Superacid‐Mediated Late‐Stage Aromatic Polydeuteration of Pharmaceuticals

Abstract

The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium‐modified drugs directly from their non‐labeled parents. While most of the recent studies focus on metal‐catalyzed C−H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late‐stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures.

Mild and selective hydrogen–deuterium exchange for aromatic hydrogen of amines

“…The deuterium incorporation was calculated as minimum values whereas the non‐aromatic moiety is estimated to be minimally deuterated and undetectable by 1 H NMR. This estimation is in line with the absence of deuterium incorporation in the non‐aromatic moiety of acetanilide skeleton as was observed in previous studies of acidic H–D exchange 11,21 …”

“…Our group has intensively studied the role of TfOD in aromatic deuteration of optically active α‐amino acids 10 and peptides, 17 indole‐3‐propionic acid derivatives, 18 selective deuteration in cyclodopa derivatives, 19 as well as the imidazole ring deuteration of histidine and histamine 20 . Very recently, the deuteration of meta ‐substituted aniline derivatives, N ‐acetyl benzylamine, paracetamol, and several nitrogen‐containing pharmaceuticals has been reported and involving utilization of TfOD under a range of temperature condition 21 …”

“…The deuteration with in situ generated TfOD, which can be prepared from mixing trifluoromethanesulfonic anhydride and D 2 O 80°C, 21 is suitable only for temperature‐stable substrates. This paper describes H–D exchange under mild conditions utilizing TfOD in a direct single step for the aromatic‐specific deuteration of aromatic amines and amides.…”

Diimidazolium Salt HBDIM: An Easily Available, Low‐Cost, CageCarbene Precursor with Broad Applications in Transition Metal‐Catalyzed Reactions

“…1 H, 13 C NMR spectroscopic data of compounds 1 – 25 , Crystallographic data for compounds 1 – 4 and 18 (CIF). Additional references cited within the Supporting Information [38–69] …”

Perdeuteration of Arenes via Hydrogen Isotope Exchange Catalyzed by the Superbasic Sodium Amide Donor Species NaTMP·PMDETA

“…This approach can be roughly divided in two main categories according to their distinct mechanisms: transition-metal-catalyzed processes (homogeneous/heterogeneous) and acid/base-mediated labeling . Whereas many advances have been made in recent years in HIE using transition metals, ,, the field of acid/base deuteration has been slower to develop due to its lower selectivity and harsher reaction conditions. , The main advances in acid-mediated HIE focused on the use of superelectrophilic acids for the perdeuteration of arenes, allowing the labeling of not only electronically activated aromatic and unsaturated molecules but also more recently nonactivated (halo)­arenes . However, the field of base-mediated HIE has remained limited to its application to relatively acidic C–H bonds (Figure b), as for example, terminal alkynes, the α-position to carbonyls, fluoroarenes, benzylic positions, or pyridines, often requiring high temperatures and extended reactions times.…”