Research and industrial interest in radical C–H activation/radical cross-coupling chemistry has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting molecular fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This Review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C–H activation. This Review includes radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M–R groups, and coupling of radical cations with nucleophiles (Nu).

Recent Advances in Radical C-H Activation/Radical Cross-Coupling.

This review, with over 600 references, summarizes the recent applications of photoredox catalysis for organic transformation and polymer synthesis. Photoredox catalysts are metallo- or organo-compounds capable of absorbing visible light, resulting in an excited state species. This excited state species can donate or accept an electron from other substrates to mediate redox reactions at ambient temperature with high atom efficiency. These catalysts have been successfully implemented for the discovery of novel organic reactions and synthesis of added-value chemicals with an excellent control of selectivity and stereo-regularity. More recently, such catalysts have been implemented by polymer chemists to post-modify polymers in high yields, as well as to effectively catalyze reversible deactivation radical polymerizations and living polymerizations. These catalysts create new approaches for advanced organic transformation and polymer synthesis. The objective of this review is to give an overview of this emerging field to organic and polymer chemists as well as materials scientists.

Photocatalysis in organic and polymer synthesis

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

Oxidative cross-coupling has proved to be one of the most straightforward strategies for forming carbon-carbon and carbon-heteroatom bonds from easily available precursors. Over the past two decades, tremendous efforts have been devoted in this field and significant advances have been achieved. However, in order to remove the surplus electrons from substrates for chemical bonds formation, stoichiometric oxidants are usually needed. Along with the development of modern sustainable chemistry, considerable efforts have been devoted to perform the oxidative cross-coupling reactions under external-oxidant-free conditions. Electrochemical synthesis is a powerful and environmentally benign approach, which can not only achieve the oxidative cross-couplings under external-oxidant-free conditions, but also release valuable hydrogen gas during the chemical bond formation. Recently, the electrochemical oxidative cross-coupling with hydrogen evolution reactions has been significantly explored. This Account presents our recent efforts toward the development of electrochemical oxidative cross-coupling with hydrogen evolution reactions. (1) We explored the oxidative cross-coupling of thiols/thiophenols with arenes, heteroarenes, and alkenes for C-S bond formation. (2) Using the strategy of electrochemical oxidative C-H/N-H cross-coupling with hydrogen evolution, we successfully realized the C-H amination of phenols, anilines, imidazopyridines, and even ethers. (3) Employing halide salts as the green halogenating reagents, we developed a clean C-H halogenation protocol under electrochemical oxidation conditions. To address the limitation that this reaction had to carry out in aqueous solvent, we also developed an alternative method that uses CBr4, CHBr3, CH2Br2, CCl3Br, and CCl4 as halogenating reagents and the mixture of acetonitrile and methanol as cosolvent. (4) We also developed an approach for constructing C-O bonds in a well-developed electrochemical oxidative cross-coupling with hydrogen evolution manner. (5) Under mild external-oxidant-free electrochemical conditions, we realized the C(sp2)-H and C(sp3)-H phosphonylation with modest to high yields. (6) We successfully achieved the S-H/S-H cross-coupling with hydrogen evolution under electrochemical oxidation conditions. By anodic oxidation instead of chemical oxidants, the overoxidation of thiols and thiophenols was well avoided. (7) The methods for constructing structurally diverse heterocyclic compounds were also developed via the electrochemical oxidative annulations. (8) We have also applied the electrochemical oxidative cross-coupling with hydrogen evolution strategy to the alkenes difunctionalization for constructing multiple bonds in one step, such as C-S/C-O bonds, C-S/C-N bonds, C-Se/C-O bonds, and C-Se/C-N bonds. We hope our studies will stimulate the research interest of chemists and pave the way for the discovery of more electrochemical oxidative cross-coupling with hydrogen evolution reactions.

Electrochemical Oxidative Cross-Coupling with Hydrogen Evolution Reactions

Radical-radical couplings are mostly nearly diffusion-controlled processes. Therefore, the selective cross-coupling of two different radicals is challenging and not a synthetically valuable transformation. However, if the radicals have different lifetimes and if they are generated at equal rates, cross-coupling will become the dominant process. This high cross-selectivity is based on a kinetic phenomenon called the persistent radical effect (PRE). In this Review, an explanation of the PRE supported by simulations of simple model systems is provided. Radical stabilities are discussed within the context of their lifetimes, and various examples of PRE-mediated radical-radical couplings in synthesis are summarized. It is shown that the PRE is not restricted to the coupling of a persistent with a transient radical. If one coupling partner is longer-lived than the other transient radical, the PRE operates and high cross-selectivity is achieved. This important point expands the scope of PRE-mediated radical chemistry. The Review is divided into two parts, namely 1) the coupling of persistent or longer-lived organic radicals and 2) "radical-metal crossover reactions"; here, metal-centered radical species and more generally longer-lived transition-metal complexes that are able to react with radicals are discussed-a field that has flourished recently.

The Persistent Radical Effect in Organic Synthesis

Oxindoles are an important class of heterocycles with unique biological activity that are found prevalently in numerous natural products and biologically active compounds. For these reasons, much attention has been given to the development of efficient methods for the preparation of such compounds. Traditionally, the practical approaches for the synthesis of oxindoles include the condensation of anilines with carbonyl compounds, such as diethyl ketomalonate, oxalyl chloride, or chloral hydrate, mediated by strong acids or bases. Recently, a step- and atom-economic C–H activation strategy was illustrated to access oxindoles through the difunctionalization of activated alkenes for these purposes. However, many of these transformations suffer from the cost of the transition-metal catalytic systems and/or limited substrate scope. In this review, we describe the recent studies of the difunctionalization of activated alkenes for the synthesis of diverse functionalized oxindoles that involves C–H oxidative radical coupling in the presence of an oxidant. These transformations are initiated either by the carbon radical resulting from the split of the carbon–hydrogen bond (1,2-dicarbofunctionalization) or by the carbon or heteroatom radical arising from the cleavage of the carbon–heteroatom (1,2-dicarbofunctionalization) or heteroatom–heteroatom bond (1,2-carboheterofunctionalization). Importantly, these C–H oxidative radical coupling transformations are generally performed with readily available oxidants and/or inexpensive iron or copper catalysts under neutral reaction conditions. 1 	Introduction 2 	Synthesis of Oxindoles via 1,2-Dicarbofunctionalization of Alkenes 2.1 	1,2-Alkylarylation 2.2 	1,2-Aryltrifluoromethylation 2.3 	1,2-Carbonylarylation 3 	Synthesis of Oxindoles via 1,2-Carboheterofunctionalization of Alkenes 3.1 	1,2-Azidoarylation or 1,2-Arylnitration 3.2 	1,2-Arylsulfonylation 3.2 	1,2-Arylphosphorylation 4 	Conclusion

/pdf/difunctionalization-of-acrylamides-through-c-h-oxidative-4m4zf9o72z.pdf

Difunctionalization of Acrylamides through C–H Oxidative Radical Coupling: New Approaches to Oxindoles

A new iron-facilitated silver-mediated radical 1,2-alkylarylation of styrenes with α-carbonyl alkyl bromides and indoles is described, and two new C-C bonds were generated in a single step through a sequence of intermolecular C(sp(3)-Br functionalization and C(sp(2))-H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

Functionalization of alkenes has been well investigated by chemists, thus it has been extensively applied in organic synthesis and industries. In the past few decades, transition-metal, such as palladium, rhodium, gold, iridium, copper and iron, catalyzed functionalization reactions of alkenes have been significantly developed and played vital roles in synthesis. The difunctionalization of alkenes are appealing as an important alternative to the traditional approaches for the construction of useful carbon centers, particularly carbon quaternary centers, which commonly existed as structural motifs in numerous natural products, pharmaceuticals, and biologically active molecules. This account will summarize our recent advances in the intermolecular difunctionalization of alkenes, and also highlight the scope and limitations as well as the mechanisms of these difunctionalization reactions. In general, in this account the difunctionalization of alkenes starting from dicarbofunctionalization will be discussed. Then carboheterofunctionalization of alkenes will be intensively reviewed, and diheterofunctionalization will also be highlighted.

Ren-Jie Song

Papers

Difunctionalization of Acrylamides through C–H Oxidative Radical Coupling: New Approaches to Oxindoles

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

Recent Advances in the Intermolecular Oxidative Difunctionalization of Alkenes

Synthesis of 3-alkyl spiro[4,5]trienones by copper-catalyzed oxidative ipso-annulation of activated alkynes with unactivated alkanes.

Intermolecular Anodic Oxidative Cross-Dehydrogenative C(sp3)-N Bond-Coupling Reactions of Xanthenes with Azoles.