Emergence of Pyrimidine-Based meta-Directing Group: Journey from Weak to Strong Coordination in Diversifying meta-C-H Functionalization

C-H activation has emerged as a powerful transformative synthetic tool to construct complex molecular frameworks, which are ubiquitous in natural products, medicines, dyes, polymers, and many more. However, reactivity and selectivity, arising from the inertness of C-H bonds and their overabundance in organic molecules, are the two major fundamental challenges in developing various carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation reactions via C-H activation technique. Functional groups with coordinating capacity to the transition metal catalysts, profoundly known as directing groups (DGs), have shown great promise in exerting selective C-H activation, often called site-selective or regioselective transformation of a target molecule. Advent of directing group (DG)-assisted strategies not only has resolved the selectivity issues but also offers a unique solution to the rapid synthesis of complex molecules in a convenient and predictable manner. Our laboratory, in this regard, is fascinated by the prospect of DG-assisted distal C-H functionalization of arenes, in which the target C-H bond is remotely located from the existing directing group. Notably, in opposition to proximal ortho-C-H activation, which proceeded via an energetically favorable five- to seven-membered metallacyde, distal C-H activation remained a formidable challenge as it required formation of a large macrocyclic metallacyde. Therefore, designing a suitable directing template that would maintain the required distance and geometric relationship between the target C-H bond and the appended directing auxiliary in order to ensure the prolific delivery of the metal catalyst to the closest proximity of targeted distal C-H bond was the key to success. In this regard, the Yu group devised an elegant U-shaped template for the first time to execute distal meta-C-H activation recruiting a cyano-based directing group. Our initial effort to diversify the scope of meta-C-H functionalization using a cyano-based template led us to realize that the cyano-based DGs are intrinsically limited with weak coordinating ability, competitive binding mode (end-on vs side-on), and incompatibility with acidic and basic reaction conditions. In search of a robust directing auxiliary, we were intrigued by the possibility of using the strongly coordinating ability of pyrimidine and quinoline-based DGs. In this Account, we describe our journey from the weakly coordinating cyano-based DG to the strongly coordinating pyrimidine-based DG to achieve diverse meta-C-H functionalization of electronically and sterically unbiased arenes. While some of the functionalizations were achieved by finding suitable reaction conditions, others were led by mechanistic understanding. Notably, initial development in this realm was constrained with short linkers, in which the DG was attached to the arene of interest through 2-4 atoms. In later studies, we demonstrated that the selective meta-C-H activation can be attained even though the DG is 10-atoms away from the targeted arene. More importantly, a transient DG was successfully utilized to deliver meta-C-H olefination of arenes via in situ imine formation, which provided a step-economic route to meta-C-H activation. We hope that this Account will stimulate further template design and will provide a guiding platform for the future development of distal meta-C-H functionalization.

Automated summary

C-H activation is a powerful synthetic tool to construct complex molecular frameworks. The use of directing groups (DGs) has resolved selectivity issues and offered a unique solution for the synthesis of complex molecules. By using different types of DGs, we achieved distal meta-C-H functionalization and gained a deeper understanding of the mechanism.