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.     

Direct Cross‐Coupling of Allylic C(sp3)−H Bonds with Aryl‐ and Vinylbromides by Combined Nickel and Visible‐Light Catalysis

An efficient protocol for the direct allylic C(sp³)?H bond activation of unactivated tri‐ and tetrasubstituted alkenes and their functionalization with aryl‐ and vinylbromides by nickel and visible‐light photocatalysis has been developed. The method allows C(sp²)?C(sp³) formation under mild reaction conditions with good functional‐group tolerance and excellent regioselectivity.     

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.     

Iodine Catalysis for C(sp3)–H Fluorination with a Nucleophilic Fluorine Source

Iodine catalysis was developed for aliphatic fluorination through light‐promoted homolytic C?H bond cleavage. The intermediary formation of amidyl radicals enables selective C?H functionalization via carbon‐centered radicals. For the subsequent C?F bond formation, previous methods have typically been limited by a requirement for electrophilic fluorine reagents. We here demonstrate that the intermediary instalment of a carbon–iodine bond sets the stage for an umpolung, thereby establishing an unprecedented nucleophilic fluorination pathway.     

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.     

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.     

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.     

Steric Effect of Carboxylate Ligands on Pd‐Catalyzed Intramolecular C(sp2)–H and C(sp3)–H Arylation Reactions

A bulky carboxylic acid bearing three cyclohexylmethyl substituents at the α‐position, namely, tri(cyclohexylmethyl)acetic acid, is demonstrated to act as an efficient ligand source in Pd‐catalyzed intramolecular C(sp²)?H and C(sp³)?H arylation reactions. The reactions proceed smoothly under mild reaction conditions, even at room temperature due to the steric bulk of the carboxylate ligands, which accelerates the rate‐determining C?H bond activation step in the catalytic cycle.     

The Uranyl Cation as a Visible‐Light Photocatalyst for C(sp3)−H Fluorination

The fluorination of unactivated C(sp³)?H bonds remains a desirable and challenging transformation for pharmaceutical, agricultural, and materials scientists. Previous methods for this transformation have used bench‐stable fluorine atom sources; however, many still rely on the use of UV‐active photocatalysts for the requisite high‐energy hydrogen atom abstraction event. Uranyl nitrate hexahydrate is described as a convenient, hydrogen atom abstraction catalyst that can mediate fluorinations of certain alkanes upon activation with visible light.     

Ligand‐Enabled β‐Methylene C(sp3)−H Arylation of Masked Aliphatic Alcohols

Despite recent advances, reactivity and site‐selectivity remain significant obstacles for the practical application of C(sp³)?H bond functionalization methods. Here, we describe a system that combines a salicylic‐aldehyde‐derived L,X‐type directing group with an electron‐deficient 2‐pyridone ligand to enable the β‐methylene C(sp³)?H arylation of aliphatic alcohols, which has not been possible previously. Notably, this protocol is compatible with heterocycles embedded in both alcohol substrates and aryl coupling partners. A site‐ and stereo‐specific annulation of dihydrocholesterol and the synthesis of a key intermediate of englitazone illustrate the practicality of this method.     

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.     

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.     

NiH‐Catalyzed Reductive Relay Hydroalkylation: A Strategy for the Remote C(sp3)−H Alkylation of Alkenes

The terminal‐selective, remote C(sp³)?H alkylation of alkenes was achieved by a relay process combining NiH‐catalyzed hydrometalation, chain walking, and alkylation. This method enables the construction of unfunctionalized C(sp³)?C(sp³) bonds under mild conditions from two simple feedstock chemicals, namely olefins and alkyl halides. The practical value of this transformation is further demonstrated by the large‐scale and regioconvergent alkylation of isomeric mixtures of olefins at low catalyst loadings.     

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp3)−H Bond Activation

An original and recyclable chiral bidentate aniline‐sulfoxide‐based directing group has been developed. This auxiliary allows challenging stereoselective Pd‐catalyzed direct functionalization of small cycloalkanes through C–aryl and C–alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary. This strategy was further applied to the preparation of enantiomerically pure 1,2,3‐trisubstituted cyclopropane carboxylic acid derivatives, with three stereogenic centers and bearing both alkyl and aromatic substituents. These molecular scaffolds are not yet reported in the literature. The synthetic utility of this approach is validated by the chiral auxiliary being readily cleaved and recovered posteriori to the C?H activation step, without deterioration of its optical purity. Finally, an unprecedented palladacycle intermediate generated through C?H activation of the cyclopropane moiety has been isolated and fully characterized. Initial DFT calculations shed additional light on the reactivity of this original intermediate.     

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.     

Synthesis of Strained γ‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Alkenylation and Application to Alkaloid Synthesis

A variety of strained α‐alkylidene‐γ‐lactams were synthesized by palladium(0)‐catalyzed intramolecular C(sp³)?H alkenylation from easily accessible acyclic and monocyclic bromoalkene precursors. These lactams are valuable intermediates for accessing various classes of mono‐ and bicylic alkaloids containing a pyrrolidine ring, as illustrated with the synthesis of an advanced model of the marine natural product plakoridine A and of the indolizidine alkaloid δ‐coniceine.     

Ligand‐Enabled γ‐C(sp3)−H Olefination of Free Carboxylic Acids

We report the ligand‐enabled C?H activation/olefination of free carboxylic acids in the γ‐position. Through an intramolecular Michael addition, δ‐lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium‐catalyzed activation of free carboxylic acids in the γ‐position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.     

Ligand‐Enabled Enantioselective C –H Activation of Tetrahydroquinolines and Saturated Aza‐Heterocycles by RhI

The first rhodium(I)‐catalyzed enantioselective intermolecular C –H activation of various saturated aza‐heterocycles including tetrahydroquinolines, piperidines, piperazines, azetidines, pyrrolidines, and azepanes is presented. The combination of a rhodium(I) precatalyst and a chiral monodentate phosphonite ligand is shown to be a powerful catalytic system to access a variety of important enantio‐enriched heterocycles from simple starting materials. Notably, the C –H activation of tetrahydroquinolines is especially challenging due to the adjacent C −H bond. This redox‐neutral methodology provides a new synthetic route to α‐N‐arylated heterocycles with high chemoselectivity and enantioselectivity up to 97 % ee.     

Micellar Catalysis for Ruthenium(II)‐Catalyzed C−H Arylation: Weak‐Coordination‐Enabled C−H Activation in H2O

Chemoselective C?H arylations were accomplished through micellar catalysis by a versatile single‐component ruthenium catalyst. The strategy provided expedient access to C?H‐arylated ferrocenes with wide functional‐group tolerance and ample scope through weak chelation assistance. The sustainability of the C?H arylation was demonstrated by outstanding atom‐economy and recycling studies. Detailed computational studies provided support for a facile C?H activation through thioketone assistance.     

MnI/AgI Relay Catalysis: Traceless Diazo‐Assisted C(sp2)–H/C(sp3)–H Coupling to β‐(Hetero)Aryl/Alkenyl Ketones

An unprecedented Mn^I/Ag^I‐relay‐catalyzed C(sp²)?H/C(sp³)?H coupling of (vinyl)arenes with α‐diazoketones is reported, wherein the diazo group was exploited as a traceless auxiliary for control of regioselectivity. Challenging β‐(hetero)aryl/alkenyl ketones were obtained through this operationally simple approach. The cascade process merges denitrogenation, carbene rearrangement, C?H activation, and hydroarylation/hydroalkenylation. The robustness of this method was demonstrated at preparative scale and applied to late‐stage diversification of natural products.