Iron(II)‐Catalyzed Site‐Selective Functionalization of Unactivated C(sp3)−H Bonds Guided by Alkoxyl Radicals

An alkoxyl radical guided strategy for site‐selective functionalization of unactivated methylene and methine C?H bonds enabled by an Fe^II‐catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional‐group tolerance. The application for one‐pot 1,4‐hydroxyl functionalization of non‐oxygenated alkane substrates initiated by aerobic C?H oxygenation is also demonstrated.     

Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp3)−H and C(sp2)−H under Rhodium(III) Catalysis

Previous direct C?H nitrogenation suffered from simple amidation/amination with limited atom‐economy and is mostly limited to C(sp²)?H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp²)?H and C(sp³)?H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species.     

Intermolecular Amination of Unactivated C(sp3)−H Bonds with Cyclic Alkylamines: Formation of C(sp3)−N Bonds through Copper/Oxygen‐Mediated C(sp3)−H/N−H Activation

The first example of intermolecular amination of unactivated C(sp³)?H bonds by cyclic alkylamines mediated by Cu(OAc)₂/O₂ is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β^{2, 2}‐amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp³)?H/N?H activation for the formation of C(sp³)?N bonds.     

Rhodium‐Catalyzed C(sp2)‐ or C(sp3)−H Bond Functionalization Assisted by Removable Directing Groups

In recent years, transition‐metal‐catalyzed C?H activation has become a key strategy in the field of organic synthesis. Rhodium complexes are widely used as catalysts in a variety of C?H functionalization reactions because of their high reactivity and selectivity. The availability of a number of rhodium complexes in various oxidation states enables diverse reaction patterns to be obtained. Regioselectivity, an important issue in C?H activation chemistry, can be accomplished by using a directing group to assist the reaction. However, to obtain the target functionalized compounds, it is also necessary to use a directing group that can be easily removed. A wide range of directed C?H functionalization reactions catalyzed by rhodium complexes have been reported to date. In this Review, we discuss Rh‐catalyzed C?H functionalization reactions that are aided by the use of a removable directing group such as phenol, amine, aldehyde, ketones, ester, acid, sulfonic acid, and N‐heteroaromatic derivatives.     

C(sp3)−H Functionalizations Promoted by the Gold Carbene Generated from Vinylidenecyclopropanes

The gold carbene generated from vinylidenecyclopropanes (VDCPs) can smoothly perform a C(sp³)?H bond insertion reaction, stereoselectively affording the intramolecular C(sp³)?H bond functionalized product, benzoxepine, with syn‐configuration in moderate to good yields under mild conditions. The KIE investigation on this bond functionalization partially revealed that the carbene insertion step might be rate‐determining. Using a chiral gold(I) catalyst, the first example on the asymmetric variant of gold carbene insertion into C(sp³)?H bond has been disclosed, giving the desired products with excellent results.     

Iron‐Catalyzed Intramolecular Aminations of C(sp3)−H Bonds in Alkylaryl Azides

The nucleophilic iron complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of unactivated C(sp³)−H bonds in alkylaryl azides, which results in the formation of substituted indoline and tetrahydroquinoline derivatives.     

Directing Group Assisted Unsymmetrical Multiple Functionalization of Arene C−H Bonds

Multiple C?H bond functionalizations promptly install diverse groups on the molecular framework and consequently fabricate complex molecular entities. This review briefly surveys the conceptual development of directing group assisted unsymmetrical multiple functionalization of arene C(sp²)?H bonds, which is exceedingly appealing and highly important.     

Direct Acylation of C(sp3)−H Bonds Enabled by Nickel and Photoredox Catalysis

Using nickel and photoredox catalysis, the direct functionalization of C(sp³)?H bonds of N‐aryl amines by acyl electrophiles is described. The method affords a diverse range of α‐amino ketones at room temperature and is amenable to late‐stage coupling of complex and biologically relevant groups. C(sp³)?H activation occurs by photoredox‐mediated oxidation to generate α‐amino radicals which are intercepted by nickel in catalytic C(sp³)?C coupling. The merger of these two modes of catalysis leverages nickel's unique properties in alkyl cross‐coupling while avoiding limitations commonly associated with transition‐metal‐mediated C(sp³)?H activation, including requirements for chelating directing groups and high reaction temperatures.     

Tertiary‐Alcohol‐Directed Functionalization of Remote C(sp3)−H Bonds by Sequential Hydrogen Atom and Heteroaryl Migrations

Reported for the first time is a tertiary‐alcohol‐guided heteroarylation of remote C(sp³)?H bonds. The mild and direct generation of alkoxyl radicals from alcohols is enabled by visible‐light photocatalysis. A remote hydrogen atom and heteroaryl migration sequence are involved in the reaction. Many sensitive groups remain intact in the reaction, thus illustrating wide functional‐group compatibility. This protocol provides a practical strategy for the late‐stage modification of alkyl ketones.     

Metal-Free Phosphorus-Directed Borylation of C(sp2)−H Bonds

Spectacular progress has recently been achieved in transition metal-catalyzed C?H borylation of phosphines as well as directed electrophilic C?H borylation. As shown here, P-directed electrophilic borylation provides a new, straightforward, and efficient access to phosphine–boranes. It operates under metal-free conditions and leverages simple, readily available substrates. It is applicable to a broad range of backbones (naphthyl, biphenyl, N-phenylpyrrole, binaphthyl, benzyl, naphthylmethyl) and gives facile access to various substitution patterns at boron (by varying the boron electrophile or post-derivatizing the borane moiety). NMR monitoring supports the involvement of P-stabilized borenium cations as key intermediates. DFT calculations reveal the existence and stabilizing effect of π-arene/boron interactions in the (biphenyl)(i-Pr)₂P→BBr₂⁺ species.     

Stereoretentive Copper‐Catalyzed Directed Thioglycosylation of C(sp2)−H Bonds of Benzamides

An efficient thioglycosylation of C(sp²)?H bonds with thiosugars has been established for the first time. Using only Cu(OAc)₂?H₂O as a catalyst and Ag₂CO₃ as an additive in DMSO, the protocol proved to have broad scope, and a variety of complex thioglycosides have been prepared in good yields with exclusive β‐selectivity.     

Synergistic Heterobimetallic Manifold for Expedient Manganese(I)‐Catalyzed C−H Cyanation

The manganese‐catalyzed cyanation of inert C?H bonds was achieved within a heterobimetallic catalysis regime. The manganese(I) catalysis proved widely applicable and enabled C?H cyanations on indoles, pyrroles and thiophenes by facile C?H manganesation. The robustness of the manganese catalyst set the stage for the racemization‐free C?H cyanation of amino acids with excellent levels of positional and chemo selectivity by the new cyanating agent NCFS. Experimental and computational mechanistic studies provided strong support for a synergistic heterobimetallic activation mode, facilitating the key C?C formation.     

Selective Methylation of Arenes: A Radical C−H Functionalization/Cross‐Coupling Sequence

A selective, nonchelation‐assisted methylation of arenes has been developed. The overall transformation, which combines a C?H functionalization reaction with a nickel‐catalyzed cross‐coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late‐stage methylation of small‐molecule pharmaceuticals.     

Revealing Silylation of C(sp2)/C(sp3)–H Bonds in Arylphosphines by Ruthenium Catalysis

The first aromatic C?H silylation between arylphosphines and hydrosilanes enabled by a ruthenium complex has been developed. The excellent ortho‐selectivity results from a four‐membered metallacyclic intermediate involving phosphorus chelation. The developed system can be extended to the benzylic C?H silylation of arylphosphines. Diverse silylated arylphosphines are produced, exhibiting broad functional group compatibility. Further functionalization of the products under mild conditions renders the formed compounds useful building blocks.     

Mechanism of Nickel(II)‐Catalyzed Oxidative C(sp2)−H/C(sp3)−H Coupling of Benzamides and Toluene Derivatives

The Ni‐catalyzed C(sp²)?H/C(sp³)?H coupling of benzamides with toluene derivatives was recently successfully achieved with mild oxidant iC₃F₇I. Herein, we employ density functional theory (DFT) methods to resolve the mechanistic controversies. Two previously proposed mechanisms are excluded, and our proposed mechanism involving iodine‐atom transfer (IAT) between iC₃F₇I and the Ni^II intermediate was found to be more feasible. With this mechanism, the presence of a carbon radical is consistent with the experimental observation that (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) completely quenches the reaction. Meanwhile, the hydrogen‐atom abstraction of toluene is irreversible and the activation of the C(sp²)?H bond of benzamides is reversible. Both of these conclusions are in good agreement with Chatani's deuterium‐labeling experiments.     

N‐Heterocyclic Carbene Ligand‐Enabled C(sp3)−H Arylation of Piperidine and Tetrahydropyran Derivatives

Pd^II‐catalyzed C(sp³)?H arylation of saturated heterocycles with a wide range of aryl iodides is enabled by an N‐heterocyclic carbene (NHC) ligand. A C(sp³)?H insertion step by the Pd^II/NHC complex in the absence of ArI is demonstrated experimentally for the first time. Experimental data suggests that the previously established NHC‐mediated Pd⁰/Pd^II catalytic manifold does not operate in this reaction. This transformation provides a new approach for diversifying pharmaceutically relevant piperidine and tetrahydropyran ring systems.     

Enantioselective Formal C(sp2)−H Vinylation

An enantioselective formal C(sp²)?H vinylation of prochiral 2,2‐disubstituted cyclopentene‐1,3‐dione is presented. This vinylative desymmetrization is realized by using a two‐step procedure that consists of a catalytic enantioselective vinylogous Michael addition of deconjugated butenolides to cyclopentene‐1,3‐dione and a base‐mediated decarboxylation. The overall process utilizes deconjugated butenolides as the source of the highly substituted vinyl unit. Five‐membered carbocycles containing a remote all‐carbon quaternary stereogenic center are obtained in good yields and with good to high enantioselectivities.