Palladium-Catalyzed Direct Arylation of Azine and Azole N-Oxides: Reaction Development, Scope and Applications in Synthesis

• Published in: Journal of the American Chemical Society Vol. 131; no. 9; pp. 3291 - 3306
• Main Authors: Campeau, Louis-Charles, Stuart, David R., Leclerc, Jean-Philippe, Bertrand-Laperle, Mégan, Villemure, Elisia, Sun, Ho-Yan, Lasserre, Sandrine, Guimond, Nicolas, Lecavallier, Melanie, Fagnou, Keith
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.03.2009; Amer Chemical Soc
• Subjects: Catalysis; Chemistry; Chemistry, Multidisciplinary; Cyclic N-Oxides - chemical synthesis; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - pharmacology; Molecular Structure; Organometallic Compounds - chemistry; Palladium - chemistry; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Science & Technology; Sodium Channel Blockers - chemical synthesis; Sodium Channel Blockers - chemistry; Stereoisomerism; ASYMMETRIC CATALYSIS; BORONIC ACIDS; CROSS-COUPLING REACTIONS; ACTIVATION; HETEROCYCLES; ARYL HALIDES; EFFICIENT DEOXYGENATION; UNACTIVATED ARENES; LIGANDLESS CONDITIONS; C-H BONDS
• DOI: 10.1021/ja808332k
• ISSN: 0002-7863

Palladium-catalyzed direct arylation reactions are described with a broad range of azine and azole N-oxides. In addition to aspects of functional group compatibility, issues of regioselectivity have been explored when nonsymmetrical azine N-oxides are used. In these cases, both the choice of ligand and the nature of the azine substituents play important roles in determining the regioisomeric distribution. When azole N-oxides are employed, preferential reaction is observed for arylation at C2 which occurs under very mild conditions. Subsequent reactions are observed to occur at C5 followed by arylation at C4. The potential utility of this methodology is illustrated by its use in the synthesis of a potent sodium channel inhibitor 1 and a Tie2 Tyrosine Kinase inhibitor 2.