Cesium Amide‐Catalyzed Selective Deuteration of Benzylic C‐H Bonds with D₂ and Application for Tritiation of Pharmaceuticals

Abstract

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium-and tritium-labeled compounds. Catalytic HIE methods that enable site-selective CÀ H bond activation and exchange labeling with gaseous isotopes D 2 and T 2 are of vital importance, in particular for highspecific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe 3 ) 2 to be an efficient catalyst for selective HIE of benzylic CÀ H bonds with D 2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between CÀ H bonds and D 2 gas. By virtue of multiple CÀ H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals.

Lithium Aluminium Hydride and Metallic Iron: A Powerful Team in Alkene and Arene Hydrogenation Catalysis

“…The combination LiAlH 4 /Fe 0 is therefore also a potential catalyst for Hydrogen‐Isotope‐Exchange (HIE) at aromatic rings. HIE is normally catalysed by the more noble transition metals, however, recently also highly effective s ‐block metal catalysts have been developed [20–23] . Whereas LiAlH 4 alone does not react with C 6 D 6 , heating a mixture of LiAlH 4 /Fe 0 in C 6 D 6 to 120 °C led to considerable H‐incorporation in the solvent but only traces of cyclohexane (Figure S14‐S16).…”

“…HIE is normally catalysed by the more noble transition metals, however, recently also highly effective s-block metal catalysts have been developed. [20][21][22][23] Whereas LiAlH 4 alone does not react with C 6 D 6 , heating a mixture of LiAlH 4 /Fe 0 in C 6 D 6 to 120 °C led to considerable H-incorporation in the solvent but only traces of cyclohexane (Figure S14-S16). This indicates that the presence of Fe 0 enables HIE between LiAlH 4 and benzene.…”

Benzylic deuteration of alkylnitroaromatics via amine‐base catalysed exchange with deuterium oxide

“…14,15 Alkalimetal amide superbase catalysis has also been used recently. 16 Unfortunately, the above approaches generally use hydrogen, deuterium or tritium gas as the initiator or isotope donor and are therefore inappropriate for the labelling of nitro-compounds, which are easily reduced species. For the labelling of alkylnitroaromatics in the benzylic positions, [17][18][19][20][21][22] therefore, we decided to avoid reductive conditions and to utilise deuterium oxide as the donor.…”

“…Of current interest are nanoparticle catalysts that have been utilised very effectively and with good regiospecificity 14,15 . Alkali‐metal amide superbase catalysis has also been used recently 16 …”

Distalp-benzylic deuterationviaN-heterocyclic carbene catalyzed ring opening ofp-cyclopropylbenzaldehydes

“…However, the developed acid-promoted methods are confined to acidic N-heteroarylmethanes, 11 while base-promoted methods usually require strong bases. 12 A metal-free benzylic deuteration protocol under mild conditions would be of great value.…”