Photo-Excited Nickel-Catalyzed Silyl-Radical-Mediated Direct Activation of Carbamoyl Chlorides To Access (Hetero)aryl Carbamides.

Amide bonds connect the amino acids in proteins and exist as a prevalent structural motif in biomolecules. Herein, we have exploited the concept of cross-electrophile coupling by merging the photo-redox and transition-metal catalysis to construct carbamides from superabundant (hetero)aryl halides along with commercially feasible carbamoyl chlorides. The success of this method relies on the prior formation of NiII -aryl halide intermediates, which involves in a photoexcited Ni-halide homolysis event by energy transfer from aryl bromide and single-electron transfer from aryl chloride to assist generation of the vital carbamoyl radical. The breadth of application of this technique is demonstrated both in inter- as well as intramolecular routes for the synthesis of a plethora of (hetero)aryl carbamides with diverse functionalities, and biologically important benzolactams.

Expanding chemical space by para-C-H arylation of arenes.

Biaryl scaffolds are privileged templates used in the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets. Biaryls are found in the structures of therapeutics, including antibiotics, anti-inflammatory, analgesic, neurological and antihypertensive drugs. However, existing synthetic routes to biphenyls rely on traditional coupling approaches that require both arenes to be prefunctionalized with halides or pseudohalides with the desired regiochemistry. Therefore, the coupling of drug fragments may be challenging via conventional approaches. As an attractive alternative, directed C-H activation has the potential to be a versatile tool to form para-substituted biphenyl motifs selectively. However, existing C-H arylation protocols are not suitable for drug entities as they are hindered by catalyst deactivation by polar and delicate functionalities present alongside the instability of macrocyclic intermediates required for para-C-H activation. To address this challenge, we have developed a robust catalytic system that displays unique efficacy towards para-arylation of highly functionalized substrates such as drug entities, giving access to structurally diversified biaryl scaffolds. This diversification process provides access to an expanded chemical space for further exploration in drug discovery. Further, the applicability of the transformation is realized through the synthesis of drug molecules bearing a biphenyl fragment. Computational and experimental mechanistic studies further provide insight into the catalytic cycle operative in this versatile C-H arylation protocol.

Toolbox for Distal C-H Bond Functionalizations in Organic Molecules.

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.

Arene diversification through distal C(sp2)-H functionalization.

Transition metal-catalyzed aryl C-H activation is a powerful synthetic tool as it offers step and atom-economical routes to site-selective functionalization. Compared with proximal ortho-C-H activation, distal (meta- and/or para-) C-H activation remains more challenging due to the inaccessibility of these sites in the formation of energetically favorable organometallic pretransition states. Directing the catalyst toward the distal C-H bonds requires judicious template engineering and catalyst design, as well as prudent choice of ligands. This review aims to summarize the recent elegant discoveries exploiting directing group assistance, transient mediators or traceless directors, noncovalent interactions, and catalyst and/or ligand selection to control distal C-H activation.

Rhodium catalyzed template-assisted distal para-C-H olefination.

Rhodium catalysis has been extensively used for ortho-C-H functionalization reactions, and successfully extended to meta-C-H functionalization. Its application to para-C-H activation remains an unmet challenge. Herein we disclose the first example of such a reaction, with the Rh-catalyzed para-C-H olefination of arenes. The use of a Si-linked cyanobiphenyl unit as a traceless directing group leads to highly para-selective arene-olefin couplings.