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.     

Palladium(II)‐Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)−H Bonds Enabled by a 2‐Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

Enantioselective functionalizations of unbiased methylene C(sp³)?H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)‐catalyzed enantioselective arylation of unbiased methylene β‐C(sp³)?H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non‐C₂‐symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing β‐arylated aliphatic carboxylic acid derivatives in high yields (up to 96 %) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)‐catalyzed enantioselective C?H activation with less reactive and cost‐effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C?H palladation step.     

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.     

Cp*CoIII‐Catalyzed C(sp3)−H Bond Amidation of 8‐Methylquinoline

An efficient and external oxidant‐free, Cp*Co^III‐catalyzed C(sp³)?H bond amidation of 8‐methylquinoline, using oxazolone as an efficient amidating agent, is reported for the first time under mild conditions. The reaction is selective and tolerates a variety of functional groups. Based on previous reports and experimental results, the deprotonation pathway proceeds through an external base‐assisted concerted metalation and deprotonation process.     

Palladium‐Catalyzed Asymmetric C(sp3)−H Allylation of 2‐Alkylpyridines

The palladium‐catalyzed asymmetric side‐chain C(α)‐allylation of 2‐alkylpyridines, without using an external base, was developed. The high linear selectivities and enantioselectivities were achieved using new chiral diamidophosphite monodentate ligands. Given that the reaction conditions do not require an external base, this catalyst system enabled chemoselective C(α)‐allylation of 2‐alkylpyridines containing α‐carbonyl C?H bonds, which are more acidic than α‐pyridyl C?H bonds.     

Ruthenium(II)‐Catalyzed Asymmetric Inert C−H Bond Activation Assisted by a Chiral Transient Directing Group

A ruthenium(II)‐catalyzed asymmetric intramolecular hydroarylation assisted by a chiral transient directing group has been developed. A series of 2,3‐dihydrobenzofurans bearing chiral all‐carbon quaternary stereocenters have been prepared in remarkably high yields (up to 98 %) and enantioselectivities (up to >99 % ee). By this methodology, a novel asymmetric total synthesis of CB2 receptor agonist MDA7 has been successfully developed.     

Rhodium(I)‐Catalyzed Cycloisomerization of Homopropargylallene‐Alkynes through C(sp3)−C(sp) Bond Activation

Upon exposure to a catalytic amount of [RhCl(CO)₂]₂ in 1,4‐dioxane, homopropargylallene‐alkynes underwent a novel cycloisomerization accompanied by the migration of the alkyne moiety of the homopropargyl functional group to produce six/five/five tricyclic compounds in good yields. A plausible mechanism was proposed on the basis of an experiment with ¹³C‐labeled substrate. The resulting tricyclic derivatives were further converted into the corresponding bicyclo[3.3.0] skeletons with vicinal cis dihydroxy groups.     

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.     

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.     

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.     

Hybrid Palladium Catalyst Assembled from Chiral Phosphoric Acid and Thioamide for Enantioselective β‐C(sp3)−H Arylation

A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β‐C(sp³)?H functionalization of thioamides (up to 99 % yield, 97 % ee). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp³)?H arylation can be achieved with high s‐factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.     

Rhodium-Catalyzed Atroposelective Access to Axially Chiral Olefins via C−H Bond Activation and Directing Group Migration

Axially chiral open-chain olefins represent an underexplored class of chiral platform. In this report, two classes of tetrasubstituted axially chiral acyclic olefins have been accessed in excellent enantioselectivity and regioselectivity via C?H activation of (hetero)arenes assisted by a migratable directing group en route to coupling with sterically hindered alkynes. The coupling of indoles bearing an N-aminocarbonyl directing group afforded C–N axially chiral acrylamides with the assistance of a racemic zinc carboxylate additive. DFT studies suggest a β-nitrogen elimination–reinsertion pathway for the directing group migration. Meanwhile, the employment of N-phenoxycarboxamide delivered C?C axially chiral enamides via migration of the oxidizing directing group. Experiments suggest that in both cases the (hetero)arene substrate adopts a well-defined orientation during the C?H activation, which in turn determines the disposition of the alkyne in migratory insertion. Synthetic applications of representative chiral olefins are demonstrated.     

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.     

Chiral N‐Heterocyclic Carbene Ligands Enable Asymmetric C−H Bond Functionalization

The asymmetric functionalization of C?H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral N‐heterocyclic carbene (NHC) ligands have become ubiquitous in enantioselective transition‐metal catalysis. Conversely, the use of chiral NHC ligands in metal‐catalyzed asymmetric C?H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.     

Rhodium‐Catalyzed Remote C(sp3)−H Borylation of Silyl Enol Ethers

A rhodium‐catalyzed remote C(sp³)?H borylation of silyl enol ethers (SEEs, E/Z mixtures) by alkene isomerization and hydroboration is reported. The reaction exhibits mild reaction conditions and excellent functional‐group tolerance. This method is compatible with an array of SEEs, including linear and branched SEEs derived from aldehydes and ketones, and provides direct access to a broad range of structurally diverse 1,n‐borylethers in excellent regioselectivities and good yields. These compounds are precursors to various valuable chemicals, such as 1,n‐diols and aminoalcohols.     

Continuous‐Flow Synthesis and Derivatization of Aziridines through Palladium‐Catalyzed C(sp3)−H Activation

A continuous‐flow synthesis of aziridines by palladium‐catalyzed C(sp³)?H activation is described. The new flow reaction could be combined with an aziridine‐ring‐opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C?H activation flow process and illustrates an approach towards first‐principles design based on novel catalytic reactions.     

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.     

Revealing the A‐Site Effect of Lead‐Free A3Sb2Br9 Perovskite in Photocatalytic C(sp3)−H Bond Activation

The lead‐free halide perovskite A₃Sb₂Br₉ is utilized as a photocatalyst for the first time for C(sp³)?H bond activation. A₃Sb₂Br₉ nanoparticles (A₃Sb₂Br₉ NPs) with different ratios of Cs and CH₃NH₃ (MA) show different photocatalytic activities for toluene oxidation and the photocatalytic performance is enhanced when increasing the amount of Cs. The octahedron distortion caused by A‐site cations can change the electronic properties of X‐site ions and further affect the electron transfer from toluene molecules to Br sites. After the regulation of A‐site cations, the photocatalytic activity is higher with A₃Sb₂Br₉ NPs than that with classic photocatalysts (TiO₂, WO₃, and CdS). The main active species involved in photocatalytic oxidation of toluene are photogenerated holes (h⁺) and superoxide anions (^.O₂^?). The octahedron distortion by A‐site cations affecting photocatalytic activity remains unique and is also a step forward for understanding more about halide‐perovskite‐based photocatalysis. The relationship between octahedron distortion and photocatalysis can also guide the design of new photocatalytic systems involving other halide perovskites.     

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.