Electrophilic Intermediates Research Articles

Electrochemical Oxidation Enables Radical Dearomative Spiroannulation to 2H-Spiro[benzofuran-3,9'-fluoren]-2-one.

Developing pragmatic strategies for accessing functional benzofuran-2-ones from 3-([1,1'-biphenyl]-2-yl)benzofuran remains an enduring challenge. Herein, we have achieved a highly discriminating electrochemical oxidative dearomative spiroannulation of 3-([1,1'-biphenyl]-2-yl)benzofuran, culminating in the synthesis of 2H-spiro[benzofuran-3,9'-fluoren]-2-one derivatives. By harnessing the electrophilic intermediates of benzofuryl radical cations supported by DFT calculations, we attain exceptional regioselectivity while eliminating the need for stoichiometric oxidants. Mechanistic investigations reveal a sequence of events involving the benzofuran radical cation, encompassing the capture of H2O, nucleophilic arene attack, and subsequent deprotonation, ultimately yielding the final benzofuran-2-ones.

Mining the Carbon Intermediates in Plastic Waste Upcycling for Constructing C-S Bond.

Postconsumer plastics are generally perceived as valueless with only a small portion of plastic waste being closed-loop recycled into similar products while most of them are discarded in landfills. Depositing plastic waste in landfills not only harms the environment but also signifies a substantial economic loss. Alternatively, constructing value-added chemical feedstocks via mining the waste-derived intermediate species as a carbon (C) source under mild electrochemical conditions is a sustainable strategy to realize the circular economy. This proof-of-concept work provides an attractive "turning trash to treasure" strategy by integrating electrocatalytic polyethylene terephthalate (PET) plastic upcycling with a chemical C-S coupling reaction to synthesize organosulfur compounds, hydroxymethanesulfonate (HMS). HMS can be produced efficiently (Faradaic efficiency, FE of ∼70%) via deliberately capturing electrophilic intermediates generated in the PET monomer (ethylene glycol, EG) upcycling process, followed by coupling them with nucleophilic sulfur (S) species (i.e., SO32- and HSO3-). Unlike many previous studies conducted under alkaline conditions, PET upcycling was performed over an amorphous MnO2 catalyst under near-neutral conditions, allowing for the stabilization of electrophilic intermediates. The compatibility of this strategy was further investigated by employing biomass-derived compounds as substrates. Moreover, comparable HMS yields can be achieved with real-world PET plastics, showing its enormous potential in practical application. Lastly, Density function theory (DFT) calculation reveals that the C-C cleavage step of EG is the rate-determining step (RDS), and amorphous MnO2 significantly decreases the energy barriers for both RDS and C-S coupling when compared to the crystalline counterpart.

Cyclization by metal-catalyzed hydrogen atom transfer/radical-polar crossover

Catalytic transformation of alkenes via the metal-hydride hydrogen atom transfer (MHAT) mechanism has notably advanced synthetic organic chemistry. This review focuses on MHAT/radical-polar crossover (MHAT/RPC) conditions, offering a novel perspective on generating electrophilic intermediates and facilitating various intramolecular reactions. Upon using cobalt hydrides, the MHAT mechanism displayed exceptional chemoselectivity and functional group tolerance, making it invaluable for the construction of complex biologically relevant molecules under mild conditions. Recent developments have enhanced regioselectivity and expanded the scope of MHAT-type reactions, enabling the formation of cyclic molecules via hydroalkoxylation, hydroacyloxylation, and hydroamination. Notably, the addition of an oxidant to traditional MHAT systems enables the synthesis of rare cationic alkylcobalt(IV) complexes, bridging radical mechanisms to ionic reaction systems. This review culminates with examples of natural product syntheses and exploration of asymmetric intramolecular hydroalkoxylation, highlighting the ongoing challenges and opportunities for future research to achieve higher enantioselectivity. This comprehensive study revisits the historical evolution of the MHAT mechanism and provides the groundwork for further innovations in the synthesis of structurally diverse and complex natural products. 1 Introduction 2 Intramolecular hydroalkoxylation and hydroacyloxylation reactions 3 Intramolecular hydroamination reactions 4 Intramolecular hydroarylation reactions 5 Deprotective cyclization 6 Asymmetric intramolecular hydroalkoxylation

Computational Analysis of Low Overpotential Ammonia Oxidation by Metal-Metal Bonded Ruthenium Catalysts, and Predictions for Related Osmium Catalysts.

The catalyzed electrochemical oxidation of ammonia to nitrogen (AOR) is an important fuel-cell half-reaction that underpins a future nitrogen-based energy economy. Our laboratory has reported spontaneous chemical and electrochemical oxidation of ammonia to dinitrogen via reaction of ammonia with the metal-metal bonded diruthenium complex Ru2(chp)4OTf (chp- = 2-chloro-6-hydroxypyridinate, TfO- = trifluoromethanesulfonate). This complex facilitates electrocatalytic ammonia oxidation at mild applied potentials of -255 mV vs ferrocene, which is the [Ru2(chp)4(NH3)]0/+ redox potential. We now report a comprehensive computational investigation of possible mechanisms for this reaction and electronic structure analysis of key intermediates therein. We extend this analysis to proposed second-generation electrocatalysts bearing structurally similar fhp and hmp (2-fluoro-6-hydroxypyridinate and 2-hydroxy-6-methylpyridinate, respectively) equatorial ligands, and we further expand this study from Ru2 to analogous Os2 cores. Predicted M24+/5+ redox potentials, which we expect to correlate with experimental AOR overpotential, depend strongly on the identity of the metal center, and to a lesser degree on the nature of the equatorial supporting ligand. Os2 complexes are easier to oxidize than analogous Ru2 complexes by ∼640 mV, on average. In contrast to mono-Ru catalysts, which oxidize ammonia via a rate-limiting activation of the strong N-H bond, we find lowest-energy reaction pathways for Ru2 and Os2 complexes that involve direct N-N bond formation onto electrophilic intermediates having terminal amido, imido, or nitrido groups. While transition state energies for Os2 complexes are high, those for Ru2 complexes are moderate and notably lower than those for mono-Ru complexes. We attribute these lower barriers to enhanced electrophilicity of the Ru2 intermediates, which is a consequence of their metal-metal bonded structure. Os2 intermediates are found to be, surprisingly, less electrophilic, and we suggest that Os2 complexes may require access to oxidation states higher than Os25+ in order to perform AOR at reasonable reaction rates.

Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study.

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

Total Synthesis of Cyclotripeptidic Natural Products Anacine, Aurantiomide C, Polonimides A and C, and Verrucine F.

The total synthesis of cyclotripeptidic natural products possessing a central piperazino[2,1-b]quinazolin-3,6-dione core is described through an original strategy involving the pivotal cyclocondensation of an electrophilic homoserine lactone intermediate. The alkylidene group was spontaneously installed by autoxidation during the cyclocondensation process, while the propionamide side chain was introduced through the nickel-catalyzed aminocarbonylation of a bromoethyl intermediate. This last reaction is unprecedented on such highly functionalized intermediates. Finally, we explored structural modifications and interconversions of the natural products. Overall, this work led to anacine, aurantiomide C, polonimides A and C, and verrucine F.

Carbocationoids, a concept for controlling highly reactive cationic species

Carbocations, which are positively charged highly electrophilic intermediates, are efficacious for the direct alkylation of low-reactive nucleophiles. The utilization of carbocations in SN1 reactions relies on the activation of their precursors in the presence of a nucleophile. However, undesirable interactions between the nucleophile and the leaving group activator limit the scope of acceptable nucleophiles. Here we report a strategy to conduct SN1 reactions involving unstable carbocations in an alternative stepwise procedure, which was demonstrated by the benzylation of various neutral nucleophiles. In the first step, carbocations were accumulated in a nucleophile-free solution in the form of carbocationoids utilizing the coordinative stabilization of triazinediones. Subsequently, the addition of these solutions in the second step enabled room-temperature alkylation without the need for acidic additives. This methodology overcomes the inherent challenges of carbocations in SN1 reactions.

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Oxyallyl cations, as powerful electrophilic intermediates, have shown versatile utilities in organic synthesis. Modular synthesis of multi‐substituted cyclobutanones enabled by oxyallyl cations provides facile access to multi‐substituted cyclobutanones via direct nucleophilic substitution of (di)chlorocyclobutanones under mild basic conditions. Both aryl or alkyl substituents could be efficiently introduced on the four‐membered ring skeleton. Further transformation leads to tetrasubstituted cyclobutane derivatives in a stereoselective manner, demonstrating potential synthetic utility. More details are discussed in the article by Lu et al. on page 459—463.image

Synthesis of Benzoxazines by Heterogeneous Multicomponent Biochemo Multienzymes Cascade Reaction.

This work describes the possibility to combine multicomponent chemistry and multienzymes cascade transformations in a unique reactive framework to yield highly functionalized 1,4-benzoxazines under favorable heterogeneous conditions. The synthetic scheme involved the generation in situ of electrophilic reactive quinone intermediates of tyrosol esters catalyzed by lipase M and tyrosinase followed by nucleophilic 1,6-Michael addition of selected α-amino acid methyl esters, and successive intramolecular lactonization and aromatization processes. The immobilization of the multienzymes cascade on electroactive lignin nanoparticles improved the sustainability and recyclability of the overall system.

Recent updates on vinyl cyclopropanes, aziridines and oxiranes: access to heterocyclic scaffolds.

This present review delineates the repertoire of vinyl cyclopropanes and their stuctural analogues to accomplish a wide array of oxa-cycles, aza-cycles, and thia-cycles under transition metal catalysis and metal-free approaches from early 2019 to the present date. The generation of electrophilic π-allyl intermediates and 1-3/1-5-dipolarophile chemistry originating from VCPs are always green, step- and atom-economical and sustainable strategies in comparsion with prefunctionalized and/or C-H activation protocols. Here, the strained ring-system extends its applicability by relieving the strain to undergo a ring-expansion reaction to accomplish 5-9 membered carbo- and heterocyclic systems. The availability of chiral ligands in the ring-expansion reaction of VCPs and their analogues has paved the way to realizing asymmetric synthetic transformations.

Microflow Synthesis of Unsymmetrical H-Phosphonates via Sequential and Direct Substitution of Chlorine Atoms in Phosphorus Trichloride with Alkoxy Groups.

Unsymmetrical H-phosphonates were synthesized by a rapid (<15 s) and mild (20 °C) process in a microflow reactor as the first example of the sequential direct substitution of the chlorine atoms in PCl3 with alkoxyl/aryloxy groups using equivalent amounts of PCl3 and alcohols. The optimal base concentration differed in each step, presumably attributed to differences in the Brønsted basicity of the electrophilic intermediates. Phosphite hydrolysis was observed, and the structure-hydrolysis relationship was quantitatively evaluated.

Role of Oxidative Stress and Reactive Metabolites in Cytotoxicity & Mitotoxicity of Clozapine, Diclofenac and Nifedipine in CHO-K1 Cells In Vitro.

To provide in vitro data on toxicity mechanisms of clozapine, diclofenac and nifedipine. CHO-K1 cells were used as in vitro model to explore mechanisms of cytotoxicity of the test drugs. Cytotoxic mechanisms of clozapine (CLZ), diclofenac (DIC) and nifedipine (NIF) were studied in CHO-K1 cells in vitro. All three drugs induce adverse reactions in some patients with partially unknown mechanisms. Following the determination of time- and dose-dependency of cytotoxicity by the MTT test, cytoplasmic membrane integrity was explored by the LDH leakage test. Both end-points were further examined in the presence of soft and hard nucleophilic agents, glutathione (GSH) and potassium cyanide (KCN), respectively, and either individual or general cytochrome P450 (CYP) inhibitors, whether CYP-catalysed formation of electrophilic metabolites play a role in the observed cytotoxicity and membrane damage. The generation of reactive metabolites during the incubations was also explored. Formation of malondialdehyde (MDA) and oxidation of dihydrofluorescein (DCFH) were monitored whether peroxidative membrane damage and oxidative stress take place in cytotoxicity. Incubations were also conducted in the presence of chelating agents of EDTA or DTPA to explore any possible role of metals in cytotoxicity by facilitating electron transfer in redox reactions. Finally, mitochondrial membrane oxidative degradation and permeability transition pore (mPTP) induction by the drugs were tested as markers of mitochondrial damage. The presence of an individual or combined nucleophilic agents significantly diminished CLZ- and NIF-induced cytotoxicities, while the presence of both agents paradoxically increased DIC-induced cytotoxicity by a factor of three with the reason remaining unknown. The presence of GSH significantly increased DIC-induced membrane damage too. Prevention of membrane damage by the hard nucleophile KCN suggests the generation of a hard electrophile upon DIC and GSH interaction. The presence of CYP2C9 inhibitor sulfaphenazol significantly diminished DIC-induced cytotoxicity, probably by preventing the formation of 4-hydroxylated metabolite of DIC, which further converts to an electrophilic reactive intermediate. Among the chelating agents, EDTA caused a marginal decrease in CLZ-induced cytotoxicity, while DIC-induced cytotoxicity was amplified by a factor of five. Both reactive and stable metabolites of CLZ could be detected in the incubation medium of CLZ with CHO-K1 cells, which are known to have low metabolic capacity. All three drugs caused a significant increase in cytoplasmic oxidative stress by means of DCFH oxidation, which was confirmed by increased MDA from cytoplasmic as well as mitochondrial membranes. The addition of GSH paradoxically and significantly increased DIC-induced MDA formation, in parallel with the increase in membrane damage when DIC and GSH combined. Our results suggested that the soft electrophilic nitrenium ion of CLZ is not responsible for the observed in vitro toxicities, and this may originate from a relatively low amount of the metabolite due to the low metabolic capacity of CHO-K1. A hard electrophilic intermediate may contribute to cellular membrane damage incubated with DIC, while a soft electrophilic intermediate seems to exacerbate cell death by a mechanism other than membrane damage. A significant decrease in cytotoxicity of NIF by GSH and KCN suggested that both soft and hard electrophiles contribute to NIF-induced cytotoxicity. All three drugs induced peroxidative cytoplasmic membrane damage, while only DIC and NIF induced peroxidative mitochondrial membrane damage, which suggested mitochondrial processes may contribute to adverse effects of these drugs in vivo.

Cover Feature: Highly Electrophilic Intermediates in the Bypass Mechanism of Glutathione Peroxidase: Synthesis, Reactivity, and Structures of Selenocysteine‐Derived Cyclic Selenenyl Amides (Chem. Eur. J. 71/2023)

Cover Feature: Highly Electrophilic Intermediates in the Bypass Mechanism of Glutathione Peroxidase: Synthesis, Reactivity, and Structures of Selenocysteine‐Derived Cyclic Selenenyl Amides (Chem. Eur. J. 71/2023)

Highly Electrophilic Intermediates in the Bypass Mechanism of Glutathione Peroxidase: Synthesis, Reactivity, and Structures of Selenocysteine-Derived Cyclic Selenenyl Amides.

Selenocysteine (Sec)-derived cyclic selenenyl amides, formed by the intramolecular cyclization of Sec selenenic acids (Sec-SeOHs), have been postulated to function as protective forms in the bypass mechanism of glutathione peroxidase (GPx). However, their chemical properties have not been experimentally elucidated in proteins or small-molecule systems. Recently, we reported the first nuclear magnetic resonance observation of Sec-SeOHs and their cyclization to the corresponding cyclic selenenyl amides by using selenopeptide model systems incorporated in a molecular cradle. Herein, we elucidate the structures and reactivities of Sec-derived cyclic selenenyl amides. The crystal structures and reactions toward a cysteine thiol or a 1,3-diketone-type chemical probe indicated the highly electrophilic character of cyclic selenenyl amides. This suggests that they can serve not only as protective forms to suppress the inactivation of Sec-SeOHs in GPx but also as highly electrophilic intermediates in the reactions of selenoproteins.

The inhibitory effect of licorice on the hepatotoxicity induced by the metabolic activation of Euodiae Fructus

Ethnopharmacological relevanceEuodiae Fructus (EF), the dried, unripe, scented fruit of Tetradium ruticarpum (A. Juss, T.G.Hartley), is a traditional food and herb with mild toxicity. In Asia, it is processed with licorice (EFP), which has been used for centuries to alleviate pain and suppress cough. Pharmacological studies have reported that this herb could cause liver injury by activating the P450 3A enzyme, thus carrying the risk of clinical application. Processing with licorice is an effective method to reduce EF toxicity. It is urgent to explore the toxic components of EF and the attenuation mechanism of licorice. Aim of the studyThis study aimed to indicate the specific pathway of EF-induced damage and identify the mechanism of action of licorice in reducing P450 activation and resulting in reduced liver damage. Materials and methodsMale C57BL-6 mice were used to investigate the toxicity of EF to the liver and determine the attenuation effect on P450 from licorice ingestion. Glutathione (GSH) was used to capture the metabolic activation intermediates of EF. The key component reducing the EF toxicity of licorice was investigated by comparing the differences in chemical components and inhibition on the EF metabolism of licorice from different habitats. ResultsThe intermediate product of evodiamine (EVO) in EF was found to be activated by the P450 enzyme during metabolism, causing liver injury and inflammation. Isoliquiritigenin and liquiritigenin in licorice produced by intestinal bacterial metabolism and glycyrrhizin inhibited the metabolic activation of EF. Glycosides in licorice are metabolized into aglycones by intestinal bacteria, inhibiting the metabolic activation of EF and alleviating hepatotoxicity. ConclusionsBy combining with GSH, the electrophilic intermediates produced by the P450 enzyme's metabolic activation of the indole ring of EVO might cause hepatotoxicity. Glycyrrhizin from licorice and the liquiritigenin and isoliquiritigenin generated by intestinal bacterial metabolism play an attenuated function by inhibiting the P450 enzyme and preventing the metabolic activation of EF.

Chemoselective, Oxidation-Induced Macrocyclization of Tyrosine-Containing Peptides.

Inspired by nature's wide range of oxidation-induced modifications to install cross-links and cycles at tyrosine (Tyr) and other phenol-containing residue side chains, we report a Tyr-selective strategy for the preparation of Tyr-linked cyclic peptides. This approach leverages N4-substituted 1,2,4-triazoline-3,5-diones (TADs) as azo electrophiles that react chemoselectively with the phenolic side chain of Tyr residues to form stable C-N1-linked cyclic peptides. In the developed method, a precursor 1,2,4-triazolidine-3,5-dione moiety, also known as urazole, is readily constructed at any free amine revealed on a solid-supported peptide. Once prepared, the N4-substituted urazole peptide is selectively oxidized using mild, peptide-compatible conditions to generate an electrophilic N4-substituted TAD peptide intermediate that reacts selectively under aqueous conditions with internal and terminal Tyr residues to furnish Tyr-linked cyclic peptides. The approach demonstrates good tolerance of native residue side chains and enables access to cyclic peptides ranging from 3- to 11-residues in size (16- to 38-atom-containing cycles). The identity of the installed Tyr-linkage, a stable covalent C-N1 bond, was characterized using NMR spectroscopy. Finally, we applied the developed method to prepare biologically active Tyr-linked cyclic peptides bearing the integrin-binding RGDf epitope.

Oxidative N-Dealkylation of N,N-Dimethylanilines by Non-Heme Manganese Catalysts

Non-heme manganese(II) complexes [(IndH)MnIICl2] (1) and [(N4Py*)MnII(CH3CN)](ClO4)2 (2) with tridentate isoindoline and pentadentate polypyridyl ligands (IndH = 1,3-bis(2′-pyridylimino)isoindoline; N4Py* = N,N-bis(2-pyridylmethyl)-1,2- di(2-pyridyl)ethylamine) proved to be suitable to catalyze the oxidative demethylation of N,N-dimethylaniline (DMA) with various oxidants such as tert-butyl hydroperoxide (TBHP), peracetic acid (PAA), and meta-chloroperoxybenzoic acid (mCPBA), resulting N-methylaniline (MA) as a main product with N-methylformanilide (MFA) as a result of a free-radical chain process under air. The effect of electron-donating and electron-withdrawing substituents on the aromatic ring on the relative reactivity of the substrates and on the product composition (MA/MFA) was also studied and showed a significant impact on the catalytic N-demethylation reaction. Based on the Hammett correlation with ρ = −0.38 (PAA), −0.45 (mCPBA), and −0.63 (TBHP) for 1 and ρ = −0.38 (PAA) and −0.37 (mCPBA) for 2, an electrophilic intermediate is suggested as the key oxidant. Furthermore, the spectral investigation (UV-Vis) resulted in direct evidence for the formation of a high-valent oxomanganese(IV) and a transient radical cation intermediate, p-Me-DMA•+, suggesting that the initial step in the manganese-catalyzed oxidations is a fast electron-transfer between the amine and the high valent oxometal species. The mechanisms of the subsequent steps are discussed.

Ultrafast C-C and C-N bond formation reactions in water microdroplets facilitated by the spontaneous generation of carbocations.

Carbocations are important electrophilic intermediates in organic chemistry, but their formation typically requires harsh conditions such as extremely low pH, elevated temperature, strong oxidants and/or expensive noble-metal catalysts. Herein, we report the spontaneous generation of highly reactive carbocations in water microdroplets by simply spraying a diarylmethanol aqueous solution. The formation of transient carbocations as well as their ultrafast in-droplet transformations through carbocation-involved C-C and C-N bond formation reactions are directly characterized by mass spectrometry. The intriguing formation and stabilization of carbocations are attributed to the super acidity of the positively charged water microdroplets as well as the high electric fields at the water-air interfaces. Without the utilization of external acids as catalysts, we believe that these microdroplet reactions would pose a new and sustainable way for the construction of aryl-substituted compounds.

Superacid Promoted Synthesis of 9,9'-Spirobifluorenes and Related Aza- and Diazaspirocycles.

A variety of 9,9'-spirobifluorenes and related azaspirocycles and diazaspirocycles have been prepared in high yields by intramolecular Friedel-Crafts reaction using the Brønsted superacid, triflic acid (CF3SO3H). Compared to weaker Brønsted acids, the superacid consistently provides better yields along with reduced reaction times and it eliminates the need for heating. The superacid is particularly effective when dicationic electrophilic intermediates are generated in the conversions, for example with the diazaspirocycle syntheses.

Construction of C-S and C-Se Bonds Mediated by Hypervalent Iodine Reagents Under Metal-Free Conditions

Abstract: In the past few decades, the chemistry of hypervalent iodine reagents has undergone a flourishing development in synthetic organic chemistry owing to their mild oxidative, low toxicity, air and moisture stability, and environmentally benign features. A plethora of oxidative coupling reactions have been conducted using hypervalent iodine reagents as nonmetallic oxidants. In particular, the C-S and C-Se bond-forming reactions mediated by hypervalent iodine reagents have emerged as a powerful approach in the construction of Scontaining and Se-containing heterocycles or building blocks. In these reactions, hypervalent iodine reagents behave as strong oxidants or electrophiles and activate the S-containing or Secontaining species to form more electrophilic cationic or radical intermediates, which participate in subsequent coupling reactions. It is anticipated that this review summarizes all C–S and C-Se bonds forming reactions enabled by hypervalent iodine reagents under metal-free conditions.