Emerging Trends in Copper-Promoted Radical-Involved C-O Bond Formations.

The C-O bond is ubiquitous in biologically active molecules, pharmaceutical agents, and functional materials, thereby making it an important functional group. Consequently, the development of C-O bond-forming reactions using catalytic strategies has become an increasingly important research topic in organic synthesis because more conventional methods involving strong base and acid have many limitations. In contrast to the ionic-pathway-based methods, copper-promoted radical-mediated C-O bond formation is experiencing a surge in research interest owing to a renaissance in free-radical chemistry and photoredox catalysis. This Perspective highlights and appraises state-of-the-art techniques in this burgeoning research field. The contents are organized according to the different reaction types and working models.

Light-empowered contra-thermodynamic stereochemical editing.

Creating, conserving and modifying the stereochemistry of organic compounds has been the subject of significant research efforts in synthetic chemistry. Most synthetic routes are designed according to the stereoselectivity-determining step. Stereochemical editing is an alternative strategy, wherein the chiral-defining or geometry-defining steps are independent of the construction of the major scaffold or complexity. It enables late-stage alterations of stereochemistry and can generate isomers from a single compound. However, in many instances, stereochemical editing processes are contra-thermodynamic, meaning the transformation is unfavourable. To overcome this barrier, photocatalysis uses photogenerated radical species and introduces thermochemical biases. A range of synthetically valuable contra-thermodynamic stereochemical editing processes have been invented, including deracemization of chiral molecules, positional alkene isomerization and dynamic epimerization of sugars and diols. In this Review, we highlight the fundamental mechanisms of visible-light photocatalysis and the general reactivity modes of the photogenerated radical intermediates towards contra-thermodynamic stereochemical editing processes.

Electrochemical Reactors Enable Divergent Site Selectivity in the C-H Carboxylation of N-Heteroarenes.

Catalytic and switchable C-H functionalization of N-heteroarenes under easily tunable conditions is a robust but challenging tool for the construction of biologically relevant compounds. Recently, a general electrochemical strategy has been developed for the direct C-H carboxylation of N-heteroarenes with CO2 , and by simply choosing different types of cell setups, carboxylated products are furnished with excellent and tunable site selectivity. This study also paves the way for regulating the reactivity modes in electrochemical synthesis.

Photoinduced Copper-Catalyzed Asymmetric Three-Component Coupling of 1,3-Dienes: An Alternative to Kharasch-Sosnovsky Reaction.

Kharasch-Sosnovsky reaction is one of the most powerful methods for allylic oxidation of alkenes. However, the inherent radical mechanism and use of peroxides as both oxidants and oxygen nucleophiles render dearth of universal catalytic systems for highly enantioselective variants and limited scope. Herein, an alternative to the asymmetric Kharasch-Sosnovsky reaction that utilized a chiral copper catalyst and purple-LED irradiation to enable the three-component coupling of 1,3-dienes, oxime esters, and carboxylic acids is reported. This protocol features mild conditions, remarkable scope and functional group tolerance as evidenced by >80 examples and utility in the late-stage modification of pharmaceuticals and natural products. Detailed mechanistic studies provide evidences for the radical-based reaction pathway.

Photoinduced Copper-Catalyzed Asymmetric C-O Cross-Coupling.

The construction of carbon-heteroatom bonds is one of the most active areas of research in organic chemistry because the function of organic molecules is often derived from the presence of heteroatoms. Although considerable advances have recently been achieved in radical-involved catalytic asymmetric C-N bond formation, there has been little progress in the corresponding C-O bond-forming processes. Here, we describe a photoinduced copper-catalyzed cross-coupling of readily available oxime esters and 1,3-dienes to generate diversely substituted allylic esters with high regio- and enantioselectivity (>75 examples; up to 95% ee). The reaction proceeds at room temperature under excitation by purple light-emitting diodes (LEDs) and features the use of a single, earth-abundant copper-based chiral catalyst as both the photoredox catalyst for radical generation and the source of asymmetric induction in C-O coupling. Combined experimental and density functional theory (DFT) computational studies suggest the formation of π-allylcopper complexes from redox-active oxime esters as bifunctional reagents and 1,3-dienes through a radical-polar crossover process.

Asymmetric three-component olefin dicarbofunctionalization enabled by photoredox and copper dual catalysis.

The intermolecular three-component alkene vicinal dicarbofunctionalization (DCF) reaction allows installation of two different carbon fragments. Despite extensive investigation into its ionic chemistry, the enantioseletive radical-mediated versions of DCF reactions remain largely unexplored. Herein, we report an intermolecular, enantioselective three-component radical vicinal dicarbofunctionalization reaction of olefins enabled by merger of radical addition and cross-coupling using photoredox and copper dual catalysis. Key to the success of this protocol relies on chemoselective addition of acyl and cyanoalkyl radicals, generated in situ from the redox-active oxime esters by a photocatalytic N-centered iminyl radical-triggered C-C bond cleavage event, onto the alkenes to form new carbon radicals. Single electron metalation of such newly formed carbon radicals to TMSCN-derived L1Cu(II)(CN)2 complex leads to asymmetric cross-coupling. This three-component process proceeds under mild conditions, and tolerates a diverse range of functionalities and synthetic handles, leading to valuable optically active ß-cyano ketones and alkyldinitriles, respectively, in a highly enantioselective manner (>60 examples, up to 97% ee).

Enantioselective Radical Ring-Opening Cyanation of Oxime Esters by Dual Photoredox and Copper Catalysis.

Catalytic enantioselective chemical reactions involving highly reactive radical species remain largely unexplored. We report herein for the first time a novel enantioselective radical ring-opening cyanation of redox-active oxime esters by dual photoreodox and copper catalysis. This mild protocol shows good functional group tolerance and broad substrate scope, producing a wide range of optically active alkyl dinitriles with high yields and excellent enantioselectivities, which are difficult to access traditionally.

Radical C-C Bond Cleavage/Addition Cascade of Benzyl Cycloketone Oxime Ethers Enabled by Photogenerated Cyclic Iminyl Radicals.

A light-driven, metal-free, and iminyl radical-mediated ring-opening C-C bond cleavage/addition cascade of O-4-methoxybenzyl oxime ethers and alkenes is described for the first time. The reaction shows a broad substrate scope and high functional group compatibility with both components, giving the corresponding valuable oxo nitriles in generally good yields. Key to the success of this protocol is the generation of cyclic iminyl radicals from the O-4-methoxybenzyl oxime ethers via a photocatalytic hydrogen atom transfer (HAT) process. The proposed main pathway is also supported by the preliminary mechanistic studies.

Hantzsch esters: an emerging versatile class of reagents in photoredox catalyzed organic synthesis.

Hantzsch esters were often previously used as reductants in thermal catalytic hydrogenation reactions. Over the last few decades, Hantzsch esters have proven to be a useful class of electron donors and proton sources in photoredox catalyzed processes. Moreover, under photoredox catalytic conditions, alkyl-1,4-dihydropyridines can serve as versatile types of alkylation reagents via oxidative fragmentation mechanisms. This minireview highlights the recent advances in the chemistry of Hantzsch esters in photoredox catalyzed organic synthesis, with particular emphasis placed on reaction mechanisms. We hope that this review will inspire further new reaction design and developments with such a class of readily accessible reagents.

Photoinduced, Copper-Catalyzed Radical Cross-Coupling of Cycloketone Oxime Esters, Alkenes, and Terminal Alkynes.

A photoinduced, copper-catalyzed three-component radical cross-coupling of cycloketone oxime esters, alkenes, and terminal alkynes is described for the first time. Key to the success of this process was the integration of photoinduced iminyl radical-mediated C-C bond cleavage with the conceptual simplicity of copper-catalyzed radical cross-coupling. This protocol provides access to cyanoalkyl-containing propargylic compounds in good yields.

A photoredox catalyzed iminyl radical-triggered C-C bond cleavage/addition/Kornblum oxidation cascade of oxime esters and styrenes: synthesis of ketonitriles.

A photoredox-catalyzed iminyl radical-triggered C-C bond cleavage/addition/Kornblum oxidation cascade of cycloketone oxime esters and styrenes in DMSO is described. This three-component, one-pot procedure features mild conditions, a broad substrate scope, and high functional group tolerance, providing an efficient approach to access diversely functionalized ketonitriles.

A photocatalytic iminyl radical-mediated C-C bond cleavage/addition/cyclization cascade for the synthesis of 1,2,3,4-tetrahydrophenanthrenes.

On the basis of the strategy of iminyl radical-mediated C-C bond cleavage, a visible light photocatalytic radical addition/cyclization cascade is described, providing an efficient and regioselective access to cyanoalkylated 1,2,3,4-tetrahydrophenanthrenes.

Dual Photoredox/Nickel-Catalyzed Regioselective Cross-Coupling of 2-Arylaziridines and Potassium Benzyltrifluoroborates: Synthesis of ß-Substitued Amines.

A dual visible light photoredox and nickel-catalyzed cross-coupling reaction of 2-arylaziridines and potassium benzyltrifluoroborates is described for the first time. This strategy features high functional group tolerance, exclusive regioselectivity for reaction at the more hindered C-N bond, easily accessible substrates, and mild redox-neutral reaction conditions. A variety of diversely substituted ß-substituted amines are obtained in generally good yields.

A Visible-Light-Driven Iminyl Radical-Mediated C-C Single Bond Cleavage/Radical Addition Cascade of Oxime Esters.

A room-temperature, visible-light-driven N-centered iminyl radical-mediated and redox-neutral C-C single bond cleavage/radical addition cascade reaction of oxime esters and unsaturated systems has been accomplished. The strategy tolerates a wide range of O-acyl oximes and unsaturated systems, such as alkenes, silyl enol ethers, alkynes, and isonitrile, enabling highly selective formation of various chemical bonds. This method thus provides an efficient approach to various diversely substituted cyano-containing alkenes, ketones, carbocycles, and heterocycles.