Palladium(II)‐Catalyzed Nondirected Late‐Stage C(sp2)−H Deuteration of Heteroarenes Enabled Through a Multi‐Substrate Screening Approach

• Published in: Angewandte Chemie International Edition Vol. 63; no. 27; pp. e202404421 - n/a
• Main Authors: Dey, Jyotirmoy, Kaltenberger, Simon, Gemmeren, Manuel
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.07.2024; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Biological activity; Catalysis; Catalysts; Chemical properties; Chemistry; Chemistry, Multidisciplinary; Deuteration; Deuterium; Heterocycles; Labeling; Ligands; Multi-substrate screening; Palladium; Physical Sciences; Science & Technology; Screening; Substrates; Deuterium; DRUG; Heterocycles; Multi-substrate screening; H/D EXCHANGE; TRITIATION; ARYLATION; ARENES; METALATION-DEPROTONATION MECHANISM; LABELED COMPOUNDS; Ligands; Catalysis; N-HETEROCYCLES
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202404421

The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug‐discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five‐membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi‐substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand‐based palladium catalysts for nondirected C(sp2)−H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules. We describe a method for the Pd‐catalyzed deuteration of heteroarenes. Reaction optimization was performed using a multi‐substrate screening approach, which enabled the identification of optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. These conditions allowed us to deuterate various heteroarenes, including bioactive molecules.