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.     

Mechanical C−C Bond Formation by Laser Driven Shock Wave

Mechanically induced C−C bond formation was demonstrated by the laser driven shock wave generated in liquid normal alkanes at room temperature. Gas chromatography mass spectrometry analysis revealed the dehydrogenation condensation between two alkane molecules, for seven normal alkanes from pentane to undecane. Major products were identified to be linear and branched alkane molecules with double the number of carbons, and exactly coincided with the molecules predicted by supposing that a C−C bond was formed between two starting molecules. The production of the alkane molecules showed that the C−C bond formation occurred almost evenly at all the carbon positions. The dependence of the production on the laser pulse energy clearly indicated that the process was attributed to the shock wave. The C−C bond formation observed was not a conventional passive chemical reaction but an unprecedented active reaction.     

Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling Involving C−O Bond Activation

An efficient Suzuki-Miyaura cross-coupling reaction of ortho-phenoxy-substituted aromatic amides with aryl boronates is described. The use of LiO^tBu is crucial for the success of the reaction. An amidate anion, which is formed through deprotonation of the amide NH bond by LiO^tBu, functions as a directing group to activate a C−O bond.     

Synthetic Advantages of Defluorinative C−F Bond Functionalization

Much progress has been made in the development of methods to both create compounds that contain C−F bonds and to functionalize C−F bonds. As such, C−F bonds are becoming common and versatile synthetic functional handles. This review summarizes the advantages of defluorinative functionalization reactions for small molecule synthesis. The coverage is organized by the type of carbon framework the fluorine is attached to for mono- and polyfluorinated motifs. The main challenges, opportunities and advances of defluorinative functionalization are discussed for each class of organofluorine. Most of the text focuses on case studies that illustrate how defluorofunctionalization can improve routes to synthetic targets or how the properties of C−F bonds enable unique mechanisms and reactions. The broader goal is to showcase the opportunities for incorporating and exploiting C−F bonds in the design of synthetic routes, improvement of specific reactions and advent of new methods.     

Homolytic C−H Bond Activation by Phosphine−Quinone-Based Radical Ion Pairs

Herein, we present the formation of transient radical ion pairs (RIPs) by single-electron transfer (SET) in phosphine−quinone systems and explore their potential for the activation of C−H bonds. PMes₃ (Mes=2,4,6-Me₃C₆H₂) reacts with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) with formation of the P−O bonded zwitterionic adduct Mes₃P−DDQ ( 1 ), while the reaction with the sterically more crowded PTip₃ (Tip=2,4,6-iPr₃C₆H₂) afforded C−H bond activation product Tip₂P(H)(2-[CMe₂(DDQ)]-4,6-iPr₂-C₆H₂) ( 2 ). UV/Vis and EPR spectroscopic studies showed that the latter reaction proceeds via initial SET, forming RIP [PTip₃]⋅⁺[DDQ]⋅⁻, and subsequent homolytic C−H bond activation, which was supported by DFT calculations. The isolation of analogous products, Tip₂P(H)(2-[CMe₂{TCQ−B(C₆F₅)₃}]-4,6-iPr₂-C₆H₂) ( 4 , TCQ=tetrachloro-1,4-benzoquinone) and Tip₂P(H)(2-[CMe₂{oQ^tBu−B(C₆F₅)₃}]-4,6-iPr₂-C₆H₂) ( 8 , oQ^tBu=3,5-di-tert-butyl-1,2-benzoquinone), from reactions of PTip₃ with Lewis-acid activated quinones, TCQ−B(C₆F₅)₃ and oQ^tBu−B(C₆F₅)₃, respectively, further supports the proposed radical mechanism. As such, this study presents key mechanistic insights into the homolytic C−H bond activation by the synergistic action of radical ion pairs.     

Stereoselective Palladium-Catalyzed C−F Bond Alkynylation of Tetrasubstituted gem-Difluoroalkenes

A stereoselective Pd(PPh₃)₄-catalyzed C−F bond alkynylation of tetrasubstituted gem-difluoroalkenes with terminal alkynes has been developed. This method gives access to a great variety of conjugated monofluoroenynes bearing a tetrasubstituted alkene moiety with well-defined stereochemistry. Chelation-assisted oxidative addition of Pd to the C−F bond is proposed to account for the high level of stereocontrol. An X-ray crystal structure of a key monofluorovinyl Pd^II intermediate has been obtained for the first time as evidence for the proposed mechanism.     

Cyclopentadienyl Complexes of IrIII for Attempted C−D Bond Activation

The complexes Cp(MeIm)IrI₂ and Cp^Me4(MeIm)IrCl₂ have been prepared and subsequently methylated to form Cp(MeIm)IrMe₂ and Cp^Me4(MeIm)IrMe₂ (Cp=η⁵-C₅H₅, Cp^Me4=η⁵-C₅HMe₄, MeIm=1,3-dimethylimidazol-2-ylidene). We attempted unsuccessfully to use the dimethyl complexes to study C−D bond activation via methyl-group abstraction. Protonation with one equivalent of a weak acid, such as 2,6-dimethylpyridinium chloride, affords methane and Ir^III methyl chloride complexes. ¹H-NMR experiments show addition of pyridinium [BArF₂₀]⁻ (BArF₂₀=[B(C₆F₅)₄]⁻) to the dimethyl species forms [Cp(MeIm)IrMe(py)]⁺[BArF₂₀]⁻ (py=pyridine) or [Cp^Me4(MeIm)IrMe(py)]⁺[BArF₂₀]⁻ respectively, alongside methane, while use of the [BArF₂₀]⁻ salts of more bulky 2,6-dimethylpyridinium and 2,6-di-tert-butylpyridinium gave an intractable mixture. Likewise, the generation of 16 e⁻ species [Cp^Me4(MeIm)IrMe]⁺[BArF₂₀]⁻ or [Cp(MeIm)IrMe]⁺[BarF₂₀]⁻ at low temperature using 2,6-dimethylpyridinium or 2,6-di-tert-butylpyridinium in thawing C₆D₆ or toluene-d₈ formed an intractable mixture and did not lead to C−D bond activation. X-ray structures of several Ir^III complexes show similar sterics as that found for the previously reported Cp* analogue.     

Aerobic C−N Bond Formation through Enzymatic Nitroso-Ene-Type Reactions**

The biocatalytic oxidation of acylated hydroxylamines enables the direct and selective introduction of nitrogen functionalities by activation of allylic C−H bonds. Utilizing either laccases or an oxidase/peroxidase couple for the formal dehydrogenation of N-hydroxycarbamates and hydroxamic acids with air as the terminal oxidant, acylnitroso species are generated under particularly mild aqueous conditions. The reactive intermediates undergo C−N bond formation through an ene-type mechanism and provide high yields both in intramolecular and intermolecular enzymatic aminations. Investigations on different pathways of the two biocatalytic systems and labelling studies provide more insight into this unprecedented promiscuity of classical oxidoreductases as catalysts for nitroso-based transformations.     

RASS-Enabled S/P−C and S−N Bond Formation for DEL Synthesis

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C−S, C−P and N−S linkages into DELs, which are underrepresented in the canonical methods.     

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.     

An Efficient Direct Arylation Polycondensation via C−S Bond Cleavage

The direct arylation polycondensation (DArP) has become one of the most important methods to construct conjugated polymers (CPs). However, the homocoupling side-reactions of aryl halides and the low regioseletive reactivities of unfunctionalized aryls hinder the development of DArP. Here, an efficient Pd and Cu co-catalyzed DArP was developed via inert C−S bond cleavage of aryl thioethers, of which robustness was exemplified by over twenty conjugated polymers (CPs), including copolymers, homopolymers, and random polymers. The capture of oxidative addition intermediate together with experimental and theoretic results suggested the important role of palladium (Pd) and copper (Cu) co-catalysis with a bicyclic mechanism. The studies of NMR, molecular weights, trap densities, two-dimensional grazing-incidence wide-angle X-ray scattering (2D-GIWAXS), and the charge transport mobilities revealed that the homocoupling reactions were significantly suppressed with high regioselectivity of unfunctionalized aryls, suggesting this method is an excellent choice for synthesizing high performance CPs.     

Not Carbon s–p Hybridization,but Coordination Number Determines C−H and C−C Bond Length

A fundamental and ubiquitous phenomenon in chemistry is the contraction of both C−H and C−C bonds as the carbon atoms involved vary, in s–p hybridization, along sp³ to sp² to sp. Our quantum chemical bonding analyses based on Kohn–Sham molecular orbital theory show that the generally accepted rationale behind this trend is incorrect. Inspection of the molecular orbitals and their corresponding orbital overlaps reveals that the above-mentioned shortening in C−H and C−C bonds is not determined by an increasing amount of s-character at the carbon atom in these bonds. Instead, we establish that this structural trend is caused by a diminishing steric (Pauli) repulsion between substituents around the pertinent carbon atom, as the coordination number decreases along sp³ to sp² to sp.     

Strengthening of the C−F Bond in Fumaryl Fluoride with Superacids

The reaction of fumaryl fluoride with the superacidic solutions XF/MF₅ (X=H, D; M=As, Sb) results in the formation of the monoprotonated and diprotonated species, dependent on the stoichiometric ratio of the Lewis acid to fumaryl fluoride. The salts [C₄H₃F₂O₂]⁺[MF₆]⁻ (M=As, Sb) and [C₄H₂X₂F₂O₂]²⁺([MF₆]⁻)₂ (X=H, D; M=As, Sb) are the first examples with a protonated acyl fluoride moiety. They were characterized by low-temperature vibrational spectroscopy. Low-temperature NMR spectroscopy and single-crystal X-ray structure analyses were carried out for [C₄H₃F₂O₂]⁺[SbF₆]⁻ as well as for [C₄H₄F₂O₂]²⁺([MF₆]⁻)₂ (M=As, Sb). The experimental results are discussed together with quantum chemical calculations of the cations [C₄H₄F₂O₂ ⋅ 2 HF]²⁺ and [C₄H₃F₂O₂ ⋅ HF]⁺ at the B3LYP/aug-cc-pVTZ level of theory. In addition, electrostatic potential (ESP) maps combined with natural population analysis (NPA) charges were calculated in order to investigate the electron distribution and the charge-related properties of the diprotonated species. The C−F bond lengths in the protonated dication are considerably reduced on account of the +R effect.     

Nickel-Mediated Trifluoromethylation of Phenol Derivatives by Aryl C−O Bond Activation

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper- and palladium-mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel-mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF₃). The strategy relies on PMe₃-promoted oxidative addition and transmetalation, and CCl₃CN-induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.     

Facile C−F Bond Activation Approach to FAMT-Based Difluoromethyl-BNCT Drug Candidates

Lithium 1,3-bis(2,6-diisopropylphenyl)-1,3,2-diazaborolidinyl-2-uide activates the C−F linkage of fluoroform (CF₃H) to provide air-stable difluoromethylborane compounds. Computational analysis of S_N2-type transition state for the C−F bond activation of fluoroform with boryllithium clarifies the mechanism involving the lithium dimeric species in the pre-reaction complex. FAMT (=3-fluoro-l -α-methyl-tyrosine)-based difluoromethyl-BNCT (boron neutron capture therapy) drug candidates is thus produced by the present C−F bond activation.     

Photocatalyzed Hydrogen Atom Transfer Degradation of Vinyl Polymers: Cleavage of a Backbone C−C Bond Triggered by Radical Activation of a C−H Bond in a Pendant

In this work, we achieved a triggering degradation of polymers composed of carbon-carbon (C−C) bonded backbone without relying on introduction of labile heteroatom-based bond. The crucial point for the achievement is using vinyl ether (VE) as a comonomer in radical copolymerization of (meth)acrylate for introduction of the carbon-hydrogen (C−H) bonds active for photocatalyzed hydrogen atom transfer (HAT) as triggers in the pendant. Interestingly, methyl methacrylate (MMA)-n-butyl vinyl ether (NBVE) copolymer underwent degradation in acetonitrile in the presence of benzophenone (Ph₂CO) under UV irradiation at 80 °C. The degradation did not take place, when any one of UV, Ph₂CO, heat, and NBVE unit was removed or HAT-active solvent such as toluene and 1,4-dioxane was used. These control experiments strongly supported the HAT-triggering degradation. Furthermore, the degradation behaviors of the copolymers with other vinyl ethers such as tert-butyl vinyl ether and methyl isopropenyl ether indicated that the C−H bond neighboring to oxygen on the pendant is mainly responsible for the trigger leading to degradation. The HAT-triggering degradation was also demonstrated even with the acrylate-based copolymer.     

Cobalt Nanoparticles-Catalyzed Widely Applicable Successive C−C Bond Cleavage in Alcohols to Access Esters

Selective cleavage and functionalization of C−C bonds have important applications in organic synthesis and biomass utilization. However, functionalization of C−C bonds by controlled cleavage remains difficult and challenging because they are inert. Herein, we describe an unprecedented efficient protocol for the breaking of successive C−C bonds in alcohols to form esters with one or multiple carbon atoms less using heterogeneous cobalt nanoparticles as catalyst with dioxygen as the oxidant. A wide range of alcohols including inactive long-chain alkyl aryl alcohols undergo smoothly successive cleavage of adjacent −(C−C)_n− bonds to afford the corresponding esters. The catalyst was used for seven times without any decrease in activity. Characterization and control experiments disclose that cobalt nanoparticles are responsible for the successive cleavage of C−C bonds to achieve excellent catalytic activity, while the presence of Co-N_x has just the opposite effect. Preliminary mechanistic studies reveal that a tandem sequence reaction is involved in this process.     

Asymmetric Pd(II)-Catalyzed C−O,C−N,C−C Bond Formation Using Alkenes as Substrates: Insight into Recent Enantioselective Developments

This Review summarizes the advances in the catalytic enantioselective mono- and difunctionalization of alkenes, highlighting the fundamental role of ligands. Several types of asymmetric reactions have been developed involving different bonds formation, C−O, C−N and C−C, highlighting the urgency to go ahead in the search for new ligands and synthetic methodologies in order to improve the control over the reaction selectivity and activity and thus, to increase the applications in the synthesis of heterocyclic scaffolds and biologically active compounds. The Review is organized into paragraphs, which discuss the type of bond formed during the nucleopalladation, C−O, C−N, C−C bonds, and the type of reaction involved.     

Intermolecular Carbophosphination of Alkynes with Phosphole Oxides via Ni−Al Bimetal-Catalyzed C−P Bond Activation

Intermolecular carbophosphination reaction of alkynes or alkenes with unreactive C−P bonds remains an elusive challenge. Herein, we used a Ni−Al bimetallic catalyst to realize an intermolecular carbophosphination reaction of alkynes with 5-membered phosphole oxides, providing a series of 7-membered phosphepines in up to 94 % yield.     

C−X Bond Activation by Palladium: Steric Shielding versus Steric Attraction

The C−X bond activation (X = H, C) of a series of substituted C(n°)−H and C(n°)−C(m°) bonds with C(n°) and C(m°) = H₃C− (methyl, 0°), CH₃H₂C− (primary, 1°), (CH₃)₂HC− (secondary, 2°), (CH₃)₃C− (tertiary, 3°) by palladium were investigated using relativistic dispersion-corrected density functional theory at ZORA-BLYP-D3(BJ)/TZ2P. The effect of the stepwise introduction of substituents was pinpointed at the C−X bond on the bond activation process. The C(n°)−X bonds become substantially weaker going from C(0°)−X, to C(1°)−X, to C(2°)−X, to C(3°)−X because of the increasing steric repulsion between the C(n°)- and X-group. Interestingly, this often does not lead to a lower barrier for the C(n°)−X bond activation. The C−H activation barrier, for example, decreases from C(0°)−X, to C(1°)−X, to C(2°)−X and then increases again for the very crowded C(3°)−X bond. For the more congested C−C bond, in contrast, the activation barrier always increases as the degree of substitution is increased. Our activation strain and matching energy decomposition analyses reveal that these differences in C−H and C−C bond activation can be traced back to the opposing interplay between steric repulsion across the C−X bond versus that between the catalyst and substrate.