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.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“… Similarly, aromatic ketones can be deuterated under ruthenium catalysis using catalytic amounts of anilines as transient directing groups. Notably, both aromatic ortho and α-carbonyl positions are deuterated under the reaction conditions with the latter being a result of acid- and amine-catalyzed deuteration …”

“…Notably, both aromatic ortho and α-carbonyl positions are deuterated under the reaction conditions with the latter being a result of acid-and amine-catalyzed deuteration. 80 2.1.1.3. Sulfur-Containing Directing Groups.…”

“…Reported directing groups for transition-metal-catalyzed aromatic HIE. 56,62,63,[67][68][69][70][71][72][73][75][76][77][79][80][81]83,[85][86][87][88][89]91,[96][97][98][99][100][101][102][103][104][105][106]109,110,112,113,118 Finally, it should be noted that, depending on the substrate, more expensive calculations which include solvation models as well as thermal corrections to the electronic energies can be needed to accurately reproduce experimental results. Building on these computational results, Kerr, Reid, and co-workers were able to successfully predict catalysts with higher or inverse selectivity by changing the steric properties of the NHC ligand.…”

Ortho-Deuteration of Aromatic Aldehydes via a Transient Directing Group-Enabled Pd-Catalyzed Hydrogen Isotope Exchange

“…Additionally, D 2 O is the most accessible deuterium-source with economic and safety benefits, favoring scale up and recovery of the isotopic resource. Fortunately, after a series of attempts in transient directing strategies, the desired ortho -deuteration reaction succeeded by employing α-amino isobutyric acid as the transient directing group (TDG) . Herein, we report our latest results in ortho -deuteration of aromatic aldehydes using Pd-catalyzed HIE in deuterium oxide with amino acids as TDGs.…”

Nickel-catalyzed regioselective hydrogen isotope exchange accelerated by 2-pyridones

“…Among the methods established, hydrogen-isotope exchange (HIE) represents a unique type of labeling, in which the protium at the site was directly replaced by deuterium. 2 During the past decade, plenty of cases of noble metal catalysis have been reported for HIE with Pd, 3 Ir, 4 Rh, 5 as well as Ru, 6 rendering perdeuterated or regioselective labeled compounds with various types of structural diversity. Meanwhile, earth-abundant metal facilitated deuteration has also attracted considerable attention.…”