Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage β-C(sp 3 )−H deuteration of free carboxylic acids. On the basis of the finding that C−H activation with our catalysts is reversible, the dedeuteration process was first optimized. The resulting method uses ethylenediamine-based ligands 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 and enables the functionalization of nonactivated methylene β-C(sp 3 )−H bonds for the first time.

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C–H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

We describe a palladium catalyzed non-directed late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acyl sulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features an extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labelling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, amongst other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

Carboxylic acid moieties are highly abundant in bioactive molecules. In this study we describe the late-stage β C(sp³)–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(sp³)–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.

We describe a palladium catalyzed non-directed late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acyl sulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features an extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labelling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, amongst other applications, will prove useful as a tool in drug development processes and for mechanistic studies.