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

Abstract

A practical and scalable ortho-selective deuteration of aromatic aldehydes was accomplished by Pd-catalyzed hydrogen isotope exchange with deuterium oxide as an inexpensive deuterium source. The use of tert-leucine as a transient directing group facilitates the exchange, affording a wide range of ortho-deuterated aromatic aldehydes with deuterium incorporation up to 97%. The control experiments suggest that the addition of silver trifluoroacetate resists the unexpected reduction of Pd­(II), while the theoretical study indicates a rapid reversible concerted metalation–deprotonation process.

Palladium-Catalyzed Ligand-Free ortho-Deuteration of Aromatic Carboxylic Acids with D2O

“…The result showed the deuteration occurred under the direction of carboxy exclusively, and the formyl could hardly promote the HIE without the assistance of transient directing groups. 10 Similar elevation of reaction performance was also observed in benzoic acids with ortho-substitutions. The deuteration of 2-fluoro benzoic acid (13) improved from 26% to 93% dramatically, while the 2-methyl derivative (11) also showed a significant elevation from 34% to over 80%.…”

“…Electron-withdrawing derivatives, including 4fluoro, 4-chloro, 4-bromo, and 4-trifluoro-benzoic acids (6-9) afforded moderate to good level of deuteration. Benzoic acid possessing formyl group at para-position also rendered considerable result under this condition (10). The result showed the deuteration occurred under the direction of carboxy exclusively, and the formyl could hardly promote the HIE without the assistance of transient directing groups.…”

“…The degree of deuteriumincorporation was calculated based on both GC-MS and 1 H-NMR methods, which had been described in our previous work. [10] General Procedure…”

“…Thus, we envisaged that this reaction condition could also promote deuteration of aromatic carboxylic acid, as it is another representative of weak-coordinating substrates (Figure 1C). To our delight, the initial assessment, using our previous condition, 10 rendered an excellent deuterium incorporation with nearly 2.0D incorporation. The ortho-distribution of deuterium was confirmed by NMR analysis, with 96% orthoprotium replaced by deuterium.…”

C–H deuteration of organic compounds and potential drug candidates

“…Pd-catalysed ortho -selective deuteration of aromatic aldehydes by using a transient directing group was nicely described by Gao and co-workers in 2021 (Scheme 116). 124 α-Amino isobutyric acids were used as the transient directing group (TDG) in this strategy. Among various α-amino acids tert -leucine provided the best result giving 70% deuterium incorporation.…”