Bond Activation Strategy Research Articles

Photoinduced Nickel-Catalyzed Homolytic C(sp3)-N Bond Activation of Isonitriles for Selective Carbo- and Hydro-Cyanation of Alkynes.

The exploration of strong chemical bonds as synthetic handles offers new disconnection strategies for the synthesis of functionalized molecules via transition metal catalysis. However, the slow oxidative addition rate of these covalent bonds to a transition metal center hampers their synthetic utility. Here, we report a C(sp3)-N bond activation strategy that bypasses thermodynamically challenging 2e- or 1e- oxidative addition via a distinct pathway in nickel catalysis. This strategy leverages a previously unknown activation pathway of photoinduced inner-sphere charge transfer of low-valent nickel(isonitriles), triggering a C(sp3)-N bond cleavage distal to the metal-ligand interaction to deliver nickel(cyanide) and versatile alkyl radicals. Utilizing this catalytic strategy, the selective intermolecular 1,2-carbocyanation reaction of alkynes with alkyl isonitriles as both alkylating and cyanating agents can be achieved, delivering a wide array of trisubstituted alkenyl nitriles with excellent atom-economy, regio-, and stereoselectivity under mild conditions. Furthermore, Markovnikov-selective hydrocyanation of aliphatic alkynes can be accomplished through the synergistic action of a photocatalyst utilizing isonitriles as the cyanation agents. Mechanistic investigations support the photogeneration of low-valent Ni(isonitrile) complexes that undergo photochemical homolysis of the C(sp3)-N bond to engage catalytic cyanation with alkynes.

Palladium-Catalyzed, Site-Selective C(sp2)8-H Halogenation and Nitration of 4-Quinolone Derivatives.

Selective installation of halo and nitro groups in heterocyclic backbone through a transition-metal-catalyzed C-H bond activation strategy is immensely alluring to access high-value scaffolds. Here in, we disclosed N-pyrimidyl-directed assisted palladium(II)-catalyzed C(sp2)8-H halogenation and nitration of substituted 4-quinolone derivatives in the presence of N-halosuccinimide and tert-butyl nitrite, respectively, offering structurally diversified 8-halo/nitro-embedded 4-quinolone frameworks in high yields. Mechanistic studies indicated that the reaction follows an organometallic pathway with a reversible C-H metalation step. This operationally simple protocol is scalable with a broad substrate scope and excellent functional group compatibility. Moreover, the postdiversifications of the synthesized derivatives are also showcased to ensure the synthetic versatility of the methodology.

Difluorocarbene-Promoted O-O Bond Activation of Peroxy Acids for Electrophilic Carboxylation of Boronic Acids.

In this study, a difluorocarbene-promoted O-O bond activation of peroxy acids is developed through the insertion of difluorocarbene into O-H bond. This activation strategy in synergy with O-B coordination with boronic acids/ester greatly polarizes the O-O bond for in-situ generation of carboxylium species that reacts with the nucleophilic part of boronic acids in a concerted way to produce carboxylic esters. Good efficiency and functional group tolerance are demonstrated. Application of this method to the functionalization of a boronic acid drug used as HSL enzyme inhibitor produces smoothly the ester derivative. This difluorocarbene-mediated O-O bond activation strategy is conceptually different from traditional radical type methods, and is also complementary to conventional esterification methods with a distinct retro-synthetic disconnection.

Cysteine Radical and Glutamate Collaboratively Enable C-H Bond Activation and C-N Bond Cleavage in a Glycyl Radical Enzyme HplG.

Hydroxyprolines are abundant in nature and widely utilized by many living organisms. Isomerization of trans-4-hydroxy-d-proline (t4D-HP) to generate 2-amino-4-ketopentanoate has been found to need a glycyl radical enzyme HplG, which catalyzes the cleavage of the C-N bond, while dehydration of trans-4-hydroxy-l-proline involves a homologous enzyme of HplG. Herein, molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) calculations are employed to understand the reaction mechanism of HplG. Two possible reaction pathways of HplG have been explored to decipher the origin of its chemoselectivity. The QM/MM calculations reveal that the isomerization proceeds via an initial hydrogen shift from the Cγ site of t4D-HP to a catalytic cysteine radical, followed by cleavage of the Cδ-N bond in t4D-HP to form a radical intermediate that captures a hydrogen atom from the cysteine. Activation of the Cδ-H bond in t4D-HP to bring about dehydration of t4D-HP possesses an extremely high energy barrier, thus rendering the dehydration pathway implausible in HplG. On the basis of the current calculations, conserved residue Glu429 plays a pivotal role in the isomerization pathway: the hydrogen bonding between it and t4D-HP weakens the hydroxyalkyl Cγ-Hγ bond, and it acts as a proton acceptor to trigger the cleavage of the C-N bond in t4D-HP. Our current QM/MM calculations rationalize the origin of the experimentally observed chemoselectivity of HplG and propose an H-bond-assisted bond activation strategy in radical-containing enzymes. These findings have general implications on radical-mediated enzymatic catalysis and expand our understanding of how nature wisely and selectively activates the C-H bond to modulate catalytic selectivity.

Platform for Multiple Isotope Labeling via Carbon-Sulfur Bond Exchange.

In this work, we explore a nickel-catalyzed reversible carbon-sulfur (C-S) bond activation strategy to achieve selective sulfur isotope exchange. Isotopes are at the foundation of applications in life science, such as nuclear imaging, and are essential tools for the determination of pharmacokinetic and dynamic profiles of new pharmaceuticals. However, the insertion of an isotope into an organic molecule remains challenging, and current technologies are element-specific. Despite the ubiquitous presence of sulfur in many biologically active molecules, sulfur isotope labeling is an underexplored field, and sulfur isotope exchange has been overlooked. This approach enables us to move beyond standardized element-specific procedures and was applied to multiple isotopes, including deuterium, carbon-13, sulfur-34, and radioactive carbon-14. These results provide a unique platform for multiple isotope labeling and are compatible with a wide range of substrates, including pharmaceuticals. In addition, this technology proved its potential as an isotopic encryption device for organic molecules.

Expanding the Scope of Alkynes in C-H Activation: Weak Chelation-Assisted Cobalt-Catalyzed Synthesis of Indole C(4)-Acrylophenone via C-O Bond Cleavage of Propargylic Ethers.

Herein, we report the facile synthesis of indole C(4)-acrylophenone using a C-H bond activation strategy. For this conversion, an unsymmetrical alkyne (phenylethynyl ether) in the presence of cobalt(III)-catalyst works efficiently. In this process, alkyne gets oxidized in the presence of in situ generated water, which is the key step for this method, for which trifluoroethanol is the water source. The pivaloyl directing group chelates effectively to generate the cobaltacycle intermediate, which was detected through high-resolution mass spectrometry (HRMS). Also, the formation of bis(2,2,2-trifluoroethyl) ether has been confirmed and quantified using 19F NMR. In addition, the applicability of obtained indole C(4)-acrylophenone product has been demonstrated by performing the Nazarov cyclization and conjugate addition to the α,β-unsaturated ketone moiety.

DFT study on isothiourea-catalyzed C-C bond activation of cyclobutenone: the role of the catalyst and the origin of stereoselectivity.

The organocatalytic C-C bond activation strategy stands out as a new reaction mode for the release of ring strain and expands the scope of organocatalysts. Thus, disclosing the role of the organocatalyst in the C-C bond cleavage process would be of interest. Here, an isothiourea-catalyzed C-C bond activation/cycloaddition reaction of cyclobutenone is selected as a computational model to uncover the role of the catalyst. Based on the calculations, the electrocyclic cleavage of cyclobutenone is calculated to be energetically more favorable than the isothiourea-catalyzed C-C bond cleavage, which is different from the NHC-catalyzed C-C bond activation of cyclobutenone. The computational results show that the isothiourea promotes the reaction by increasing the nucleophilicity of vinyl ketene and thus lowers the energy barrier of the cycloaddition process. Moreover, NCI and AIM analyses are performed to disclose the origin of stereoselectivity.

Solvent-exchange triggered hydrogen bond activation strategy toward self-adaptive strong and tough organohydrogel artificial muscle

Hydrogel actuators have aroused tremendous interests in various fields such as artificial muscles, biomedicine and wearable devices. However, hydrogel actuators face persistent challenges due to their intrinsic weak and hydrophilic networks, which result in brittle and weak mechanical properties after swelling. Here, we proposed a solvent-exchange hydrogen bond activation strategy to fabricate a highly strong and tough self-adaptive organohydrogel actuators (SOA). The glycerol releasing and water retention triggers abnormal swelling of SOA due to the cross-linking of tannic acid (TA) and polyvinyl alcohol (PVA) nanofibrillar network. After the hydrogen bond activation between PVA and TA, SOA shows a denser and porous nanofibrillar network with high tensile strength (5.4 ± 0.2 MPa), high fracture energy (134.9 ± 7.6 kJ/m2), and high toughness (18.5 ± 0.7 MJ/m3). Owing to its good processibility, an anisotropic multi-filament twisted fiber actuator that exhibits ultra-high modulus (83.5 ± 2.6 MPa) and humidity-sensitive actuation performance was developed. The proposed solvent-exchange strategy shows great potential for the rational design and fabrication of bionic strong and tough artificial muscles.

Comparison of Diastereoselective ortho-Metalations and C–H ­Activations of Chiral Ferrocenes

AbstractChiral ferrocene derivatives possessing a planar stereogenic unit are important as chiral catalysts and materials. The principle method to obtain 1,2-disubstituted planarly chiral ferrocenes is base-mediated ortho-metalation performed on a chiral ferrocene derivative, typically using organolithium bases. A multitude of chiral ligands and other useful compounds have been synthesized by using this methodology. Newer methodologies employing transition-metal-catalyzed C–H bond activation strategies complement ortho-metalation methods and affords access to different types of planar chiral ferrocene derivatives.1 Introduction2 Base-Mediated ortho-Deprotonations3 Diastereoselective C–H Activations4 Examples of Enantioselective C–H Activations5 Conclusions

Synthesis of Pyrazolidinone-Fused Benzotriazines through C-H/N-H Bond Functionalization of 1-Phenylpyrazolidinones with Oxadiazolones.

Presented herein is an efficient synthesis of pyrazolidinone-fused benzotriazines through the cascade reaction of 1-phenylpyrazolidinones with oxadiazolones. The formation of the title products is initiated by Rh(III)-catalyzed C-H/N-H bond metallation of 1-phenylpyrazolidinone and subsequent coordination with oxadiazolone followed by migratory insertion along with CO2 liberation, proto-demetallation, and intramolecular condensation. To our knowledge, this is the first synthesis of pyrazolidinone-fused benzotriazines based on the C-H bond activation strategy by using oxadiazolone as an easy-to-handle amidine surrogate. In general, this new protocol has advantages such as valuable products, easily accessible substrates, redox neutral conditions, concise synthetic procedure, high efficiency, and compatibility with diverse functional groups. Moreover, the usefulness of this method is further showcased by scale-up synthetic scenario and suitability to substrates derived from natural products such as thymol and nerol.

Electrooxidative Activation of B-B Bond in B2 cat2 : Access to gem-Diborylalkanes via Paired Electrolysis.

This report describes the unprecedented electrooxidation of a solvent (e.g., DMF)-ligated B2 cat2 complex, whereby a solvent-stabilized boryl radical is formed via quasi-homolytic cleavage of the B-B bond in a DMF-ligated B2 cat2 radical cation. Cyclic voltammetry and density functional theory provide evidence to support this novel B-B bond activation strategy. Furthermore, a strategy for the electrochemical gem-diborylation of gem-bromides via paired electrolysis is developed for the first time, affording a range of versatile gem-diborylalkanes, which are widely used in synthetic society. Notably, this reaction approach is scalable, transition-metal-free, and requires no external activator.

Electrooxidative Activation of B−B Bond in B2cat2: Access to gem‐Diborylalkanes via Paired Electrolysis

AbstractThis report describes the unprecedented electrooxidation of a solvent (e.g., DMF)‐ligated B2cat2 complex, whereby a solvent‐stabilized boryl radical is formed via quasi‐homolytic cleavage of the B−B bond in a DMF‐ligated B2cat2 radical cation. Cyclic voltammetry and density functional theory provide evidence to support this novel B−B bond activation strategy. Furthermore, a strategy for the electrochemical gem‐diborylation of gem‐bromides via paired electrolysis is developed for the first time, affording a range of versatile gem‐diborylalkanes, which are widely used in synthetic society. Notably, this reaction approach is scalable, transition‐metal‐free, and requires no external activator.

Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation

Macrocycles are commonly synthesized via late-stage macrolactamization and macrolactonization. Strategies involving C–C bond macrocyclization have been reported, and examples include the transition-metal-catalyzed ring-closing metathesis and coupling reactions. In this mini-review, we summarize the recent progress in the direct synthesis of polyketide and polypeptide macrocycles using a transition-metal-catalyzed C–H bond activation strategy. In the first part, rhodium-catalyzed alkene–alkene ring-closing coupling for polyketide synthesis is described. The second part summarizes the synthesis of polypeptide macrocycles. The activation of indolyl and aryl C(sp2)–H bonds followed by coupling with various coupling partners such as aryl halides, arylates, and alkynyl bromide is then documented. Moreover, transition-metal-catalyzed C–C bond macrocyclization reactions via alkyl C(sp3)–H bond activation are also included. We hope that this mini-review will inspire more researchers to explore new and broadly applicable strategies for C–C bond macrocyclization via intramolecular C–H activation.

Rhodium‐Catalyzed Annulations of 6‐Arylimidazothiazoles with Alkynes through Rollover Dual C−H Bond Activation Strategy

AbstractWe developed an efficient method for thesynthesis of 5,6‐diarylnaphthoimidazo[2,1‐b]thiazoles from6‐arylimidazo[2,1‐b]thiazoles with alkynes through rollover C−H activation strategy by using Rh(III)‐catalyst. Alternatively, the imidazo[2,1‐b]thiazole fused isoquinolinium tetrafluoroborate salts also have been achieved by tuning the reaction conditions with good yields.

Enaminone-directed ruthenium(II)-catalyzed C-H activation and annulation of arenes with diazonaphthoquinones for polycyclic benzocoumarins.

The weakly coordinating enaminone functionality has been leveraged for a C-H bond activation strategy under ruthenium catalysis and employed in the regioselective annulative coupling of arenes with diazonaphthoquinones, offering polycyclic benzocoumarins in very high yields. The enaminone motif plays a dual role and the protocol operates through a Ru(II)/Ru(IV) catalytic pathway which is amenable to the diversification of various pharmacophore-coupled substrates.

C-C bond formation via photocatalytic direct functionalization of simple alkanes.

The direct functionalization of alkanes represents a very important challenge in the goal to develop more atom-efficient and clean C-C bond forming reactions. These processes, however, are hampered by the low reactivity of the aliphatic C-H bonds. Photocatalytic processes based on hydrogen atom transfer C-H bond activation strategies have become a useful tool to activate and functionalize these inert compounds. In this article, we summarize the main achievements in this field applied to the development of C-C bond forming reactions, and we discuss the key mechanistic features that enable these transformations.

Organic photoredox catalyzed dealkylation/acylation of tertiary amines to access amides.

A mild metal-free C-N bond activation strategy for the direct conversion of inert tertiary amines with acyl chlorides into tertiary amides via organic photoredox catalysis is presented. In this protocol, a novel organic photocatalyst (Cz-NI-Ph) that showed excellent catalytic performance during C-N bond cleavage is developed. Moreover, this reaction features green and mild conditions, broad substrate scope, and readily available raw materials.

Visible-Light-Induced C-F Bond Activation for the Difluoroalkylation of Indoles.

An aryl disulfide mediated C-F bond activation of the trifluoromethyl group to generate valuable gem-difluoroalkylindoles is described. This method relies on readily available commodity reagents under mild reaction conditions and represents the first transition-metal-free redox-neutral C-F bond activation strategy. The reaction employs various substituted indoles and α-fluoro-substituted esters. Further, this mode of C-F activation was also amenable to the activation of trifluoromethylated arenes for the preparation of bis-benzylic gem-difluoromethylenes between indole and arene substructures, providing access to a unique chemical space.

Ruthenium(II)-Catalyzed (4+2) Annulative Difunctionalization of Non-conjugated Alkenyl Amides with Hydroxamic Acid Esters.

Ru(II)-catalyzed C-H bond activation strategy has been capitalized through a (4+2) annulative difunctionalization of non-conjugated alkenyl amides. Under mild conditions, a broad range of (hetero)aromatic amides embedded with NH-OMe unit as an internal oxidant produced high-value dihydroisoquinolinone scaffolds in good to excellent yields. This heteroannulation is also effective with acrylamides to dispense dihydro-2-pyridones and accommodates bioactive scaffolds such as tocopherol, estrone, and amino acids.

Regioselective Annulation of Allenylphosphine Oxides with Aromatic Amides under Ruthenium(II) Catalysis.

Engaging allenes in transition-metal-catalyzed C-H bond activation strategy is immensely promising to access high-value scaffolds. However, such a reaction manifold remains largely elusive using cheap and sustainable ruthenium catalysis. We disclose an unprecedented ruthenium-catalyzed (4 + 2) annulation between aromatic amides and allenylphosphine oxides, furnishing NH-free isoquinolinones in high yields. This operationally simple methodology leverages weak coordination assistance, displays high selectivity, and is amenable to the late-stage functionalization of several biologically relevant motifs.