Organic reactions that involve the direct functionalization of non-activated C–H bonds represent an attractive class of transformations which maximize atom- and step-economy, and simplify chemical synthesis. Due to the high stability of C–H bonds, these processes, however, have most often required harsh reaction conditions, which has drastically limited their use as tools for the synthesis of complex organic molecules. Following the increased understanding of mechanistic aspects of C–H activation gained over recent years, great strides have been taken to design and develop new protocols that proceed efficiently under mild conditions and duly benefit from improved functional group tolerance and selectivity. In this review, we present the current state of the art in this field and detail C–H activation transformations reported since 2011 that proceed either at or below ambient temperature, in the absence of strongly acidic or basic additives or without strong oxidants. Furthermore, by identifying and discussing the major strategies that have led to these improvements, we hope that this review will serve as a useful conceptual overview and inspire the next generation of mild C–H transformations.

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Mild metal-catalyzed C–H activation: examples and concepts

The preparation, structure, and chemistry of hypervalent iodine compounds are reviewed with emphasis on their synthetic application. Compounds of iodine possess reactivity similar to that of transition metals, but have the advantage of environmental sustainability and efficient utilization of natural resources. These compounds are widely used in organic synthesis as selective oxidants and environmentally friendly reagents. Synthetic uses of hypervalent iodine reagents in halogenation reactions, various oxidations, rearrangements, aminations, C–C bond-forming reactions, and transition metal-catalyzed reactions are summarized and discussed. Recent discovery of hypervalent catalytic systems and recyclable reagents, and the development of new enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important achievement in the field of hypervalent iodine chemistry. One of the goals of this Review is to attract the attention of the scientific community as to the benefits of...

Advances in Synthetic Applications of Hypervalent Iodine Compounds

The high utility of halogenated organic compounds has prompted the development of a vast number of transformations which install the carbon–halogen motif. Traditional routes to these building blocks have commonly involved multiple steps, harsh reaction conditions, and the use of stoichiometric and/or toxic reagents. In this regard, using transition metals to catalyze the synthesis of organohalides has become a mature field in itself, and applying these technologies has allowed for a decrease in the production of waste, higher levels of regio- and stereoselectivity, and the ability to produce enantioenriched target compounds. Furthermore, transition metals offer the distinct advantage of possessing a diverse spectrum of mechanistic possibilities which translate to the capability to apply new substrate classes and afford novel and difficult-to-access structures. This Review provides comprehensive coverage of modern transition metal-catalyzed syntheses of organohalides via a diverse array of mechanisms. Atte...

Modern Transition-Metal-Catalyzed Carbon–Halogen Bond Formation

A palladium-catalyzed intramolecular oxidative aryltrifluoromethylation reaction of activated alkenes has been explored. The reaction allows for an efficient synthesis of a variety of CF(3)-containing oxindoles. Preliminary mechanistic study indicated that the reaction involves a C(sp(3))-Pd(IV)(CF(3)) intermediate, which undergoes reductive elimination to afford a C(sp(3))-CF(3) bond.

Palladium-catalyzed oxidative aryltrifluoromethylation of activated alkenes at room temperature.

The exponential increase in the number of catalytic transformations that involve a metal-promoted activation of hitherto considered inert C−H bonds is promoting a fundamental change in the field of synthetic chemistry. Although most reactions involving C−H activations consist of simple functionalizations or additions, recent years have witnessed an upsurge in related transformations that can be formally considered as cycloaddition processes. These transformations are particularly appealing from a synthetic perspective because they allow the conversion of readily available substrates into highly valuable cyclic products in a rapid and sustainable manner. In many cases, these annulations involve the formation of metallacyclic intermediates that resemble those proposed for standard metal-catalyzed cycloadditions of unsaturated precursors.

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Metal-Catalyzed Annulations through Activation and Cleavage of C-H Bonds.

Palladium-catalyzed carbo-heterofunctionalization of alkenes for the synthesis of oxindoles and spirooxindoles.

Heck shortens the distance. Palladium-catalyzed activation of C(sp3)-H bond by a σ-alkyl Pd(II) complex generated in situ from a remote arylhalide function is developed. The novel domino carbopalladation/C(sp3)-C(sp3) bond forming process allowed a rapid access to biologically relevant spirooxindoles.

Activation of a C(sp3)-H bond by a transient σ-alkylpalladium(II) complex: synthesis of spirooxindoles through a palladium-catalyzed domino carbopalladation/C(sp3)-C(sp3) bond-forming process.

Palladium two step: Linear anilides were converted into the title compounds in good to excellent yields through a palladium-catalyzed domino carbopalladation/1,4-palladium shift sequence. The C(sp(3) )-H activation involves a seven-membered palladacycle, and is chemoselective in the presence of competitive C(sp(2) )H bonds. DMA=N,N-dimethylacetamide, OPiv=pivalate.

Palladium-Catalyzed Through-Space C(sp3)H and C(sp2)H Bond Activation by 1,4-Palladium Migration: Efficient Synthesis of [3,4]-Fused Oxindoles†

N-Enoxyphthalimides undergo a Rh(III)-catalyzed C–H activation initiated cyclopropanation of electron deficient alkenes. The reaction is proposed to proceed via a directed activation of the olefinic C–H bond followed by two migratory insertions, first across the electron-deficient alkene and then by cyclization back onto the enol moiety. A newly designed isopropylcyclopentadienyl ligand drastically improves yield and diastereoselectivity.

https://pubs.acs.org/doi/pdf/10.1021/ja506579t

Rh(III)-Catalyzed Cyclopropanation Initiated by C–H Activation: Ligand Development Enables a Diastereoselective [2 + 1] Annulation of N-Enoxyphthalimides and Alkenes

Tiffany Piou

Papers

Palladium-catalyzed carbo-heterofunctionalization of alkenes for the synthesis of oxindoles and spirooxindoles.

Activation of a C(sp3)-H bond by a transient σ-alkylpalladium(II) complex: synthesis of spirooxindoles through a palladium-catalyzed domino carbopalladation/C(sp3)-C(sp3) bond-forming process.

Palladium-Catalyzed Through-Space C(sp3)H and C(sp2)H Bond Activation by 1,4-Palladium Migration: Efficient Synthesis of [3,4]-Fused Oxindoles†

Rh(III)-Catalyzed Cyclopropanation Initiated by C–H Activation: Ligand Development Enables a Diastereoselective [2 + 1] Annulation of N-Enoxyphthalimides and Alkenes

Iodo-carbocyclization of electron-deficient alkenes: synthesis of oxindoles and spirooxindoles.