Hypervalent Iodine Research Articles

Skeletal Editing by Hypervalent Iodine Mediated Nitrogen Insertion.

Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single-nitrogen-atom insertion reaction, and skeletal editing to construct N-heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen-atom into hydrocarbons to generate N-heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen-containing heterocycles, and the current mechanistic understanding of these processes.

Recent Progress in Synthetic Applications of Hypervalent Iodine(III) Reagents.

Hypervalent iodine(III) compounds have found wide application in modern organic chemistry as environmentally friendly reagents and catalysts. Hypervalent iodine reagents are commonly used in synthetically important halogenations, oxidations, aminations, heterocyclizations, and various oxidative functionalizations of organic substrates. Iodonium salts are important arylating reagents, while iodonium ylides and imides are excellent carbene and nitrene precursors. Various derivatives of benziodoxoles, such as azidobenziodoxoles, trifluoromethylbenziodoxoles, alkynylbenziodoxoles, and alkenylbenziodoxoles have found wide application as group transfer reagents in the presence of transition metal catalysts, under metal-free conditions, or using photocatalysts under photoirradiation conditions. Development of hypervalent iodine catalytic systems and discovery of highly enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important recent achievement in the field of hypervalent iodine chemistry. Chemical transformations promoted by hypervalent iodine in many cases are unique and cannot be performed by using any other common, non-iodine-based reagent. This review covers literature published mainly in the last 7-8 years, between 2016 and 2024.

Regioselective Halogenation of 2‐Oxindoles and β‐Keto Esters Using Oxone‐Halide With or Without Aryl Iodine

AbstractEfficient and environmentally benign regioselective halogenation protocols have been achieved through the mediation of oxone‐halide, with or without the assistance of aryl iodine. The key to the success of the regioselectivity process is the controlled generation of the active [X]+ or halogen‐substituted hypervalent iodine (III) by manipulating the components of the oxone‐halide‐aryl iodine system.

Elektrochemische Gerüst‐Editierung von Indolen durch Stickstoffatom‐Insertion mit nachhaltiger Sauerstoff‐Reduktionsreaktion

AbstractMolekulares Editieren hat in letzter Zeit stark an Bedeutung gewonnen und sich als einzigartiges Werkzeug für Late‐Stage Diversifizierungen erwiesen. Bislang waren für die Indol‐Editierung meist überstöchiometrische Mengen an teuren hochvalenten Iod(III)‐Reagenzien erforderlich. Im Gegensatz dazu zeigen wir hier, dass Elektrizität nachhaltige Stickstoffatom‐Insertionsreaktionen ermöglicht, um bio‐relevante Chinazolin‐Gerüste ohne stöchiometrische chemische Redox‐Abfallprodukte zu erhalten. Die Übergangsmetall freie Elektro‐Editierung wurde durch die Sauerstoff‐Reduktionsreaktion (ORR) ermöglicht und erwies sich in großem Maßstab als robust, wobei eine Vielzahl wertvoller funktioneller Gruppen toleriert wurden.

Hypervalent-Iodine-Mediated Base-Free Oxidative Olefination of Benzylic Amines to Access α,β-Unsaturated Ketones

AbstractWe report a one-pot base-free protocol for the oxidative olefination of benzylic amines promoted by a hypervalent iodine reagent for the synthesis of α,β-unsaturated ketones. Mechanistically, (diacetoxyiodo)benzene oxidizes the benzylic amine to the corresponding imine, which, on reaction with a phenacyl(triphenyl)phosphonium bromide salt and an in situ generated acetoxy anion leads to an α,β-unsaturated ketone. A wide range of α,β-unsaturated ketones were easily accessed through direct oxidative olefination of substituted benzylic amines in good to excellent yields and with high E-selectivity.

Synthesis of pyrazole and pyrazoline derivatives of β-ionone: Exploring anti-inflammatory potential, cytotoxicity, and molecular docking insights

In the present paper, pyrazole and pyrazoline derivatives of β-ionone were synthesized. The protocol involved intramolecular oxidative C–H amination of hydrazone to yield corresponding pyrazole in moderate to good yields. Another methodology comprising of condensation of hydrazine hydrochloride with β-ionone in methanol leading to pyrazoline and its oxidative dehydrogenation using hypervalent iodine reagent to synthesize pyrazole is also achieved. One pot methodology for synthesis of pyrazole is also developed by refluxing the hydrazine hydrochloride with β-ionone in acetic acid. The structures of the synthesized compounds were elucidated using 1H NMR, 13C NMR, FTIR and mass spectrometry. All the pyrazole and pyrazoline derivatives were subjected to bovine serum albumin assay for in-vitro anti-inflammatory activity and all the compounds exhibited good to excellent activity. Compounds containing bromo and sulfonamide group exhibited inhibition rates of 87.36 % and 85.82 %, respectively, at a concentration of 0.5 mg/mL, surpassing the efficacy of the standard drug celecoxib (81.67 %). Further, cytotoxicity of the compounds was also evaluated against VERO cell line and all the compounds exhibited the cytotoxic values almost similar to the standard. Molecular docking was performed to study binding affinity of the potent compounds i. e bromo bearing pyrazole and sulfonamide bearing pyrazoline into the crystal structure of COX-II enzyme (PDB ID: 3LN1) at celecoxib binding site to determine the binding energy and interactions.

Hypervalent Iodine Mediated Ring-Opening 1,3-Difluorination of Benzylidenecyclopropanes

Abstract1,3-Difluorinated compounds are characterized by their unique conformation, influenced by 1,3-dipolar minimization effects. However, their synthetic methods are relatively limited. Here, a ring-opening 1,3-difluorination of benzylidenecyclopropanes (BCPs) using HF·Py, mediated by an electron-poor hypervalent iodine reagent, which is generated in situ by the oxidation of o-nitroiodobenzene with mCPBA is described. The protocol features mild reaction conditions, good functional group tolerance, and moderate to good yields. Additionally, the synthetic utility of this method is showcased by further transformations of the olefin group and allylic fluoride motif.

Photocatalytic Oxyalkynylation of Unactivated Alkenes Enabled by Hypervalent Iodine(III) Reagents

Photocatalytic Oxyalkynylation of Unactivated Alkenes Enabled by Hypervalent Iodine(III) Reagents

Structural Modification and Characteristics of Lappaconitine Alkaloid for the Discovery of Bioactive Components by Hypervalent Iodine Reagent.

Lappaconitine, a diterpene alkaloid isolated from Aconitum sinomontanum Nakai, exhibits a wide range of biological activities, making it a promising candidate for the development of novel derivatives with therapeutic potential. In our research, we executed a two-step transformation via oxidative cleavage of lappaconitine's vicinal diol using the hypervalent iodine reagent PhI(OAc)2, followed by strong alkaline hydrolysis. This approach yielded four new unanticipated compounds, whose structures were identified by spectroscopic methods and/or X-ray crystallography. Thus, we proposed plausible reaction mechanisms for their formations and particularly investigated the remarkable diastereoselectivity for the formation of single stereoisomer 8 observed during the alkaline hydrolysis step. Among them, compound 8 (code name: QG3030) demonstrated both enhanced osteogenic differentiation of human mesenchymal stem cells and significant osteogenic effect in an ovariectomized rat model with no acute oral toxicity.

Transition-Metal-Free Sulfoximidation of Sulfonylhydrazones for the Synthesis of N-Sulfanylidenehydrazonamides.

Herein, we report a transition-metal-free C-H bond sulfoximidation protocol of sulfonyl hydrazones with hypervalent iodine(III) reagents. A library of novel N-sulfaneylidenehydrazonamides was constructed via chemoselective C-N bond formation reactions at aldehyde C-H bonds of sulfonyl hydrazones in the presence of a base. The reaction demonstrated broad substrate group diversity under exceedingly mild reaction conditions, and excellent yields were achieved at room temperature.

2,2‐Difluoroethylation of Heteroatom Nucleophiles via a Hypervalent Iodine Strategy

AbstractThe 2,2‐difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2‐difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2‐difluoro‐ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2‐difluoroethylation methods and allows access to a wide range of 2,2‐difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine.

2,2-Difluoroethylation of Heteroatom Nucleophiles via a Hypervalent Iodine Strategy.

The 2,2-difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2-difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2-difluoro-ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2-difluoroethylation methods and allows access to a wide range of 2,2-difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine.

Organocatalytic Dearomatization of 5-Aminopyrazoles: Synthesis of 4-Hydroxypyrazolines.

Dearomatization is a fundamental chemical reaction that affords complex three-dimensional heterocyclic frameworks. We disclose the first organocatalytic dearomatization of 5-aminopyrazoles, which yields a range of structurally diversified C4-hydroxylated pyrazolines with yields of ≤95% in <1.5 h at room temperature. This catalytic process is achieved using in situ-generated hypervalent iodine. The method also yields a spirolactone via an intramolecular dearomatization process. Furthermore, we demonstrate that substrate-directed reduction of the resulting iminopyrazoline leads to 4,5-difunctionalized pyrazoline as a single diastereomer. Mechanistic studies suggest that the reaction proceeds through a dearomatized cationic intermediate.

Hypervalent Iodine (III)-Based Complexation for Chiroptical Supramolecular Glass, Deep Eutectic Solvent and Luminescent Switch.

Hypervalent iodine(III) have widely been utilized for organic synthetic reagents. They are also recognized as positive charge-assisted, exceptionally robust biaxial halogen bond donors, while their potential in supramolecular materials is barely explored. This work reports a cyclic diaryliodonium ion as biaxial halogen bonding donor that displays remarkable binding affinity toward phenanthroline or acridine acceptors with chiral pendants. Biaxial halogen bonding enables chiroptical evolution in solution, allowing for rational control over supramolecular chirality. Leveraging their strong binding affinity, the halogen bonding complexes manifested amorphous properties and deep eutectic behavior in the solid state. Capitalizing on these attributes, this work achieves the successful preparation of supramolecular glasses and deep eutectic solvents. Additionally, halogen bonding appended light irradiation-triggered luminescence through a hydrogen atom transfer process, showing applications in anti-counterfeit and display.

Visible-Light-Mediated Ring-Opening Geminal Dibromination of Alkenes via Alkoxy Radicals Enabled by Electron Donor-Acceptor Complex.

An electron donor-acceptor complex was utilized to generate alkoxy radicals from alcohols under mild conditions using visible light. This approach was combined with a hydroxybromination process to achieve the deconstructive functionalization of alkenes, leading to the production of geminal dibromides. Mechanistic investigations indicated the intermediacy of hypervalent iodine (III) compounds.

Hypervalent Iodine Promoted Selective [2 + 2 + 1] Cycloaddition of Aromatic Ketones and Methylamines: A One-Pot Access to 1-Pyrrolines.

Herein, a versatile highly regioselective three-component annulation of simple aromatic ketones and methylamines using a hypervalent iodine reagent for polyarylated 1-pyrrolines has been described in good to excellent yields. Meanwhile, unsymmetrical 1-pyrroline isomers could be realized and synthesized. Such an intriguing one-pot two-step tandem assembly strategy with green conditions and high regioselectivity shows predictable inspiration in related annulation reactions.

Computational Design of Bidentate Hypervalent Iodine Catalysts in Halogen Bond-Mediated Organocatalysis.

In recent years, halogen bond-based organocatalysis has garnered significant attention as an alternative to hydrogen-based catalysis, capturing considerable interest within the scientific community. This transition has witnessed the evolution of catalytic scaffolds from monodentate to bidentate architectures, and from monovalent to hypervalent species. In this DFT-based study, we explored a bidentate hypervalent iodine(III)-based system that has already undergone experimental validation. Additionally, we explore various functionalisations (-CF3, -CH3, -tBu, -OH, -OMe, -NO2, -CN) and scaffold modifications, such as sulfur oxidation, theoretically proposed for an indole-based Michael addition. The investigated systems favour bidentate O-type binding, underlining the importance of ligand coordination in catalytic activity. Electron-deficient scaffolds exhibited stronger binding and lower activation energies, indicating the pivotal role of electronic properties for σ-hole-based catalysis. Of these groups, Lewis-base-like moieties formed stabilising intramolecular interactions with hypervalent iodines when in the ortho-position. Furthermore, inductive electron withdrawal was deemed more effective than mesomeric withdrawal in enhancing catalytic efficacy for these systems. Lastly, increasing sulfur oxidation was theoretically proven to improve catalytic activity significantly.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction.

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, we herein show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Hypervalent Iodine-Catalyzed Fluorination of Diene-Containing Compounds: A Computational Study.

Studies have shown that the incorporation of fluorine into materials can improve their properties, but C-F bonds are not readily formed in nature. Although some researchers have studied the reaction of fluorinating alkenes catalyzed by hypervalent iodine, far too little attention has been paid to its reaction mechanism. This study aimed to explore the mechanism of the hypervalent iodine-catalyzed 1,4-difluorination of dienes. We found that the catalyst is favorable for the activation of C1=C2 double bonds through halogen bonds, and then two HFs interact with one F atom in the catalyst via hydrogen bonds, resulting in the cleavage of I-F bonds and the formation of [F-H∙∙∙F]-. Subsequently, the catalyst interacts with C1, and the roaming [F-H···F]- attacks C4 from the opposite side of the catalyst. After the fluorination step is completed, the nucleophile F- substitutes the catalyst via the SN2 mechanism. Our calculations demonstrated that the interaction between HF and F- is favorable for the stabilization of the transition state within the fluorination process for which the presence of two HFs in the reaction is the best. We also observed that [F-H∙∙∙F]- attacking C4 from the opposite side of the catalyst is more advantageous than attacking from the same side. This study therefore offers a novel perspective on the mechanism of the hypervalent iodine-catalyzed fluoridation of dienes.

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation.

Hypervalent iodine catalysis has been widely utilized in olefin functionalization reactions. Intermolecularly, the regioselective addition of two distinct nucleophiles across the olefin is a challenging process in hypervalent iodine catalysis. We introduce here a unique strategy using simple lithium salts for hypervalent iodine catalyst activation. The activated hypervalent iodine catalyst allows the intermolecular coupling of soft nucleophiles such as amides onto electronically activated olefins with high regioselectivity.