Transition Metal‐Free <i>Ortho‐</i> Deuteration of Electron‐Deficient <i>N</i> ‐Heteroarenes

Selectively deuterated electron‐deficient N ‐containing heteroaromatic systems can enable modulation of metabolism with enhanced therapeutic efficacy in pharmaceuticals and improved properties and stability of functional materials, e.g., imaging dyes, light emitters, and catalysts. Current synthetic approaches to selectively deuterate N ‐heteroaromatic rings largely rely on transition metal (TM) catalysts, prone to inducing over‐deuteration while posing several environmental and sustainability concerns and requiring onerous purification to remove metal traces. In this work, an alternative TM‐free approach is reported based on directed ortho metalation, which employs lithium 2,2,6,6‐tetramethylpiperidide (LiTMP) such as the base and D 2 O as a green and accessible electrophilic source of deuterium (D). Since the O ‐carbamate and carboxamide directing groups (DGs) can be transformed into other functional groups or cross‐coupled with aromatic or aliphatic moieties, this enables a modular approach to synthesize a series of drug analogs, as exemplified by the synthesis of a precursor to momelotinib‐ d 1 and the key building block pyrimidine‐4‐carboxylic‐5‐ d 1 acid.