Hydrogen–deuterium exchange of aromatic amines and amides using deuterated trifluoroacetic acid

Abstract

The H-D exchange of aromatic amines and amides, including pharmaceutically relevant compounds such as acetaminophen and diclofenac, was investigated using CF3COOD as both the sole reaction solvent and source of deuterium label. The described method is amenable to efficient deuterium incorporation for a wide variety of substrates possessing both electron-donating and electron-withdrawing substituents. Best results were seen with less basic anilines and highly activated acetanilides, reflecting the likelihood of different mechanistic pathways.

H–D exchange in deuterated trifluoroacetic acid via ligand-directed NHC–palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and amino acids

“…12 However, this method was ineffective for more electron-poor substrates such as acetophenone and its derivatives, and the use of a homogeneous palladium catalyst in conjunction with CF 3 COOD was considered to improve the extent of deuteration.…”

“…5c The palladium-catalyzed ortho -selective H-D exchange of acetanilides was envisaged proceeding in a similar fashion to ketones under identical conditions. Our previous work 12 identified acetanilides as substrates well-suited for electrophilic H-D exchange in CF 3 COOD, so care was taken to identify any improvement in ortho -selective deuterium incorporation by catalyst 1 .…”

“…6c The use of CF 3 COOD as a solvent, catalyst, and source of deuterium label for anilines and acetanilides has also been established. 12 Herein is reported an H-D exchange methodology that utilizes both of these strategies simultaneously to effect the ortho -selective H-D exchange of aromatic amides, ketones, and amino acids. In several cases, this ligand-directed C-H activation process occurs in conjunction with electrophilic H-D exchange by CF 3 COOD, allowing for complete H-D exchange of pharmaceutically relevant compounds such as acetaminophen.…”

Trifluoromethanesulfonic Acid as Acylation Catalyst: Special Feature for C- and/or O-Acylation Reactions

“…A study that used a D 2 O/D 2 SO 4 system found that conditions will lead to either partial or complete racemization of phenylalanine H/D exchange, which is indicated by the exchange of α-protons [79]. Deuterated TFA (TFA-d) is appropriate for slow H/D exchange [80], but its application to aromatic amides and amines [81] is less effective for more electron-poor substrates such as acetophenone and its derivatives [82]. In Scheme 17, a comparison can be made between phenylalanine 120 and tyrosine 121 treated with TFA-d [82] and TfOD [74,83].…”

“…On the basis of the time dependence of H/D exchange using TfOD as monitored by mass spectroscopy, the favored sites for H/D exchange can be summarized as the o-position with respect to the hydroxyl group on tyrosine > the hydrogen atoms of phenylalanine > the m-position with respect to the hydroxyl group on tyrosine. but its application to aromatic amides and amines [81] is less effective for more electron-poor substrates such as acetophenone and its derivatives [82]. In Scheme 17, a comparison can be made between phenylalanine 120 and tyrosine 121 treated with TFA-d [82] and TfOD [74,83].…”