Ruthenium-Catalyzed Deuteration of Aromatic Carbonyl Compounds with a Catalytic Transient Directing Group.

Abstract

A novel ruthenium‐catalyzed C−H activation methodology for hydrogen isotope exchange of aromatic carbonyl compounds is presented. In the presence of catalytic amounts of specific amine additives, a transient directing group is formed in situ, which directs selective deuteration. A high degree of deuteration is achieved for α‐carbonyl and aromatic ortho‐positions. In addition, appropriate choice of conditions allows for exclusive labeling of the α‐carbonyl position while a procedure for the preparation of merely ortho‐deuterated compounds is also reported. This methodology proceeds with good functional group tolerance and can be also applied for deuteration of pharmaceutical drugs. Mechanistic studies reveal a kinetic isotope effect of 2.2, showing that the C−H activation is likely the rate‐determining step of the catalytic cycle. Using deuterium oxide as a cheap and convenient source of deuterium, the methodology presents a cost‐efficient alternative to state‐of‐the‐art iridium‐catalyzed procedures.