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.

The transition-metal-catalyzed addition of C–H bonds to carbonyls, imines, and related polarized π bonds has emerged as a particularly efficient and powerful approach for the construction of an incredibly diverse array of heteroatom-substituted products. Readily available and stable inputs are typically employed, and reactions often proceed with very high functional group compatibility and without the production of waste byproducts. Additionally, many transition-metal-catalyzed C–H bond additions to polarized π bonds occur within cascade reaction sequences to provide rapid access to a diverse array of different heterocyclic as well as carbocyclic products. This review highlights the diversity of transformations that have been achieved, catalysts that have been used, and types of products that have been prepared through the transition-metal-catalyzed addition of C–H bonds to carbonyls, imines, and related polarized π bonds.

Transition-Metal-Catalyzed C–H Bond Addition to Carbonyls, Imines, and Related Polarized π Bonds

Formal [4+1] Annulation Reactions in the Synthesis of Carbocyclic and Heterocyclic Systems

Rh(III)-catalyzed C–H activation assisted by an oxidizing directing group has evolved to a mild and redox-economic strategy for the construction of heterocycles. Despite the success, these coupling systems are currently limited to cleavage of an oxidizing N–O or N–N bond. Cleavage of an oxidizing C–N bond, which allows for complementary carbocycle synthesis, is unprecedented. In this article, α-ammonium acetophenones with an oxidizing C–N bond have been designed as substrates for Rh(III)-catalyzed C–H activation under redox-neutral conditions. The coupling with α-diazo esters afforded benzocyclopentanones, and the coupling with unactivated alkenes such as styrenes and aliphatic olefins gave ortho-olefinated acetophenoes. In both systems the reactions proceeded with a broad scope, high efficiency, and functional group tolerance. Moreover, efficient one-pot coupling of diazo esters has been realized starting from α-bromoacetophenones and triethylamine. The reaction mechanism for the coupling with diazo este...

Rhodium-catalyzed C-H activation of phenacyl ammonium salts assisted by an oxidizing C-N bond: a combination of experimental and theoretical studies.

Transition metal-catalyzed direct C–H functionalization has drawn great attention in the past several decades owing to its advantages compared to conventional organic transformations, including higher atom-, step- and cost-economy and the avoidance of tedious prefunctionalization and waste emission. At the current stage, to make the C–H functionalization more applicable, chemists have devoted themselves to expanding the substrate and reaction scope. In the past decade, we exerted ourselves to develop new transformations based on direct C–H functionalization. In this minireview we report on our recent achievements on the addition of C–H bonds to carbonyls and imines. The addition of organometallic reagents, such as Grignard reagents, toward carbon–heteroatom double bonds is one of the most powerful reactions in organic synthesis to produce secondary and tertiary alcohols and amines. This chemistry is broadly used in both laboratory and industry. However, this powerful transformation suffers from some drawbacks: (1) the preparation of initial organohalides from easily available fossil feedstocks is tedious and sluggish; (2) substantial amounts of metal halide salts are emitted as waste; (3) last but not least, the manipulation of organometallic reagents is complicated due to their sensitivity to air and moisture. In contrast, direct insertion of polar double bonds to C–H bonds via transition-metal catalysis is ideal from the viewpoint of atom-, step- and cost-economy and the avoidance of the waste emission, as well as of the complex manipulation of sensitive reagents. Starting from this point, we made a commitment to this project years ago and have made credible achievements in this field. We first carried out Ir-catalyzed addition of pyridinyl C–H bonds to aldehydes promoted by silane, showing an unusual C-3 selectivity. Later on, we developed Rh-catalyzed addition of aryl C–H bonds with aldimines in the absence of any additives with directing strategy with highest atom- and step-economy. The mechanism was investigated in depth by the isolation of key intermediates and systematic thermodynamic and kinetic studies. Such a concept was expanded to the coupling of aryl/alkenyl C–H bonds with aldehydes and imines. Notably, a tandem process of relayed C–H activation/alkyne insertion/cyclization between benzoates/benzimide and alkynes was developed, indicating the potential of the direct coupling of esters and amides with C–H bonds. Ideally, this strategy opens a new window to approach the ideal reactions to produce amines and alcohols from hydrocarbons.

Transition metal-catalyzed direct nucleophilic addition of C–H bonds to carbon–heteroatom double bonds

Cascade reactions are a powerful route to rapidly increase molecular complexity Here, the authors show how a C–H activation step can lead to intermediates capable of partaking in cascade reactions, giving easy access to a number of heterocyclic products

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A multitasking functional group leads to structural diversity using designer C–H activation reaction cascades

We report a palladium-catalyzed intermolecular [4 + 1] annulation pathway for N-phenoxyacetamides with aldehydes to form 1,2-benzisoxazoles. By activating the C–H bonds ortho to phenol-derived O–N bonds, the method enables the simultaneous construction of C–C and CN bonds in 1,2-benzisoxazoles with the O–N bonds intact. The method has been successfully applied to the synthesis of active pharmaceutical intermediates, such as risperidone.

Dongqi Wang

Papers

A multitasking functional group leads to structural diversity using designer C–H activation reaction cascades

Palladium-catalyzed benzo[d]isoxazole synthesis by C–H activation/[4 + 1] annulation

Palladium-Catalyzed Benzo[d]isoxazole Synthesis by C—H Activation/[4 + 1] Annulation.