Controlling Reactivity and Selectivity in the Nondirected C-H Activation of Arenes with Palladium

Aromatic structures are widespread motifs throughout organic chemistry, and C-H activation has been recognized as a major tool for enabling their sustainable and efficient functionalization. Through C-H activation, arenes can be modified without the need for prefunctionalization, leading to inherent atom- and step-economic advantages over traditional methods. However, for the development of synthetically useful methods, several hurdles have to be overcome. The strength of C-H bonds necessitates the development of sufficiently reactive catalysts, while the presence of multiple C-H bonds within a substrate poses challenges in terms of site-selectivity. Traditionally these challenges have been addressed by substrate control. By attaching different directing groups (DGs), the reactivity of the respective arene was significantly enhanced and the DG guided the metal in close proximity to specific C-H bonds, resulting in high site-selectivity. However, the introduction and removal of the DG add additional steps to the synthetic sequence, and the scope of the reaction is limited to a specific substrate class. The development of complementary nondirected methods that can be applied to a broad range of arenes without the necessity to carry a specific functional group that coordinates to Pd (referred to as simple arenes) is therefore highly desirable. However, the intrinsically lower reactivity of such substrates and the absence of a selectivity-determining DG pose significant challenges that can be solved only by the development of highly efficient catalysts. Consequently, the field of nondirected C-H activation, especially with respect to Pd-catalyzed methods, remained comparatively underdeveloped when we initiated our research program in 2017. At that time, state-of-the-art methods required the arene to be used in large excess, precluding its use in late-stage functionalization. Since organopalladium species are among the most versatile synthetic intermediates, we realized that developing a system, which can effectively and selectively activate C-H bonds in simple arenes with the arene as the limiting reagent, would be a powerful tool in synthetic organic chemistry. This account summarizes our groups' research toward the development and application of catalytic systems offering this desired reactivity and focuses explicitly on Pd-catalyzed nondirected C-H functionalization reactions of arenes, where the arene is employed as a limiting reagent. After an introduction that summarizes the state of Pd-catalyzed C-H activation of arenes before 2017 and the associated challenges, experimental and mechanistic details about the development of the first arene-limited, nondirected C-H functionalization of simple arenes with palladium will be discussed. This reactivity was enabled by the identification and combination of two complementary ligands, an N-heterocycle and an amino acid-derived ligand. Afterward we will discuss the expansion of this dual-ligand approach to further arene-limited transformations. Finally, we describe two methodologies that originated from the observations we made during our studies, namely, the late-stage deuteration of simple arenes and a highly selective olefination method that uses noncovalent interactions to induce meta selectivity.