Regiodivergent C-H Acylation of Arenes by Switching from Ionic- to Radical-Type Chemistry Using NHC Catalysis.

The Friedel-Crafts acylation reaction, which belongs to the class of electrophilic aromatic substitutions is a highly valuable and versatile reaction in synthesis. Regioselectivity is predictable and determined by electronic as well as steric factors of the (hetero)arene substrate. Herein, a radical approach for the acylation of arenes and heteroarenes is presented. C-H acylation is achieved through mild cooperative photoredox/NHC radical catalysis with the cross-coupling of an arene radical cation with an NHC-bound ketyl radical as a key step. As compared to the classical Friedel-Crafts acylation, a regiodivergent outcome is observed upon switching from the ionic to the radical mode. In these divergent reactions, aroyl fluorides act as the acylation reagents in both the ionic as well as the radical process.

Visible Light-Driven Radical-Mediated C-C Bond Cleavage/Functionalization in Organic Synthesis.

Thermal C-C bond cleavage reactions allow the construction of structurally diverse molecular skeletons via predictable and efficient bond reorganizations. Visible light photoredox-catalyzed radical-mediated C-C bond cleavage reactions have recently emerged as a powerful alternative method for overcoming the thermodynamic and kinetic barrier of C-C bond cleavage in diverse molecular scaffolds. In recent years, a plethora of elegant and useful reactions have been invented, and the products are sometimes otherwise inaccessible by classic thermal reactions. Considering the great influence and synthetic potential of these reactions, we provide a summary of the state of art visible light-driven radical-mediated C-C bond cleavage/functionalization strategies with a specific emphasis on the working models. We hoped that this review will be useful for medicinal and synthetic organic chemists and will inspire further reaction development in this interesting area.

When Light Meets Nitrogen-Centered Radicals: From Reagents to Catalysts.

Nitrogen-centered radicals (NCRs) are a versatile class of highly reactive species that have a longer history than the classical carbon-based radicals in synthetic chemistry. Depending on the N-hybridization and substitution patterns, NCRs can serve as electrophiles or nucleophiles to undergo various radical transformations. Despite their power, progress in nitrogen-radical chemistry is still slow compared with the popularity of carbon radicals, and their considerable synthetic potential has been largely underexplored, which is, as concluded by Zard, mainly hampered by "a dearth of convenient access to these species and a lack of awareness pertaining to their reactivity".Over the past decade, visible-light photoredox catalysis has been established as a powerful toolbox that synthetic chemists can use to generate a diverse range of radical intermediates from native organic functional groups via a single electron transfer process or energy transfer under mild reaction conditions. This catalytic strategy typically obviates the need for external stoichiometric activation reagents or toxic initiators and often enables traditionally inaccessible ionic chemical reactions. On the basis of our long-standing interest in nitrogen chemistry and catalysis, we have emphasized the use of visible-light photoredox catalysis as a tactic to discover and develop novel methods for generating NCRs in a controlled fashion and synthetic applications. In this Account, we describe our recent advances in the development of visible-light-driven photoredox-catalyzed generation of NCRs and their synthetic applications.Inspired by the natural biological proton-coupled electron transfer (PCET) process, we first developed a strategy of visible-light-driven photoredox-catalyzed oxidative deprotonation electron transfer to activate the N-H bonds of hydrazones, benzamides, and sulfonamides to give the corresponding NCRs under mild reaction conditions. With these reactive species, we then achieved a range of 5-exo and 6-endo radical cyclizations as well as cascade reactions in a highly regioselective manner, providing access to a variety of potentially useful nitrogen heterocycles. To further expand the repertoire of possible reactions of NCRs, we also revealed that iminyl radicals, derived from O-acyl cycloalkanone oxime esters, can undergo facile ring-opening C-C bond cleavage to give cyanoalkyl radicals. These newly formed radical species can further undergo a variety of C-C bond-forming reactions to allow the synthesis of diverse distally functionalized alkyl nitriles. Stimulated by these studies, we further developed a wide variety of visible-light-driven copper-catalyzed radical cross-coupling reactions of cyanoalkyl radicals. Because of their inherent highly reactive and transient properties, the strategy of heteroatom-centered radical catalysis is still largely underexplored in organic synthesis. Building on our understanding of the fundamental chemistry of NCRs, we also developed for the first time the concept of NCR covalent catalysis, which involves the use of in situ-photogenerated NCRs to activate allyl sulfones, vinylcyclopropanes, and N-tosyl vinylaziridines. This catalytic strategy has thus enabled efficient difunctionalization of various alkenes and late-stage modification of complex biologically active molecules.In this Account, we describe a panoramic picture of our recent contributions since 2014 to the development and application of the visible-light-driven photoredox systems in the field of NCR chemistry. These studies provide not only efficient methods for the synthesis of functionally rich molecules but also some insight into the exploration of new reactivity or reaction modes of NCRs.

Visible-Light-Driven Copper-Catalyzed C(sp3)-O Cross-Coupling of Benzylic Radicals with Phenols.

A visible-light-driven, copper-catalyzed C(sp3)-O coupling of benzylic radicals with phenols is described for the first time. This operationally simple and robust process features mild conditions, broad scope, and high functional-group tolerance, enabling the construction of a diverse range of cyanoalkylated aryl ethers (33 examples). Key to this protocol is the dual role of copper salt that acts not only as a photosensitizer but also as a cross-coupling catalyst.

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.

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.

Photogenerated Neutral Nitrogen Radical Catalyzed Bifunctionalization of Alkenes.

Alkene bifunctionalizations are powerful tools for the rapid construction of structurally complex and valuable scaffolds, and such reactions typically involve the use of transition-metal catalysts or organocatalysts. Here, we report for the first time a photogenerated neutral nitrogen radical catalyzed intermolecular alkene bifunctionalization by using allyl sulfones as the source of both the carbon and the sulfone functionalities under mild conditions. The key to the success of this protocol involves the visible-light-mediated photocatalytic in situ generation of a nitrogen-centered radical from the N-(2-acetylphenyl) benzenesulfonamide catalyst, and its activation of the allyl sulfones to generate reactive species. The preliminary control experiments supported the postulated mechanism.

Copper-Catalyzed Radical Cross-Coupling of Redox-Active Oxime Esters, Styrenes, and Boronic Acids.

A visible-light-driven, copper-catalyzed three-component radical cross-coupling of oxime esters, styrenes, and boronic acids has been developed. Key steps of this protocol involve catalytic generation of an iminyl radical from a redox-active oxime ester and subsequent C-C bond cleavage to generate a cyanoalkyl radical. Upon its addition to styrene, the newly formed benzylic radical undergoes coupling with a boronic-acid-derived ArCuII complex to achieve 1,1-diarylmethane-containing alkylnitriles.

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.

Visible-Light-Driven Aza-ortho-quinone Methide Generation for the Synthesis of Indoles in a Multicomponent Reaction.

A visible-light-driven radical-mediated strategy for the in situ generation of aza-ortho-quinone methides from 2-vinyl-substituted anilines and alkyl radical precursors is described. This process enables an efficient multicomponent reaction of 2-vinylanilines, halides, and sulfur ylides, and has a wide substrate scope and good functional group tolerance. Treatment of the cycloaddition products with a base leads to densely functionalized indoles in a single-flask operation.

Catalytic Asymmetric Cycloaddition of In Situ-Generated ortho-Quinone Methides and Azlactones by a Triple Brønsted Acid Activation Strategy.

A convergent and highly stereoselective [4+2] cycloaddition of in situ-generated ortho-Quinone methides (o-QMs) and azlactone enols has been successfully developed through a triple Brønsted acid catalysis strategy. This protocol provides an efficient and mild access to various densely functionalized dihydrocoumarins bearing adjacent quaternary and tertiary stereogenic centers in high yields with excellent diastereo- and enantioselectivity.

Enantioselective direct functionalization of indoles by Pd/sulfoxide-phosphine-catalyzed N-allylic alkylation.

A general and efficient Pd/sulfoxide-phosphine complex-catalyzed direct asymmetric N-allylic alkylation of indoles has been developed to allow for the preparation of various N-allylated indoles in generally good yields with excellent enantioselectivities. This catalytic system could also be extended to other N-containing heterocycles with good results.

Rational design of sulfoxide-phosphine ligands for Pd-catalyzed enantioselective allylic alkylation reactions.

A new type of chiral sulfoxide-phosphine ligands have been developed by a rational combination of two privileged scaffolds for Pd-catalyzed asymmetric allylic alkylation reactions. Under optimized conditions, generally high yields (up to 97%) and excellent enantioselectivities (up to >99% ee) were obtained.