Late-Stage β-C(sp3)–H Deuteration of Carboxylic Acids

Abstract

Carboxylic acid moieties are highly abundant in bioactive molecules. In this study we describe the late-stage β C(sp<sup>3</sup>)–H deuteration of free carboxylic acids. Based on our finding that the C–H activation with our catalyst systems is reversible, the de-deuteration process was first optimized. The resulting conditions involve a novel type of ligands, which, amongst other positions, for the first time enables the functionalization of non-activated methylene β-C(sp<sup>3</sup>)–H bonds and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…Building on precedence in directed palladium-catalyzed C(sp 3 )−H functionalization chemistry, a first methodology for the challenging β deuteration of unactivated aliphatic carboxylic acids was achieved most recently using newly developed sterically hindered ethylenediamine ligands (Scheme 53b). 196 Remarkably, under the reaction conditions, both methyl and methylene positions were deuterated to similar extents. However, no reaction took place on tertiary carbon atoms, and the selectivity of this HIE reaction with respect to aliphatic α positions and aromatic C−H bonds is improvable.…”