The direct functionalization of C-H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C-H bond, this selective C-H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C-H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C-H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C-H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.

Transient Directing Groups in Metal-Organic Cooperative Catalysis.

Considerable advances have been made in the area of C-H functionalization in the last few decades. A number of approaches including both directed or non-directed strategies have been developed thus far. Among the various C-H functionalizations, C-H borylation is of special interest due to the wide applications of organoborons. In this regard, various transition-metal-catalyzed regio-selective strategies have been appeared. However, the major concern regarding metal-catalyzed C-H borylation protocols is the requirement of a precious metal as well as the contamination of metal precursor in the desired products, which limit the application of this process in large-scale synthesis. Therefore, the recent trends have involved the use of transition-metal-free systems. We summarize this recent ongoing interest of transition-metal-free regio-selective C-H borylation. We believe that this review will definitely help to increase interest in this field and it will stimulate further progress.

Regio-Selective Transition-Metal-Free C(sp2)-H Borylation: A Subject of Practical and Ongoing Interest in Synthetic Organic Chemistry.

Adamantane-1-Carbonyl-Directed C–H Borylation and Hydroxylation of Benzenethiols

Metal-Free Boron-Mediated ortho-C-H Hydroxylation of N-Benzyl-3,4,5-tribromopyrazoles.

Pd(II)-catalyzed γ-C(sp3)-H (hetero)arylation of aliphatic ketones is developed using α-amino acid as transient directing groups (TDG). A variety of aliphatic ketones were (hetero)arylated at the γ-position via a 5,6-membered fused cyclopalladation intermediate to afford the remotely arylated products in up to 88% yield. The crucial ligand effect of 2-pyridone is further enhanced by reducing the loading of acid additives. Consequentially, the improved reactivity of this catalytic system has also made possible the cyclic γ-methylene C(sp3)-H arylation of ketones. Mechanistic investigtigation and comparison to the γ-C-H arylation of aldehydes revealed a structural insight for designing site selective TDG.

PdII-Catalyzed γ-C(sp3)-H (Hetero)Arylation of Ketones Enabled by Transient Directing Groups.

A novel route for ortho-selective C-H borylation of 2-phenylthiopyridines using BBr3 as the boron source under metal-free conditions has been reported. The reaction exhibited site exclusivity, and the synthesized aryl boronates were freely converted to various useful intermediates. Thus, this facile method would be beneficial to synthesize structurally diversified phenylthioethers derivatives and other materials containing boron-nitrogen coordination.

Metal-Free ortho-Selective C-H Borylation of 2-Phenylthiopyridines Using BBr3.

The direct arylation of aliphatic ketones has been developed via Pd-catalyzed β-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.

Palladium-Catalyzed β-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group.

Metal-free directed C−H borylation of 2-(N-methylanilino)-5-fluoropyridines and 2-benzyl-5-fluoropyridines

Rhodium(III)-Catalyzed Cascade C−H Activation/Annulation of N-carbamoylindoles with Silyl Enol Ethers for the Construction of Dihydropyrimidoindolone Skeletons

Binghan Pang

Papers

Metal-Free ortho-Selective C-H Borylation of 2-Phenylthiopyridines Using BBr3.

Palladium-Catalyzed β-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group.

Metal-free directed C−H borylation of 2-(N-methylanilino)-5-fluoropyridines and 2-benzyl-5-fluoropyridines

Rhodium(III)-Catalyzed Cascade C−H Activation/Annulation of N-carbamoylindoles with Silyl Enol Ethers for the Construction of Dihydropyrimidoindolone Skeletons

Ligand-Enabled Sequential C(sp3)-H and C(sp2)-H Diolefination Reaction via Palladium Catalyst.