Ruthenium Catalysed Transfer Deuteration of Heteroaromatics in D2O

Abstract

There is a growing interest in deuterated derivatives in various fields, including the pharmaceutical industry. In this industry, partially hydrogenated heterocycles are also a target. Combining these two concepts, it was studied the reduction of heterocycles with simultaneous deuterium incorporation by transfer deuteration, a process of introducing two deuterium atoms into an organic molecule using non‐D₂ sources, avoiding the use of a gas or harmful reagents. Formic acid/sodium formate and D₂O as the sole deuterium source were used under mild conditions. The precatalyst was [RuCl(p‐cym)(dmbpy)]BF₄, (p‐cym=p‐cymene, dmbpy=4,4’‐dimethyl‐2,2’‐bipyridine), which is able to generate the “Ru−D” fragment from D⁺ by a polarity inversion process (“umpolung”). A wide range of heterocycles were tested. Selective reduction in the nitrogen‐containing ring with deuterium incorporation into the same ring was achieved. The experiments were carried out in a biphasic D₂O/toluene medium, which allowed excellent catalyst recycling with a simple work‐up. Through detailed studies for 3‐methylquinoline using DCOOD/DCOONa, the reaction mechanism that involves D⁺ incorporation at the nitrogen atom and an initial 1,2‐type addition was elucidated. In single‐phase D₂O experiments, a distinct selectivity with deuterium incorporation in the non‐hydrogenated ring was observed thus enabling to modulate it by the choice of the medium.