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.

Photocatalytic Late-Stage C-H Functionalization.

Abstract The electrochemical synthesis of fluorinated allyl silanes and boronates was disclosed. The addition of electrogenerated boryl or silyl radicals onto many α‐trifluoromethyl or α‐difluoromethylstyrenes in an undivided cell allowed the formation of a large panel of synthetically useful gem‐difluoro and γ‐fluoroallyl boronates and silanes (64 examples, from 31 % to 95 % yield). In addition, a scale up of the reactions under continuous flow was showcased using an electrochemical reactor with promising volumetric productivity (688 g.L−1.h−1 and 496 g.L−1.h−1). Moreover, the synthetic utility of these building blocks was highlighted through versatile transformations. Finally, plausible reaction mechanisms were suggested to explain the formation of the products.

Electrochemical Synthesis of gem‐Difluoro‐ and γ‐Fluoro‐Allyl Boronates and Silanes

Electrochemistry employs electrons as reagents and avoids the use of traditional redox reagents, which becomes a powerful tool in oxidative dehydrogenation cross-coupling reactions. 1,3-Dicarbonyl derivatives are common and easily available...

Recent advances in electrochemical generation of 1,3-dicarbonyl radicals from C–H bonds

Non-phosphorus recyclable Rh/triethanolamine catalytic system for tandem hydroformylation/hydrogenation and hydroaminomethylation of olefins under biphasic conditions

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite of physiochemical properties that match key criteria in drug design and is tunable by varying their substituents. Developments in synthetic chemistry, therefore, directly impact these efforts, and methods that can install various groups from azine C-H bonds are particularly valuable. Furthermore, there is a growing interest in late-stage functionalization (LSF) reactions that focus on advanced candidate compounds that are often complex structures with multiple heterocycles, functional groups, and reactive sites. Because of factors such as their electron-deficient nature and the effects of the Lewis basic N atom, azine C-H functionalization reactions are often distinct from their arene counterparts, and the application of these reactions in LSF contexts is difficult. However, there have been many significant advances in azine LSF reactions, and this review will describe this progress, much of which has occurred over the past decade. It is possible to categorize these reactions as radical addition processes, metal-catalyzed C-H activation reactions, and transformations occurring via dearomatized intermediates. Substantial variation in reaction design within each category indicates both the rich reactivity of these heterocycles and the creativity of the approaches involved.

Late-Stage C-H Functionalization of Azines.

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 β-fluoro elimination.

https://pubs.rsc.org/en/content/articlepdf/2022/sc/d2sc02732a

Catalytic defluorinative ketyl–olefin coupling by halogen-atom transfer

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 Knolker-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.

https://pubs.rsc.org/en/content/articlepdf/2021/dt/d1dt01252e

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

/pdf/author-correction-deaminative-chlorination-of-3m983ant.pdf

Teresa Faber

Papers

Photocatalytic Late-Stage C-H Functionalization.

Catalytic defluorinative ketyl–olefin coupling by halogen-atom transfer

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

Author Correction: Deaminative chlorination of aminoheterocycles