Evaluation of C3-substituents on pyrazoles as remote directing groups in palladium-catalyzed direct arylation

The palladium-catalyzed C–H bond functionalization of pyrazoles frequently presents significant challenges in terms of control of the selectivity of the reaction. This is due to the similar reactivity of their C4 and C5 positions, which frequently leads to the formation of mixtures of C4- and C5-mono-arylated pyrazoles, as well as C4,C5-di-arylated pyrazoles. This study demonstrates that the incorporation of suitable substituents at the C3-position of pyrazoles, such as trifluoromethyl or formyl, can result in the regioselective formation of the C5-arylated pyrazoles. These reactions demonstrate a high degree of tolerance for a variety of substituents on the aryl bromide. Moreover, our procedure utilizes an air-stable palladium catalyst that is readily available and a cost-effective base. In contrast, the presence of nitrile or bromo substituents at the C3-position of pyrazoles resulted in the formation of mixtures of products.