Perdeuteration of Arenes in Pharmaceuticals by SEAr Mechanism with Heavy Water Using pTSA Catalyst.

Aromatic rings are widely recognized in the realm of natural products and bioactive molecules, highlighting their importance in various applications. The development of deuterated analogues of pharmaceuticals is particularly significant in pharmaceutical and medicinal chemistry. In this study, we present a novel catalytic method for hydrogen/deuterium (H/D) exchange in aromatic compounds, employing D2O as the deuterium source, which is not only easily accessible but also cost-effective. This approach demonstrates impressive deuterium incorporation under mild reaction conditions, yielding good to excellent results in a single run. Utilizing para-toluenesulfonic acid (pTSA) as a catalyst, this metal-free protocol exhibits broad applicability in the late-stage deuteration of a variety of bioactive molecules, pharmaceuticals, and small molecules. Furthermore, our method is scalable; it has been successfully implemented at the gram-scale with a reduced catalyst loading of 2.0 mol% for Tyrosol, illustrating its practical utility. Moreover, our thorough mechanistic studies and detailed DFT studies enhance our understanding of how the catalyst and solvent contribute to the aromatic electrophilic substitution process. This innovative method provides a sustainable alternative to traditional transition metal-catalyzed H/D exchange techniques. It addresses key challenges such as the use of expensive metals, the risk of undesired reactions, and the need to remove metal impurities from products. Overall, this research enhances the efficiency and environmental friendliness of H/D exchange in aromatic compounds.