Site-Selective Silver-Catalyzed C–H Bond Deuteration of Five-Membered Aromatic Heterocycles and Pharmaceuticals

Abstract

Catalytic methods for the direct introduction of hydrogen isotopes into organic molecules are essential to the development of improved pharmaceuticals and to the alteration of their absorption, distribution, metabolism, and excretion (ADME) properties. However, the development of homogeneous catalysts for selective incorporation of isotopes in the absence of directing groups under practical conditions remains a long-standing challenge. Here, we show that a phosphine-ligated, silver-carbonate complex catalyzes the site-selective deuteration of C–H bonds in five-membered aromatic heterocycles and active pharmaceutical ingredients that have been resistant to catalytic H/D exchange. The reactions occur with CH3OD as a low-cost source of the isotope. The silver catalysts react with five-membered heteroarenes lacking directing groups, tolerate a wide range of functional groups, and react in both polar and nonpolar solvents. Mechanistic experiments, including deuterium kinetic isotope effects, determination of kinetic orders, and identification of the catalyst resting state, support C–H bond cleavage from a phosphine-ligated, silver-carbonate intermediate as the rate-determining step of the catalytic cycle.

Ortho-Deuteration of Aromatic Aldehydes via a Transient Directing Group-Enabled Pd-Catalyzed Hydrogen Isotope Exchange

“…The conventional deuteration methods developed in the last century have enabled the production of per-deuterated chemicals such as benzene-d 6 5 and DMSO-d 6 . 6 With the recent burgeoning of site-selected deuterated chemicals as a deuterated organic light-emitting diode 7 and active pharmaceutical ingredients, represented by deutetrabenzazine, 8 research interest has increased in the precise deuteration at certain positions, 9 to which the conventional techniques may not be adequate. A novel deuteration technique has to be developed for specific needs.…”

Exploiting a silver–bismuth hybrid material as heterogeneous noble metal catalyst for decarboxylations and decarboxylative deuterations of carboxylic acids under batch and continuous flow conditions

“…87,88 In contrast to deuterations of C-C or C-X (X = hetero atom) multiple bonds, [89][90][91][92][93] synthetic processes for the site-specific incorporation of a single deuterium into an aromatic ring are more challenging. 74,76,77,94,95 In most cases, these methods involve halogen/D exchange and are commonly mediated by strong bases which severely limits the functional group tolerance. 96 Furthermore, catalytic and acid-or basemediated H/D exchange reactions are also available, however, unlike halogen/D exchange reactions, these often involve selectivity issues.…”

Manganese‐Catalysed Deuterium Labelling of Anilines and Electron‐Rich (Hetero)Arenes

“…Consequently, HIE is of great importance for late-stage functionalisation of bioactive compounds. [13][14][15][16][17][18][19] In this respect, anilines are key building blocks in molecular chemistry, as reflected by their occurrence in 3 of the top 10 selling medications of 2019. [20] Owing to the significance of such compounds, a number of methodologies has been reported for the deuterium labelling of anilines (Scheme 1).…”