Electrophilic Activation Research Articles

Cobalt-Catalyzed Regioselective para-Amination of Azobenzenes via Nucleophilic Aromatic Substitution of Hydrogen.

The metal-catalyzed nucleophilic aromatic substitution of hydrogen (SNArH) via coordination of the substituent on the aromatic ring to the metal catalyst, in terms of reactivity, substrate type, and reaction selectivity, complements the transition metal-catalyzed C-H functionalization that proceeds via C-H metalation but remains an elusive target. Described herein is the development of an unprecedented cobalt-catalyzed para-selective amination of azobenzenes, which is essentially a metal-promoted SNArH process as revealed by Hammett analysis, thus illustrating the concept that coordination of the substituent on the arene ring to the metal catalyst may result in electrophilic activation of the arene ring toward SNArH. This cobalt-catalyzed protocol allows the use of a variety of both aliphatic amines and anilines as aminating reagents, tolerates electronically diverse substituents of azobenzene, and furnishes the corresponding products in good yields with a regiospecific selectivity for para-amination.

Montmorillonite-based heterogeneous catalysts for efficient organic reactions

In this review, we give a brief overview of recently developed montmorillonite-based heterogeneous catalysts used for efficient organic reactions. Cation-exchanged montmorillonite catalysts, metal catalysts supported on montmorillonite, and an interlayer design used for selective catalysis are introduced and discussed. In traditional syntheses, homogeneous acids and metal salts were used as catalysts, but the difficulty in separation of catalysts from products was a bottleneck when considering industrialization. The use of solid heterogeneous catalysts is one of the major solutions to overcome this problem. Montmorillonite can be used as a heterogeneous catalyst and/or catalyst support. This clay material exhibits strong acidity and a stabilizing effect on active species, such as metal nanoparticles, due to its unique layered structure. These advantages have led to the development of montmorillonite-based heterogeneous catalysts. Acidic montmorillonite, such as proton-exchanged montmorillonite, exhibits a high catalytic activity for the activation of electrophiles, such as alcohols, alkenes, and even alkanes. The montmorillonite interlayer/surface also functions as a good support for various metal species used for oxidation and carbon-carbon bond forming reactions. The use of an interlayer structure enables selective reactions and the stabilization of catalytically active species.

Asymmetric α‐Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts

AbstractOwing to the strong nucleophilicity of the NH2 group, free‐NH2 glycinates react with MBH acetates to usually deliver N‐allylated products even in the absence of catalysts. Without protection of the NH2 group, chiral pyridoxal catalysts bearing an amide side chain at the C3 position of the naphthyl ring switched the chemoselectivity of the glycinates from intrinsic N‐allylation to α‐C allylation. The reaction formed chiral multisubstituted glutamic acid esters as SN2′–SN2′ products in good yields with excellent stereoselectivity (up to 86 % yield, >20 : 1 dr, 97 % ee). As compared to pyridoxal catalysts bearing an amide side arm at the C2 position, the pyridoxals in this study have a bigger catalytic cavity to enable effective activation of larger electrophiles, such as MBH acetates and related intermediates. The reaction is proposed to proceed via a cooperative bifunctional catalysis pathway, which accounts for the high level of diastereo‐ and enantiocontrol of the pyridoxal catalysts.

Asymmetric α-Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts.

Owing to the strong nucleophilicity of the NH2 group, free-NH2 glycinates react with MBH acetates to usually deliver N-allylated products even in the absence of catalysts. Without protection of the NH2 group, chiral pyridoxal catalysts bearing an amide side chain at the C3 position of the naphthyl ring switched the chemoselectivity of the glycinates from intrinsic N-allylation to α-C allylation. The reaction formed chiral multisubstituted glutamic acid esters as SN 2'-SN 2' products in good yields with excellent stereoselectivity (up to 86 % yield, >20 : 1 dr, 97 % ee). As compared to pyridoxal catalysts bearing an amide side arm at the C2 position, the pyridoxals in this study have a bigger catalytic cavity to enable effective activation of larger electrophiles, such as MBH acetates and related intermediates. The reaction is proposed to proceed via a cooperative bifunctional catalysis pathway, which accounts for the high level of diastereo- and enantiocontrol of the pyridoxal catalysts.

Synthesis of α-Aryl Primary Amides from α-Silyl Nitriles and Aryl Sulfoxides through [3,3]-Sigmatropic Rearrangement.

A simple and efficient protocol was developed for the preparation of challenging α-aryl primary amides. This metal-free coupling process was triggered by TfOH-promoted electrophilic activation of α-silyl nitrile to generate keteniminium ion species, followed by reaction with aryl sulfoxide through [3,3]-sigmatrophic rearrangement to provide the target product. To the best of our knowledge, α-silyl nitrile has been rarely used as a pro-electrophilic reagent. Computational investigations confirmed the transient existence of a highly electrophilic keteniminium intermediate.

Electrophilic (Ethoxycarbonyl)difluoromethylthiolation Using Difluoroalkyl Sulfonium Salts

AbstractWe report a simple protocol for (ethoxycarbonyl)difluoromethylthiolation of nucleophilic compounds using a difluoroalkyl sulfonium salt which can be prepared in situ via Tf2O-triggered electrophilic activation of a benzyl difluoroalkyl sulfoxide. With the protocol, difluoroalkylthiolated arenes, heteroarenes, α-difluoroalkylthiolated carbonyl compounds, etc. were obtained smoothly with good to excellent yields. Merits of the reaction include the readily available difluoroalkylthiolation reagent and substrates, mild conditions, and excellent regioselectivity.

Boronic-Acid-Accelerated Electrophilic Activation of Unprotected Maltols to N-Substituted Hydroxypyridinones in Water.

3,4-Hydroxypyridinone (3,4-HOPO) is a vital metal-chelating pharmacophore. However, the efficient synthesis has been a long-standing problem in drug development. In this paper, we report an efficient electrophilic activation of unprotected maltols via reversible covalent bonds between boronic acid and 3-hydroxyl/4-carbonyl. This one-pot reaction proceeded well on a gram scale in water with excellent efficiencies up to 97%. Moreover, taking advantage of the covalent interactions via the transient boronate, most of the previously tough amine donors, including sterically hindered amines, aromatic amines, and amino acids and amino alcohols, were well-tolerated. Importantly, the potential of this strategy in the pharmaceutical industry was highlighted with a successful synthesis of 3,4-HOPOs containing iron-chelating active pharmaceutical ingredients on 10 g and kilogram scales.

Merging Halogen-Atom Transfer (XAT) and Copper Catalysis for the Modular Suzuki-Miyaura-Type Cross-Coupling of Alkyl Iodides and Organoborons.

We report here a mechanistically distinct approach to achieve Suzuki–Miyaura-type cross-couplings between alkyl iodides and aryl organoborons. This process requires a copper catalyst but, in contrast with previous approaches based on palladium and nickel systems, does not utilizes the metal for the activation of the alkyl electrophile. Instead, this strategy exploits the halogen-atom-transfer ability of α-aminoalkyl radicals to convert secondary alkyl iodides into the corresponding alkyl radicals that then are coupled with aryl, vinyl, alkynyl, benzyl, and allyl boronate species. These novel coupling reactions feature a simple setup and conditions (1 h at room temperature) and facilitate access to privileged motifs targeted by the pharmaceutical sector.

Wood ash biocatalyst as a novel green catalyst and its application for the synthesis of benzochromene derivatives

Wood ash is a naturally alkaline derived substance containing organic and inorganic constituents. This study investigates the catalytic activity of wood ash as a heterogeneous catalyst for the synthesis of benzochromene derivatives. Several wood ash catalysts, comprising calcium- and potassium-rich carbonates, were prepared from different natural resources under various combustion temperatures. The prepared catalysts were characterized by Fourier transform infrared, scanning electron microscopy, energy dispersive X-ray analysis, transmission electron microscopy, and X-ray diffraction techniques. Catalytic efficiency of the resultant catalysts was tested in the synthesis of benzochromene derivatives. The experimental studies clarified that the catalyst prepared at 850 °C could efficiently expedite the formation of three-component synthesis of benzochromene derivatives in water at 80 °C with high yields. Indeed, alkali, alkaline metal, and metal oxides such as Al2O3, SiO2, MgO, CaO, and Fe2O3, are widely utilized as both catalyst and catalyst support in the heterogeneous catalytic processes. The prepared wood ash catalysts (possessing metal oxides, e.g., CuO, Al2O3, SiO2, and CaO) could effectively prompt the electrophilic activity of the carbonyl groups during the nucleophilic attack intermediate, enhancing the efficiency of the reactions.

Boosting Gold(I) Catalysis via Weak Interactions: New Fine-Tunable Impy Ligands.

A series of modular ImPy-carbene-Au(I) complexes are synthesized and fully characterized both in the solid state and in solution. The presence of oligoaryl units (phenyl and thienyl rings) at the C5-position of the ImPy core (in close proximity to the gold center) imprints on the organometallic species fine-tunable and predictable catalytic properties. A marked accelerating effect was recorded in several [Au(I)]-catalyzed electrophilic activations of unsaturated hydrocarbons when a CF3-containing aromatic ring was accommodated at the ImPy core.

Triflic Anhydride (Tf2O)-Activated Transformations of Amides, Sulfoxides and Phosphorus Oxides via Nucleophilic Trapping

AbstractTrifluoromethanesulfonic anhydride (Tf2O) is utilized as a strong electrophilic activator in a wide range of applications in synthetic organic chemistry, leading to the transient generation of a triflate intermediate. This versatile triflate intermediate undergoes nucleophilic trapping with diverse nucleophiles to yield novel compounds. In this review, we describe the features and applications of triflic anhydride in organic synthesis reported in the past decade, especially in amide, sulfoxide, and phosphorus oxide chemistry through electrophilic activation. A plausible mechanistic pathway for each important reaction is also discussed.1 Introduction2 Amide Chemistry2.1 Carbon Nucleophiles2.2 Hydrogen Nucleophiles2.3 Nitrogen Nucleophiles2.4 Oxygen and Sulfur Nucleophiles2.5 hosphorus Nucleophiles2.6 A Vilsmeier-Type Reagent2.7 Umpolung Reactivity in Amides3 Sulfoxide Chemistry3.1 Oxygen Nucleophiles3.2 Carbon Nucleophiles3.3 Nitrogen Nucleophiles3.4 Thionium Reagents4 Phosphorus Chemistry4.1 Hendrickson’s Reagent4.2 Diaryl Phosphine Oxides4.3 Phosphonates, Phosphates and Phosphinates5 Conclusion and Outlook

Electrophilic thymol isobutyrate from Inula nervosa Wall. (Xiaoheiyao) ameliorates steatosis in HepG2 cells via Nrf2 activation

• Electrophilic components from Xiaoheiyao are knocked out using magnetic GSH probe. • Electrophilic components have the potential to ameliorate steatosis in HepG2 cells. • 10-Isobutyryloxy-8,9-epoxythymol isobutyrate is discovered as a bioactive compound. • 10-Isobutyryloxy-8,9-epoxythymol isobutyrate improves steatosis via Nrf2 activation. Xiaoheiyao , the rhizomes of Inula nervosa Wall., is a culinary spice known to contain some electrophilic Nrf2 activators that could potentially intervene in nonalcoholic fatty liver disease (NAFLD). In this study, the electrophilic components from Xiaoheiyao were annotated by comprehensive cheminformatics analyses on UHPLC-MS/MS data after being knocked out with glutathione (GSH)-immobilized magnetic microspheres. Their intervention effects against hepatic steatosis were investigated in free fatty acid (FFA)-treated HepG2 cells. The electrophilic components in Xiaoheiyao were found to be the major bioactive components preventing hepatic steatosis in FFA-treated HepG2 cells. In particular, 10-isobutyryloxy-8,9-epoxythymol isobutyrate (XHY-1) improved hepatic lipid metabolism disorder, Krebs cycle activity, oxidative phosphorylation, and the cellular and mitochondrial redox status. Moreover, XHY-1 activates the Nrf2-ARE signaling pathway through the up-regulation of Nrf2 expression and promotion of Nrf2 nuclear translocation. Molecular docking further showed that XHY-1 could conjugate with Cys151 in the BTB domain of Keap1 through the epoxy group. In conclusion, the electrophilic components of Xiaoheiyao , especially XHY-1, attenuated hepatic steatosis in FFA-treated HepG2 cells through activation of the Nrf2-ARE signaling pathway.

Electrophilic activation of alkynes promoted by a cationic alkylidene complex of Pt(II).

Pt(II) alkylidene 1a has been reacted with terminal alkynes to afford ylide complexes 3a-d, resulting from electrophilic activation of the CC bond and its insertion into the platinacyclic fragment of 1a that contains the carbene functionality. DFT calculations indicate that the observed regioselectivity is determined by the nucleophilic attack of the alkyne to the alkylidene carbon.

Strain-Release-Driven Friedel-Crafts Spirocyclization of Azabicyclo[1.1.0]butanes.

The identification of spiro N‐heterocycles as scaffolds that display structural novelty, three‐dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain‐release‐driven Friedel–Crafts spirocyclization of azabicyclo[1.1.0]butane‐tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro‐tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel–Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel–Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels–Alder adduct in one‐pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain‐release‐driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.

Strain‐Release‐Driven Friedel–Crafts Spirocyclization of Azabicyclo[1.1.0]butanes

AbstractThe identification of spiro N‐heterocycles as scaffolds that display structural novelty, three‐dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain‐release‐driven Friedel–Crafts spirocyclization of azabicyclo[1.1.0]butane‐tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro‐tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel–Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel–Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels–Alder adduct in one‐pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain‐release‐driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen-Substituted Bicyclo[1.1.1]pentanes.

Strategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron‐neutral nucleophiles such as anilines and azoles to give nitrogen‐substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Electrophilic Activation of [1.1.1]Propellane for the Synthesis of Nitrogen‐Substituted Bicyclo[1.1.1]pentanes

AbstractStrategies commonly used for the synthesis of functionalised bicyclo[1.1.1]pentanes (BCP) rely on the reaction of [1.1.1]propellane with anionic or radical intermediates. In contrast, electrophilic activation has remained a considerable challenge due to the facile decomposition of BCP cations, which has severely limited the applications of this strategy. Herein, we report the electrophilic activation of [1.1.1]propellane in a halogen bond complex, which enables its reaction with electron‐neutral nucleophiles such as anilines and azoles to give nitrogen‐substituted BCPs that are prominent motifs in drug discovery. A detailed computational analysis indicates that the key halogen bonding interaction promotes nucleophilic attack without sacrificing cage stabilisation. Overall, our work rehabilitates electrophilic activation of [1.1.1]propellane as a valuable strategy for accessing functionalised BCPs.

Divergent Synthesis of α-Fluorinated Carbonyl and Carboxyl Derivatives by Double Electrophilic Activation of Amides.

A straightforward and divergent entry to α-fluorinated carbonyl and carboxyl derivatives is reported. Upon activation of amides with triflic anhydride and a 2-halo-pyridine and subsequent trapping of the resulting keteniminium ions with nucleophiles followed by a second electrophilic activation with NFSI and final hydrolysis, a range of amides can be transformed to α-fluorinated ketones, esters, and amides under mild conditions. Moreover, this reaction can be performed to yield enantioenriched products with a traceless chiral auxiliary.

Front Cover: Lewis Superacidic Tellurenyl Cation‐Induced Electrophilic Activation of an Inert Carborane (Chem. Eur. J. 59/2021)

In a metastable N-coordinated Lewis superacidic tellurenyl cation–carborane ion pair, the Te atom is trying to steal the H atom with help of a N atom. However, although at first glance the N atom is helping, he is actually planning to steal the asset for himself. The Town Musicians came to scare off the robbers, but they arrived too late, and thus nothing can stop nitrogen's plan. The broken window opens full insight into the electrophilic activation mechanism of the carborane moiety, which has been poorly understood so far. Elemental Te is watching the whole show and wondering how this is even possible; but was it the Te atom that broke the window? More information can be found in the Communication by M. Hejda, S. Ketkov, S. Mebs, J. Beckmann, et al. (DOI: 10.1002/chem.202103181).

Bischler-Napieralski Synthesis of 6-Alkynyl Phenanthridines Based on Tf2O-Promoted Electrophilic Activation of N-Aryl-2-propynamides.

An efficient method for the synthesis of 6-alkynyl phenanthridines was developed. The method offered the first example to use 2-propynamides as substrates in the Bischler-Napieralski reaction and to create alkynylnitrilium triflates as new active intermediates in organic synthesis.