Metal-free, Selective Ortho-Deuteration of N-heterocyclic oxides

Replacing hydrogen with deuterium raises the activation energy for C‒D bond cleavage. This approach has gained attention in drug design, especially to protect the ortho-position of pyridines, which are susceptible to enzymatic oxidation. Until now, direct hydrogen isotope exchange has been largely restricted to the use of reactive organolithium reagents or metal-catalysed deuteration methods. In this work, we present a metal-free, selective ortho-deuteration of N-heterocycles starting from their N-oxides, proceeding at room temperature in just 5 minutes. This method achieves high deuterium incorporation across a broad range of N-heterocycles, including bioactive compounds. Experimental and computational studies have elucidated the mechanism of the reaction, showing that regioselectivity is driven by a successful increase in acidity at the ortho-position, enabling deprotonation by the in-situ generated dimsyl anion.