Late-Stage ß-C(sp3)-H Deuteration of Carboxylic Acids.

Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage ß-C(sp3)-H deuteration of free carboxylic acids. On the basis of the finding that C-H activation with our catalysts is reversible, the de-deuteration 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 ß-C(sp3)-H bonds for the first time.

Direct ß- and γ-C(sp3 )-H Alkynylation of Free Carboxylic Acids*.

In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp3 )-H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α-quaternary and challenging α-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal γ-position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained.

Ligand-Enabled γ-C(sp3 )-H Olefination of Free Carboxylic Acids.

We report the ligand-enabled C-H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.

Direct ß-C(sp3)-H Acetoxylation of Aliphatic Carboxylic Acids.

The controlled construction of defined oxidation patterns is one of the key aspects in the synthesis of natural products and bioactive molecules. Towards this goal, we herein report a novel protocol for the Pd-catalyzed direct ß-C(sp3)-H acetoxylation of aliphatic carboxylic acids. The protocol enables the use of free carboxylic acids in one step and without the need of introducing specialized strong directing groups. In our studies, we found that the use of a "traceless base" was crucial for the development of a synthetically useful transformation. Furthermore, the synthetic utility of the products obtained was demonstrated by their use in subsequent transformations.