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.     

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.     

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.     

Carbon Monoxide Activation by a Molecular Aluminium Imide: C−O Bond Cleavage and C−C Bond Formation

Anionic molecular imide complexes of aluminium are accessible via a rational synthetic approach involving the reactions of organo azides with a potassium aluminyl reagent. In the case of K₂[( NON )Al(NDipp)]₂ ( NON =4,5-bis(2,6-diisopropylanilido)-2,7-di-tert-butyl-9,9-dimethyl-xanthene; Dipp=2,6-diisopropylphenyl) structural characterization by X-ray crystallography reveals a short Al−N distance, which is thought primarily to be due to the low coordinate nature of the nitrogen centre. The Al−N unit is highly polar, and capable of the activation of relatively inert chemical bonds, such as those found in dihydrogen and carbon monoxide. In the case of CO, uptake of two molecules of the substrate leads to C−C coupling and C≡O bond cleavage. Thermodynamically, this is driven, at least in part, by Al−O bond formation. Mechanistically, a combination of quantum chemical and experimental observations suggests that the reaction proceeds via exchange of the NR and O substituents through intermediates featuring an aluminium-bound isocyanate fragment.     

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.     

Diverse Reactivity of bis(Silylene) and bis(Germylene) [LE−EL (E=Si and Ge: L=PhC(NtBu)2)] in the Oxidative Activation of C−F Bond: Si−Si Bond is Retained While the Ge−Ge Bond Is Cleaved

Herein we report the reactions of 3,4,5,6-tetrafluoroterephthalonitrile ( 1 ) with bis(silylene) and bis(germylene) LE−EL [E=Si ( 2 ) and Ge( 3 ): L=PhC(N^tBu)₂)]. The reaction of LSi−SiL (L=PhC(N^tBu)₂) ( 2 ) with two equivalents of 1 resulted in an unprecedented oxidative addition of a C−F bond of 1 leading to disilicon(III) fluoride {L(4-C₈F₃N)FSi−SiF(4-C₈F₃N)L}( 4 ), wherein the Si−Si single bond was retained. In contrast, the reaction of LGe−GeL (L=PhC(N^tBu)₂) ( 3 ) with one equivalent of 1 resulted in the oxidative cleavage of Ge−Ge bond leading to L(4-C₈F₃N₂)Ge ( 5 ) and LGeF ( 6 ). All three compounds ( 4 – 6 ) were characterized by NMR spectroscopy, EI-MS spectrometry, and elemental analysis. X-ray single-crystal structure determination of compound 4 unequivocally established that the Si^III−Si^III bond remains uncleaved.     

C−H Bond Activation by Iridium(III) and Iridium(IV) Oxo Complexes

Oxidation of an iridium(III) oxo precursor enabled the structural, spectroscopic, and quantum-chemical characterization of the first well-defined iridium(IV) oxo complex. Side-by-side examination of the proton-coupled electron transfer thermochemistry revealed similar driving forces for the isostructural oxo complexes in two redox states due to compensating contributions from H⁺ and e⁻ transfer. However, C−H activation of dihydroanthracene revealed significant hydrogen tunneling for the distinctly more basic iridium(III) oxo complex. Our findings complement the growing body of data that relate tunneling to ground state properties as predictors for the selectivity of C−H bond activation.     

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.     

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.     

α-Boryl Carbanions: The Influence of Geminal Heteroatoms in C−C Bond Formation

The wide applications of alpha-boryl carbanions in selective coupling with organohalides, imines/carbonyls and conjugated unsaturated substrates has become an interesting tool for organic synthesis. Strategically, the inclusion of heteroatoms, such as Si, S, N, F, Cl, Br and I in the alpha position opens a new venue towards multifunctionalities in molecular design. Here, a conceptual and practical view on powerful carbanions, containing α-silicoboron, α-thioboron, α-haloboron and α-aminoboron is given, as well as a prespective on their efficient application for selective electrophilic trapping.     

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.     

Mutability-Landscape-Guided Engineering of l-Threonine Aldolase Revealing the Prelog Rule in Mediating Diastereoselectivity of C−C Bond Formation

l -threonine aldolase (LTA) catalyzes C−C bond synthesis with moderate diastereoselectivity. In this study, with LTA from Cellulosilyticum sp (CpLTA) as an object, a mutability landscape was first constructed by performing saturation mutagenesis at substrate access tunnel amino acids. The combinatorial active-site saturation test/iterative saturation mutation (CAST/ISM) strategy was then used to tune diastereoselectivity. As a result, the diastereoselectivity of mutant H305L/Y8H/V143R was improved from 37.2 %_syn to 99.4 %_syn. Furthermore, the diastereoselectivity of mutant H305Y/Y8I/W307E was inverted to 97.2 %_anti. Based on insight provided by molecular dynamics simulations and coevolution analysis, the Prelog rule was employed to illustrate the diastereoselectivity regulation mechanism of LTA, holding that the asymmetric formation of the C−C bond was caused by electrons attacking the carbonyl carbon atom of the substrate aldehyde from the re or si face. The study would be useful to expand LTA applications and guide engineering of other C−C bond-forming enzymes.     

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.     

Cationic Rhodium(I) Tetrafluoroborate Catalyzed Intramolecular Carbofluorination of Alkenes via Acyl Fluoride C−F Bond Activation**

The C−F bond of acyl fluorides can be cleaved and added across tethered alkenes in the presence of a cationic rhodium(I) tetrafluoroborate catalyst. This 1,2-carbofluorination reaction offers a powerful method for the synthesis of tertiary alkyl fluoride derivatives with an atom economy of 100 %. Mechanistic studies indicate that the concerted action of a rhodium cation and a tetrafluoroborate anion is key for the success of this catalytic cleavage and formation of C−F bonds in a controlled manner.     

Enantioselective Cleavage of Cyclobutanols Through Ir-Catalyzed C−C Bond Activation: Mechanistic and Synthetic Aspects

The Ir-catalyzed conversion of prochiral tert-cyclobutanols to β-methyl-substituted ketones proceeds under comparably mild conditions in toluene (45–110 °C) and is particularly suited for the enantioselective desymmetrization of β-oxy-substituted substrates to give products with a quaternary chirality center with up to 95 % ee using DTBM-SegPhos as a chiral ligand. Deuteration experiments and kinetic isotope effect measurements revealed major mechanistic differences to related Rh^I-catalyzed transformations. Supported by DFT calculations we propose the initial formation of an Ir^III hydride intermediate, which then undergoes a β-C elimination (C−C bond activation) prior to reductive C−H elimination. The computational model also allows the prediction of the stereochemical outcome. The Ir-catalyzed cyclobutanol cleavage is broadly applicable but fails for substrates bearing strongly coordinating groups. The method is of particular value for the stereo-controlled synthesis of substituted chromanes related to the tocopherols and other natural products.     

Room-Temperature-Observable Interconversion Between Si(IV) and Si(II) via Reversible Intramolecular Insertion Into an Aromatic C−C Bond

An easily isolable silacycloheptatriene (silepin) 1 b was synthesized from the reaction of a N-heterocyclic imino (IPrN) substituted tribromosilane IPrNSiBr₃ with the sterically congested bis(trimethylsilyl)triisopropylsilyl silanide KSi(TMS)₂Si(ⁱPr)₃ (BTTPS). In solution, the Si(IV) silepin 1 b is in a thermodynamic equilibrium with the acyclic Si(II) silylene 1 a . The relative concentration of the Si(II) or Si(IV) isomers can be controlled by temperature variation and observed by variable temperature NMR and UV/Vis spectroscopy. DFT calculations show a small reaction barrier for the Si(II)⇌Si(IV) interconversion and a small energy gap between the Si(II) and Si(IV) species. The reactivity of 1 a/b is demonstrated on a variety of small molecules.     

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.