Ligand-accelerated non-directed C–H functionalization of arenes

Using a ligand as a promoter enhances the reactivity of the palladium catalyst in non-directed C–H functionalization of arenes, enabling the arene to be used as the limiting reagent. The functionalization of a carbon–hydrogen (C–H) bond is one of the most useful reactions in organic synthesis as it precludes the need to install reactive groups to perform a reaction. However, the reactivity and number of C–H bonds that are present in organic molecules mean that selectively targeting one is challenging. Typically this has been achieved by 'directing groups', where proximity to a specific C–H bond guides the reaction. Now, Jin-Quan Yu and colleagues report a palladium-catalysed non-directed arene C–H functionalization method using a 2-pyridone ligand. The ligand makes the catalyst more reactive, allowing the arene to be used as the limiting reagent—overcoming a key limitation in the use of such reactions in the derivatization of complex molecules. The ligand also enhances the effects of sterics on site selectivity, in some cases improving it significantly without the need for a directing group. The directed activation of carbon–hydrogen bonds (C–H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups1,2,3,4,5,6. Palladium-catalysed non-directed C–H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts7,8. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used9,10,11,12,13,14,15,16,17,18, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C–H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C–H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C–H functionalization.