Indazoles bearing aryl groups attached at the N2 position have become increasingly prevalent amongst novel drug candidates.1-4. The primary aim of the research project proposed here is the development of a highly selective, palladium- catalyzed N2-arylation of unprotected indazoles. This goal is expected to be achieved through a comprehensive experimental and computational study of the catalytic cycle that effects the known N1-arylation of these heterocycles,5-9 and to aply that understanding towards manipulating the reaction components to achieve the desired N2- coupling. Finally, efforts will be made to ensure the generality of the method for a wide range of potential substrates. The successful development of this method would have a significant impact on the ease of synthesis of these important biologically active substructures particularly in a medicinal chemistry setting, allowing for the more rapid generation and screening of potential novel pharmaceuticals.
Indazoles bearing aryl substituents at the N2 position have recently become prevalent substructures amongst potential drug candidates indicated for the treatment of a wide variety of human health-related conditions including metabolic syndrome and hepatitis C. 1-4 The successful development of a protocol for the selective N2-arylation of unprotected indazoles, as proposed here, would allow for the rapid generation of a wide variety of these structures for biological screening and SAR studies, particularly in a medicinal chemistry setting.
| McGowan, Meredeth A; McAvoy, Camille Z; Buchwald, Stephen L (2012) Palladium-catalyzed N-monoarylation of amidines and a one-pot synthesis of quinazoline derivatives. Org Lett 14:3800-3 |
| McGowan, Meredeth A; Henderson, Jaclyn L; Buchwald, Stephen L (2012) Palladium-catalyzed N-arylation of 2-aminothiazoles. Org Lett 14:1432-5 |
