Transition-metal-catalyzed C−H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted to take the help of this methodology to plan their synthetic discourses. This paradigm shift has helped in the development of industrial units as well, making the synthesis of natural products and pharmaceutical drugs step-economical. In the vast zone of C−H bond activation, the functionalization of proximal C−H bonds has gained utmost popularity. Unlike the activation of proximal C−H bonds, the distal C−H functionalization is more strenuous and requires distinctly specialized techniques. In this review, we have compiled various methods adopted to functionalize distal C−H bonds, mechanistic insights within each of these procedures, and the scope of the methodology. With this review, we give a complete overview of the expeditious progress the distal C−H activation has made in the field of synthetic organic chemistry while also highlighting its pitfalls, thus leaving the field open for further synthetic modifications.

General consideration S3 Experimental section S3 2.1 Preparation of starting materials S3 -S11 2.2 Optimization details for meta-CH alkynylation with (bromoethynyl)triisopropylsilane Screening of scaffolds S12 -S19 S20 2.3 2.3.1.a 2.3.1.b 2.3.1.c 2.3.1.d General procedure for palladium catalyzed meta-selective CH alkynylation of arene General procedure for palladium catalyzed meta-selective sequential hetero difunctionalization of arene General procedure for gram scale synthesis of meta-alkynylated protocol General procedure for directing group removal of meta-alkynylated protocol General procedure for different application of meta-alkynylated product S20 S21-S22 S23 S23 S24-S25 2.4 Characterization data of meta-alkynylated products S25 -S60 2.5 Mechanistic studies S60 -S66 2.6 Computational methods S67 -S115 References S115 -S122 NMR spectra S123 -S205S10 TBDMSO Br Ph ((1-(bromoethynyl)-4-phenylcyclohexyl)oxy)(tert-butyl)dimethylsilane: 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (t,

Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important endeavor in contemporary organic synthesis. In this vein, template engineering and mechanistic understanding of new functionalization strategies are essential for enhancing the scope of such methods. Herein, meta-C–H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a critical solvent in this transformation. The role of HFIP throughout the catalytic cycle has been systematically studied. A broad substrate scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid, and 2-phenylbenzoic acid derivatives has been demonstrated. Interestingly, conformationally flexible arenes have also been selectively allylated at the meta-position using allyl phosphate. A combination of 1H NMR, 31P NMR, ESI-MS, kinetic experiments, and density functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta-C–H activation, allyl addition forming a Pd-π-allyl complex which is then followed by a turnover determining the C–C bond formation step leading to the meta-allylated product.

An efficient method has been developed to afford highly C-5 selective olefination of thiazole derivatives utilizing a bifunctional template in an intermolecular fashion. Coordinative interaction between the substrates and the metal chelated template backbone plays a crucial role in high C-5 selectivity. Excellent selectivity for the C-5 position was observed while mono substituted (2- or 4-) or even more challenging unsubstituted thiazoles were employed.

Achieving site-selective C-H functionalization of arene is a fundamental challenge, as it is mainly controlled by the electronic nature of the molecules. A chelation-assisted C-H functionalization strategy overcomes the selectivity issues by utilizing distance and geometry of covalently attached directing groups (DGs). This strategy requires stoichiometric DG installation/removal and a suitable functional group on which to tether the DG. Such strategies are ineffective for small heterocycles unless suitable functional groups are added. Moreover, heterocycles are not the judicious choice as substrates owing to the possibilities of catalyst deactivation. Inspired by recent developments, this work demonstrates the utilization of a chelating template backbone bearing covalently attached directing groups, which enables site-selective remote C-H functionalization of heterocycles. The observed selectivity is the outcome of non-covalent interactions between the heterocycles and bifunctional template backbone.