Metal‐free, Selective Ortho‐Deuteration of N‐heterocyclic Oxides

Abstract

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.