Atropoisomeric (hetero)biaryls are scaffolds with increasing importance in the pharmaceutical and agrochemical industries. Although it is the most obvious disconnection to construct such compounds, the direct enantioselective C-H arylation through the concomitant induction of the chiral information remains extremely challenging and uncommon. Herein, the unprecedented earth-abundant 3d-metal-catalyzed atroposelective direct arylation is reported, furnishing rare atropoisomeric C2-arylated indoles. Kinetic studies and DFT computation revealed an uncommon mechanism for this asymmetric transformation, with the oxidative addition being the rate- and enantio-determining step. Excellent stereoselectivities were reached (up to 96% ee), while using an unusual N-heterocyclic carbene ligand bearing an essential remote substituent. Attractive dispersion interactions along with positive C-H---π interactions exerted by the ligand were identified as key factors to guarantee the excellent enantioselection.

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Cobalt-Catalyzed Enantioselective C-H Arylation of Indoles.

C-H deuteration has been intricately developed to satisfy the urgent need for site-selectively deuterated organic frameworks. Deuteration has been primarily used to study kinetic isotope effects of reactions but recently its significance in pharmaceutical chemistry has been discovered. Deuterium labelled compounds have stolen the limelight since the inception of the first FDA-approved deuterated drug, for the treatment of chorea-associated Huntington's disease, and their pharmacological importance was realised by chemists, although surprisingly very late. Various approaches were developed to carry out site-selective deuteration. However, the most common and efficient method is hydrogen isotope exchange (HIE). This review summarises deuteration methods of various organic motifs containing C(sp2)-H and C(sp3)-H bonds utilizing C-H bond functionalisation as a key step along with a variety of catalysts, and exemplifies their biological relevance.

C-H deuteration of organic compounds and potential drug candidates.

Transition metal catalyzed C–H activation has surfaced as a powerful tool to improve the efficacy of molecular synthesis. Last two decades have witnessed a considerable progress in the activation of otherwise inert C–H bonds. However, during recent years, focus has shifted to address rising concerns to achieve high levels of resource economy in molecular syntheses. Herein, we discuss the advent and recent emerging strategies to improve the sustainability and environmentally benign nature of C–H activation manifolds.

https://pubs.rsc.org/en/content/articlepdf/2021/QO/D1QO00727K

Green strategies for transition metal-catalyzed C–H activation in molecular syntheses

Modern strategies for C–H functionalization of heteroarenes with alternative coupling partners

Nickel and Palladium Catalysis: Stronger Demand than Ever

Since the definition of the "12 Principles of Green Chemistry" more than 20 years ago, chemists have become increasingly mindful of the need to conserve natural resources and protect the environment through the judicious choice of synthetic routes and materials. The direct activation and functionalization of C-H bonds, bypassing intermediate functional group installation is, in abstracto, step and atom economic, but numerous factors still hinder the sustainability of large-scale applications. In this Outlook, we highlight the research areas seeking to overcome the sustainability challenges of C-H activation: the pursuit of abundant metal catalysts, the avoidance of static directing groups, the replacement of metal oxidants, and the introduction of bioderived solvents. We close by examining the progress made in the subfield of aryl C-H borylation from its origins, through highly efficient but precious Ir-based systems, to emerging 3d metal catalysts. The future growth of this field will depend on industrial uptake, and thus we urge researchers to strive toward sustainable C-H activation.

Teresa Faber

Papers

C-H Activation: Toward Sustainability and Applications.