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

Abstract

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.

Manganese‐Catalysed Deuterium Labelling of Anilines and Electron‐Rich (Hetero)Arenes

“…Consequently, HIE is of great importance for late-stage functionalisation of bioactive compounds. [13][14][15][16][17][18][19] In this respect, anilines are key building blocks in molecular chemistry, as reflected by their occurrence in 3 of the top 10 selling medications of 2019. [20] Owing to the significance of such compounds, a number of methodologies has been reported for the deuterium labelling of anilines (Scheme 1).…”

Catalyst-controlled site-selective methylene C–H lactonization of dicarboxylic acids

“…Although directed C-H activation of aliphatic carboxylic acids has been achieved with platinum (1, 2) and palladium catalysis (3)(4)(5)(6)(7)(8)(9)(10)(11), development of catalysts for the activation of methylene C-H bonds is nascent, and identification of methods for distinguishing between the similar C-H bonds of multiple adjacent methylene units is an enduring challenge. Recent breakthroughs in ligand development have provided a glimmer of hope for the palladium-catalyzed, carboxylic acid-directed activation of b-methylene C-H bonds, culminating in reports of a dehydrogenation reaction and a deuteration reaction (12,13). However, no other C-heteroatom bond-formation reaction or activation of the g-methylene C-H bonds has yet been identified with this approach.…”

Ligand-controlled divergent dehydrogenative reactions of carboxylic acids via C–H activation

“…However, methylene C-H activation reactions of acyclic aliphatic substrates directed by innate functionalities such as carboxylic acids remain a substantial challenge (Fig. 1B) (16)(17)(18).…”