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

Abstract

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...

Transition Metal Catalyzed Remote C-H Activation: A New Direction Towards Site-Selective Chemical Reactions

“…We came up with a biphenyl pyrimidine template that offers strong coordination to metal for doing diverse chemical reactions at meta C-H bond. 5 A plethora of meta-selective reactions such as cyanation, alkylation, reactions. C-H bond which is the most abundant part in any organic compound is being utilized in C-H activation to make a new bond, making it a lucrative approach of performing chemical reactions.…”

“…Over the last few years, our focus has been to address these challenges and take remote C-H activation to a level where it could be routinely applied in academic and industrial settings. [4][5][6][7] Transition Metal Catalyzed Remote C(sp 2 )-H Activation Aromatic compounds are prevalent in nature in the form of pharmacoactives, agrochemicals, fragrance molecules, etc. C-H functionalization of these molecules is of utmost importance to improve their utility and significance.…”

Ruthenium-catalyzed (spiro)annulation of N-aryl-2,3-dihydrophthalazine-1,4-diones with quinones to access pentacyclic spiro-indazolones and fused-cinnolines

“…The exploration for the construction of complex heterocyclic architectures has become straightforward with the synthetic shortcuts pioneered by chelation-guided directive C–H functionalization under transition-metal catalysis in the last decade. 1 In this realm, a plethora of strong and weak directing groups (DGs), 2 including N -heterocycles 3 ( e.g. pyridine, pyrimidine, triazole, pyrazole, oxazoline, 8-aminoquinoline, picolinamide) and functionalities 4 ( e.g.…”

OrthoC−H Functionalizations of 2‐Aryl‐2H‐Indazoles

“…Recently, directed site-selective CÀ H functionalization is getting immense interest due to providing a go-to general method for installing various functional groups at a particular position of a heterocycle. [12] Depending on the length and structure of directing group or template and formation of metallacyclic intermediate, ortho-, [13] meta-, [14] and even para-selective CÀ H bond activations and functionalizations [15] can be easily attainable. Among them, ortho CÀ H functionalization is largely expanded as it generally advances through five to sevenmembered metallacyclic intermediates.…”