Photocatalytic Late-Stage C-H Functionalization.

The emergence of modern photocatalysis, characterized by mildness and selectivity, has significantly spurred innovative late-stage C-H functionalization approaches that make use of low energy photons as a controllable energy source. Compared to traditional late-stage functionalization strategies, photocatalysis paves the way toward complementary and/or previously unattainable regio- and chemoselectivities. Merging the compelling benefits of photocatalysis with the late-stage functionalization workflow offers a potentially unmatched arsenal to tackle drug development campaigns and beyond. This Review highlights the photocatalytic late-stage C-H functionalization strategies of small-molecule drugs, agrochemicals, and natural products, classified according to the targeted C-H bond and the newly formed one. Emphasis is devoted to identifying, describing, and comparing the main mechanistic scenarios. The Review draws a critical comparison between established ionic chemistry and photocatalyzed radical-based manifolds. The Review aims to establish the current state-of-the-art and illustrate the key unsolved challenges to be addressed in the future. The authors aim to introduce the general readership to the main approaches toward photocatalytic late-stage C-H functionalization, and specialist practitioners to the critical evaluation of the current methodologies, potential for improvement, and future uncharted directions.

Catalytic defluorinative ketyl-olefin coupling by halogen-atom transfer.

Ketyl-olefin coupling reactions stand as one of the fundamental chemical transformations in synthetic chemistry and have been widely employed in the generation of complex molecular architectures and natural product synthesis. However, catalytic ketyl-olefin coupling, until the recent development of photoredox chemistry and electrosynthesis through single-electron transfer mechanisms, has remained largely undeveloped. Herein, we describe a new approach to achieve catalytic ketyl-olefin coupling reactions by a halogen-atom transfer mechanism, which provides innovative and efficient access to various gem-difluorohomoallylic alcohols under mild conditions with broad substrate scope. Preliminary mechanistic experimental and computational studies demonstrate that this radical-to-polar crossover transformation could be achieved by sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and ß-fluoro elimination.

Deaminative chlorination of aminoheterocycles.

Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)‒NH2 can be converted into C(sp2)‒Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents.

Chemoselective formation of cyclo-aliphatic and cyclo-olefinic 1,3-diols via pressure hydrogenation of potentially biobased platform molecules using Knölker-type catalysts.

The hydrogenative conversions of the biobased platform molecules 4-hydroxycyclopent-2-enone and cyclopentane-1,3-dione to their corresponding 1,3-diols are established using a pre-activated Knölker-type iron catalyst. The catalyst exhibits a high selectivity for ketone reduction, and does not induce dehydration. Moreover, by using different substituents of the ligand, the cis-trans ratio of the products can be affected substantially. A decent compatibility of this catalytic system with various structurally related substrates is demonstrated.

C-H Activation: Toward Sustainability and Applications.

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.