Conspectus
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 metallacycle, distal C–H
activation remained a formidable challenge as it required formation
of a large macrocyclic metallacycle. 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 target...
