The
metabolic oxidation of drug-like small molecules by aldehyde
oxidase (AO) has commonly been mitigated through the incorporation
of deuterium at the oxidation site. We report that dimethylformamide
dimethyl acetal and related compounds undergo rapid CH to CD isotopic
exchange upon exposure to methanol-d and similar
deuterated alcohols. This isotopic exchange process can be used to
synthesize Me2NCD(OMe)2 and has significant
implications for the use of Me2NCD(OMe)2 in
the synthesis of specifically deuterium-labeled compounds. The application
of Me2NCD(OMe)2 to the synthesis of various
heterocycles that have been associated with AO metabolism is described,
and we report the impact of deuteration on the rate of in
vitro AO-mediated metabolism.