange was also successfully achieved via the design of dedicated amide ligands but this method can suffer from low deuterium incorporation at sterically hindered positions or from catalyst poisoning by nitrogen‐containing substrates (Figure 1B) [6d] …”