Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

Decarboxylative C?H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step‐ and atom‐economical features and the pervasiveness of carboxylic acids and C?H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C?H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late‐stage functionalization of drug molecules.     

Scalable Photoelectrochemical Dehydrogenative Cross‐Coupling of Heteroarenes with Aliphatic C−H Bonds

Heteroarenes are structural motifs found in many bioactive compounds and functional materials. Dehydrogenative cross‐coupling of heteroarenes with aliphatic C?H bonds provides straightforward access to functionalized heteroarenes from readily available materials. Established methods employ stoichiometric chemical oxidants under conditions of heating or light irradiation. By merging electrochemistry and photochemistry, we have achieved efficient photoelectrochemical dehydrogenative cross‐coupling of heteroarenes and C(sp³)?H donors through H₂ evolution, without the addition of metal catalysts or chemical oxidants. Mechanistically, the C(sp³)?H donor is converted to a nucleophilic carbon radical through H‐atom transfer with chlorine atom, which is produced by light irradiation of anodically generated Cl₂ from Cl^?. The carbon radical then undergoes radical substitution to the heteroarene to afford alkylated heteroarene products.     

Regioselective C−H Xanthylation as a Platform for Polyolefin Functionalization

Polyolefins that contain polar functional groups are important materials for next‐generation lightweight engineering thermoplastics. Post‐polymerization modification is an ideal method for the incorporation of polar groups into branched polyolefins; however, it typically results in chain scission events, which have deleterious effects on polymer properties. Herein, we report a metal‐free method for radical‐mediated C?H xanthylation that results in the regioselective functionalization of branched polyolefins without coincident polymer‐chain scission. This method enables a tunable degree of polymer functionalization and capitalizes on the versatility of the xanthate functional group to unlock a wide variety of C?H transformations previously inaccessible on branched polyolefins.     

Visible‐Light‐Induced Direct Oxidative C−H Amidation of Heteroarenes with Sulfonamides

A direct oxidative C?H amidation of heteroarenes with sulfonamides via nitrogen‐centered radicals has been achieved. Nitrogen‐centered radicals are directly generated from oxidative cleavage of N?H bonds under visible‐light photoredox catalysis. Sulfonamides, which are easily accessed, are used as tunable nitrogen sources and bleach (aqueous NaClO solution) is used as the oxidant. A variety of heteroarenes, including indoles, pyrroles and benzofurans, can undergo this amidation with high yields (up to 92 %). These reactions are highly regioselective, and all the products are isolated as single regioisomer.     

Triiodide‐Mediated δ‐Amination of Secondary C−H Bonds

The C_δ?H amination of unactivated, secondary C?H bonds to form a broad range of functionalized pyrrolidines has been developed by a triiodide (I₃^?)‐mediated strategy. By in situ 1) oxidation of sodium iodide and 2) sequestration of the transiently generated iodine (I₂) as I₃^?, this approach precludes undesired I₂‐mediated decomposition which can otherwise limit synthetic utility to only weak C(sp³)?H bonds. The mechanism of this triiodide‐mediated cyclization of unbiased, secondary C(sp³)?H bonds, by either thermal or photolytic initiation, is supported by NMR and UV/Vis data, as well as intercepted intermediates.     

α‐Aminoxy‐Acid‐Auxiliary‐Enabled Intermolecular Radical γ‐C(sp3)−H Functionalization of Ketones

A method for site‐specific intermolecular γ‐C(sp³)?H functionalization of ketones has been developed using an α‐aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5‐hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C‐radicals thus formed at the γ‐position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding γ‐functionalized ketones.     

Multiple Catalytic C−H Bond Functionalization for Natural Product Synthesis

In the past decade, multiple catalytic C?H bond functionalization has been successfully applied in natural product synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This minireview presents selected examples making use of multiple C?H bond functionalization in conceptually different ways. First, linear syntheses are discussed, wherein multiple C?H functionalization is employed either from simple (hetero)cyclic cores, at a late stage, or to build polycyclic systems. Second, the use of multiple C?H functionalization as a strategic tool in convergent synthesis to access and couple complex fragments is discussed. Information on the scalability of the employed methods is provided when available. The presented cases indicate that multiple C?H functionalization strategies should play a great role to shape the future synthesis of functional complex molecules with improved sustainability.     

CH Functionalization of Phenols Using Combined Ruthenium and Photoredox Catalysis: In Situ Generation of the Oxidant

A combination of ruthenium and photoredox catalysis allowed the ortho olefination of phenols. Using visible light, the direct C? H functionalization of o‐(2‐pyridyl)phenols occurred, and diverse phenol ethers were obtained in good yields. The regeneration of the ruthenium catalyst was accomplished by a photoredox‐catalyzed oxidative process.     

Metal‐ and Oxidant‐Free Alkenyl C−H/Aromatic C−H Cross‐Coupling Using Electrochemically Generated Iodosulfonium Ions

A three‐step transformation consisting of 1) addition of electrochemically generated iodosulfonium ions to vinylarenes to give (1‐aryl‐2‐iodoethoxy)sulfonium ions, 2) nucleophilic substitution by subsequently added aromatic compounds to give 1,1‐diaryl‐2‐iodoethane, and 3) elimination of HI with a base to give 1,1‐diarylethenes was developed. The transformation serves as a powerful metal‐ and chemical‐oxidant‐free method for alkenyl C?H/aromatic C?H cross‐coupling.     

C−H Functionalization of Commodity Polymers

Synthetic manipulation of polymer substrates is one of the oldest and most reliable methods to increase the functional diversity of soft materials. Modifying the chemical structure of polymers that are already produced on a commodity scale leverages the current high‐volume and low‐cost production of commodity plastics for the discovery of modern materials. A myriad of polymer C?H functionalization methods have been developed which enable the modification of material properties on both a laboratory and industrial scale. More recently, driven by advances in C?H activation, photoredox catalysis, and radical chemistry, chemoselective approaches have emerged as a means to impart precise functionality onto commodity polymer substrates. This Review discusses the historical significance of and contemporary advances in the C?H functionalization of commodity polymers. The conceptual approach outlined herein presents exciting new directions for the field, including increasing the value of otherwise pervasive materials, uncovering entirely new material properties, and a viable path to upcycle post‐consumer plastic waste.     

A General Approach to Site‐Specific,Intramolecular C−H Functionalization Using Dithiocarbamates

Intramolecular hydrogen atom transfer is an established approach for the site‐specific functionalization of unactivated, aliphatic C?H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C?H halogenations or intramolecular aminations. Herein, we report a site‐specific C?H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N‐dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.     

Generation of Alkoxyl Radicals by Photoredox Catalysis Enables Selective C(sp3)−H Functionalization under Mild Reaction Conditions

Reported herein is the first visible‐light‐induced formation of alkoxyl radicals from N‐alkoxyphthalimides, and the Hantzsch ester as the reductant is crucial for the reaction. The selective hydrogen atom abstraction by the alkoxyl radical enables C(sp³)?H allylation and alkenylation reactions under mild reaction conditions at room temperature. Broad substrate variations, including a structurally complexed steroid, undergo the C(sp³)?H functionalization reaction effectively with high regio‐ and chemoselectivity.     

Eosin Y as a Direct Hydrogen‐Atom Transfer Photocatalyst for the Functionalization of C−H Bonds

Eosin Y, a well‐known economical alternative to metal catalysts in visible‐light‐driven single‐electron transfer‐based organic transformations, can behave as an effective direct hydrogen‐atom transfer catalyst for C?H activation. Using the alkylation of C?H bonds with electron‐deficient alkenes as a model study revealed an extremely broad substrate scope, enabling easy access to a variety of important synthons. This eosin Y‐based photocatalytic hydrogen‐atom transfer strategy is promising for diverse functionalization of a wide range of native C?H bonds in a green and sustainable manner.     

Late‐Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis

The direct C? H functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible‐light photoredox catalysis to achieve the direct methyl‐, ethyl‐, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.     

N‐Centered Radical Directed Remote C−H Bond Functionalization via Hydrogen Atom Transfer

The N‐centered radical directed remote C?H bond functionalization via hydrogen‐atom‐transfer at distant sites has developed as an enormous potential tool for the organic synthetic chemists. Unactivated and remote secondary and tertiary, as well as selected primary C?H bonds, can be utilized for functionalization by following these methodologies. The synthesis of the heterocyclic scaffolds provides them extra attention for the modern days′ developments in this field of unactivated remote C?H bonds functionalizations.     

Site‐Selective Remote Radical C−H Functionalization of Unactivated C−H Bonds in Amides Using Sulfone Reagents

A general and practical strategy for remote site‐selective functionalization of unactivated aliphatic C?H bonds in various amides by radical chemistry is introduced. C?H bond functionalization is achieved by using the readily installed N‐allylsulfonyl moiety as an N‐radical precursor. The in situ generated N‐radical engages in intramolecular 1,5‐hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C?H functionalized amides. The generality of the approach is documented by the successful remote C?N₃, C?Cl, C?Br, C?SCF₃, C?SPh, and C?C bond formation. Unactivated tertiary and secondary C?H bonds, as well as activated primary C?H bonds, can be readily functionalized by this method.     

Oxidation‐Induced C—H Functionalization: A Formal Way for C—H Activation

Cross‐coupling reactions have developed widely and provided a powerful means to synthesize a variety of compounds in each chemical field. The compounds which have C—H bonds are widespread in fossil fuels, chemical raw materials, biologically active molecules, etc. Using these readily‐ available substances as substrates is high atom‐ and step‐economy for cross‐coupling reactions. Over the past decades, our research group focused on finding and developing new strategies for C—H functionalization. Compared with classical C—H activation methods, for example, C—H bonds are deprotonated by strong base or converted into C—M bonds, oxidation‐induced C—H functionalization would be another pathway for C—H bond activation. This perspective shows a brief introduction of our recent works in this oxidation‐induced C—H functionalization. We categorized this approach of these C—H bond activations by the key intermediates, radical cations, radicals and cations.     

Tryptamine Synthesis by Iron Porphyrin Catalyzed C−H Functionalization of Indoles with Diazoacetonitrile

The functionalization of C?H bonds with non‐precious metal catalysts is an important research area for the development of efficient and sustainable processes. Herein, we describe the development of iron porphyrin catalyzed reactions of diazoacetonitrile with N‐heterocycles yielding important precursors of tryptamines, along with experimental mechanistic studies and proof‐of‐concept studies of an enzymatic process with YfeX enzyme. By using readily available FeTPPCl, we achieved the highly efficient C?H functionalization of indole and indazole heterocycles. These transformations feature mild reaction conditions, excellent yields with broad functional group tolerance, can be conducted on gram scale, and thus provide a unique streamlined access to tryptamines.