Selective Hydrogen Isotope Exchange Catalysed by Simple Alkali-Metal Bases in DMSO

Dedicated to Proferssor Robert E. Mulvey on the occasion of his 65^th birthday. Isotope Exchange processes are becoming the preferred way to prepare isotopically labelled molecules, avoiding the redesign of multistep synthetic protocols. In the case of deuterium incorporation, the most used strategy has employed transition metals, that offer high reactivity under mild reaction conditions. Despite their success, the trade-off is that these metals are precious, so expensive, and often exhibit high toxicity. Therefore, alternative transition-metal-free protocols would be a welcome addition to this field. In this report we show how the simple bases NaHMDS (HMDS=hexamethyldisilazide) and NaCH₂SiMe₃ can efficiently and selectively promote deuteration of a wide range of C(sp²)-H and C(sp³)-H bonds in DMSO-d₆, providing an easy and direct access to deuterated compounds. Heterocycles, fluoroarenes, N-heterocyclic carbenes, amides and other aromatic molecules could be deuterated under mild conditions using catalytic amounts of base. Mechanistic studies along with the isolation and characterisation of reaction intermediates have flagged up the importance of the metalated substrate and metalated solvent in solution, establishing an equilibrium between these compounds is crucial for the success of this approach. An alkali-metal effect was observed, with heavier alkali-metal amides being more reactive at room temperature, but their lower stability at higher temperatures made sodium bases the optimal reagents for Hydrogen Isotope Exchange.