Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

Cationic cobalt complexes enable unprecedented cobalt‐catalyzed C?H/C?C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C?H/C?C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.     

Rhodium(I)‐Catalyzed C−C Bond Activation of Siloxyvinylcyclopropanes with Diazoesters

The rhodium(I)‐catalyzed C?C bond activation reaction of siloxyvinylcyclopropanes with diazoesters demonstrates a novel mode of C?C bond cleavage of siloxyvinvylcyclopanes. The alkene products were obtained as single E‐configured isomers in good yields. A σ,η³‐allyl rhodium complex, which has been previously proposed as the key intermediate in rhodium(I)‐catalyzed cycloaddition of vinylcyclopropanes, has been isolated and characterized by X‐ray crystallography.     

Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

Transformations of Aryl Ketones via Ligand‐Promoted C−C Bond Activation

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon–carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon–carbon cleavage triggered by ring‐strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand‐promoted β‐carbon elimination strategy to activate the carbon–carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine‐oxazoline ligand is crucial for this catalytic transformation. A gram‐scale borylation reaction of an aryl ketone via a simple one‐pot operation is reported. The potential utility of this strategy is also demonstrated by the late‐stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.     

Transition Metal Catalyzed Coupling Reactions under C−H Activation

C−C coupling by transition metal catalyzed C−H activation has developed into a diverse area of research. The applicable catalysts are manifold, and the variety of products obtained range from basic chemicals to pharmaceuticals and building blocks for carbon networks. One reaction, in which several C−C bonds are formed under C−H activation of a methyl group, is the conversion of ortho-iodoanisole according to Equation (1).     

Direct Synthesis of Protoberberine Alkaloids by Rh‐Catalyzed C−H Bond Activation as the Key Step

A one‐pot reaction of substituted benzaldehydes with alkyne–amines by a Rh‐catalyzed C?H activation and annulation to afford various natural and unnatural protoberberine alkaloids is reported. This reaction provides a convenient route for the generation of a compound library of protoberberine salts, which recently have attracted great attention because of their diverse biological activities. In addition, pyridinium salt derivatives can also be formed in good yields from α,β‐unsaturated aldehydes and amino–alkynes. This reaction proceeds with excellent regioselectivity and good functional group compatibility under mild reaction conditions by using O₂ as the oxidant.     

Rhodium(I)‐Catalyzed Carboacylation/Aromatization Cascade Initiated by Regioselective C−C Activation of Benzocyclobutenones

Described here is the first example of a rhodium‐catalyzed carboacylation/aromatization cascade of a C=O bond by C?C activation. In this transformation, a reactive rhodaindanone complex is regioselectively generated and adds across a C=O bond with subsequent elimination, thus providing a unique strategy to access a multisubstituted benzofuran scaffold. A diverse range of benzofuran analogues were obtained in good yields. Mechanistic studies show a tricyclic lactone was a viable intermediate. Application of this methodology to the total synthesis of C13‐deOH‐viniferifuran and C13‐deOH‐diptoindonesin G was achieved.     

Transition‐Metal‐Mediated and ‐Catalyzed C−F Bond Activation by Fluorine Elimination

The activation of carbon–fluorine (C?F) bonds is an important topic in synthetic organic chemistry. Metal‐mediated and ‐catalyzed elimination of β‐ or α‐fluorine proceeds under milder conditions than oxidative addition to C?F bonds. The β‐ or α‐fluorine elimination is initiated from organometallic intermediates having fluorine substituents on carbon atoms β or α to metal centers, respectively. Transformations through these elimination processes (C?F bond cleavage), which are typically preceded by carbon–carbon (or carbon–heteroatom) bond formation, have been increasingly developed in the past five years as C?F bond activation methods. In this Minireview, we summarize the applications of transition‐metal‐mediated and ‐catalyzed fluorine elimination to synthetic organic chemistry from a historical perspective with early studies and from a systematic perspective with recent studies.     

Copper‐Catalyzed N−F Bond Activation for Uniform Intramolecular C−H Amination Yielding Pyrrolidines and Piperidines

The dual function of the N?F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C?H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio‐ and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N?F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.     

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N‐methoxy benzamides and α,α‐difluoromethylene alkynes is enabled by C?H activation with a chiral CpRh^III catalyst. Remarkably, product formation is solvent‐dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in ⁱPrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E‐configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z‐configured monofluoroalkene upon protonation in the ⁱPrCN system and into an alkyne by an unusual anti β‐F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z‐monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.     

Intramolecular Acetyl Transfer to Olefins by Catalytic C−C Bond Activation of Unstrained Ketones

A rhodium‐catalyzed intramolecular acetyl‐group transfer has been achieved through a “cut and sew” process. The challenge arises from the existence of different competitive pathways. Preliminary success has been achieved with unstrained enones that contain a biaryl linker. The use of an electron‐rich N‐heterocycilc carbene (NHC) ligand is effective to inhibit undesired β‐hydrogen elimination. Various 9,10‐dihydrophenanthrene derivatives can be prepared with excellent functional‐group compatibility. The ¹³C‐labelling study suggests that the reaction begins with cleavage of the unstrained C?C bond, followed by migratory insertion and reductive elimination.     

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

Palladium‐catalyzed regio‐ and diastereoselective C?H functionalization with bromoalkynes and electronically unbiased olefins is reported. The picolinamide directing group enables the formation of putative 5 and 6‐exo‐metallacycles as intermediates to afford monoalkynylated products in up to 91 % yield in a stereospecific fashion. The systematic study reveals that substrates with a wide range of substituents on the olefin and bromoalkyne coupling partners are tolerated. Chemoselective transformations were demonstrated for the obtained amides, olefins, and alkynes.     

Rhodium‐Catalyzed Enantioselective Silylation of Cyclopropyl C−H Bonds

Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C?H bonds in high yields and with high enantiomeric excesses in the presence of a rhodium catalyst derived from a rhodium precursor and the bisphosphine (S)‐DTBM‐SEGPHOS. The resulting enantioenriched oxasilolanes are suitable substrates for the Tamao–Fleming oxidation to form cyclopropanols with conservation of the ee value from the C?H silylation. Preliminary mechanistic data suggest that C?H cleavage is likely to be the turnover‐limiting and enantioselectivity‐determining step.     

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.     

Photoredox‐Catalyzed Isomerization of Highly Substituted Allylic Alcohols by C−H Bond Activation

Photoredox‐catalyzed isomerization of γ‐carbonyl‐substituted allylic alcohols to their corresponding carbonyl compounds was achieved for the first time by C?H bond activation. This catalytic redox‐neutral process resulted in the synthesis of 1,4‐dicarbonyl compounds. Notably, allylic alcohols bearing tetrasubstituted olefins can also be transformed into their corresponding carbonyl compounds. Density functional theory calculations show that the carbonyl group at the γ‐position of allylic alcohols are beneficial to the formation of their corresponding allylic alcohol radicals with high vertical electron affinity, which contributes to the completion of the photoredox catalytic cycle.     

Cobalt‐Catalyzed Cyclization of N‐Methoxy Benzamides with Alkynes using an Internal Oxidant through C−H/N−O Bond Activation

The cyclization of substituted N‐methoxy benzamides with alkynes in the presence of an easily affordable cobalt complex and NaOAc provides isoquinolone derivatives in good to excellent yields. The cyclization reaction is compatible with a range of functional group‐substituted benzamides, as well as ester‐ and alcohol‐substituted alkynes. The cobalt complex [Co^IIICp*(OR)₂] (R=Me or Ac) serves as an efficient catalyst for the cyclization reaction. Later, isoquinolone derivatives were converted into 1‐chloro and 1‐bromo substituted isoquinoline derivatives in excellent yields in the presence of POCl₃ or PBr₃.     

Rhodium(III)‐Catalyzed Redox‐Neutral Coupling of α‐Trifluoromethylacrylic Acid with Benzamides through Directed C−H Bond Cleavage

A rhodium(III)‐catalyzed redox‐neutral coupling of α‐trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide‐directed C?H bond cleavage to produce β‐[2‐(aminocarbonyl)phenyl]‐α‐trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox‐neutral coupling of α‐trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen‐containing directing group can also be conducted under similar conditions.     

Cooperative Lewis Acid/Cp*CoIII Catalyzed C−H Bond Activation for the Synthesis of Isoquinolin‐3‐ones

A facile route toward the synthesis of isoquinolin‐3‐ones through a cooperative B(C₆F₅)₃‐ and Cp*Co^III‐catalyzed C?H bond activation of imines with diazo compounds is presented. The inclusion of a catalytic amount of B(C₆F₅)₃ results in a highly efficient reaction, thus enabling unstable NH imines to serve as substrates.