Iodine Catalysis Research Articles

Hypervalent Iodine Catalyzed Cascade C−H Functionalization: An Atom‐Economical Strategy to Access Diverse 2‐Substituted Benzothiazoles

AbstractA metal‐free 4,5‐difluoro‐2‐iodobenzoic acid catalyzed C−H functionalization strategy has been developed for the synthesis of 2‐(hetero)aryl benzothiazoles from aryl isothiocyanates and unfunctionalized arenes/thiophenes/furans at room temperature. The procedure entails one‐pot cascade carbon−carbon and carbon−sulfur bond formation facilitated by triflic acid, which serves as both a Brønsted acid and a ligand source at the in situ generated I(III) center. This process is atom‐economical and offers benefits over existing protocols for synthesizing benzothiazoles in terms of ease of use, eco‐friendliness, and not requiring the typical use of aryl aldehyde/carboxylic acid precursors. Mechanistic studies were carried out, and the synthetic utility of the protocol was demonstrated for the synthesis of the benzothiazole‐based antitumor drug GW‐610.

Cascade [3 + 2] Annulation of 1,3-Dicarbonyl Compounds and Ethyl Secondary Amines for Pyrrole Synthesis via Poly C(sp3)-H Bond Functionalization.

The synthesis of polyfunctionalized pyrroles via the cascade reactions of 1,3-dicarbonyl compounds and two molecules of ethyl secondary amines has been realized via simple iodine catalysis in the presence of Dess-Martin periodinane (DMP). The formation of the target pyrrole products involves the formation of one new C-C and two new C-N bonds via the major functionalization of six C(sp3)-H bonds, presenting a highly novel and efficient synthetic protocol toward pyrrole scaffolds.

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.

An emerging strategy towards the iodine catalyzed synthesis of Streptindole and its derivatives in water medium.

In this study, we propose an alternative metal‐free methodology for the synthesis of Streptindole and its derivatives. This approach employs economically viable and easily handled molecular iodine (I2) as the catalyst in an aqueous medium. The method demonstrates remarkable tolerance towards a diverse array of functional groups. The versatility of the developed protocol is highlighted by its application in the efficient total syntheses of the alkaloid natural products, Streptindole and Arsindoline B accomplished in a single step from indole. Furthermore, the methodology is also useful for the synthesis of pharmaceutically significant compounds, specifically anti‐TMV agents (5c, 5d, and 5e) and an anticancer agent (5f). Control experiments have been carried out to study the plausible catalytic cycle by finding the key intermediates. The experimental findings support the mechanistic pathway involving halogen bond activation in molecular iodine catalysis

Electrochemical Desulfurizative Amination of Heteroaromatic Thiols by Iodine Catalysis

AbstractN‐Heterocyclic amines have been known as an important class of nitrogen‐containing molecules with a wide range of applications. Described here is a mild and efficient electrochemical desulfurizative amination of readily accessible heteroaromatic thiols without necessity of metal catalyst. The key to success for this reaction is the in‐situ generation of a hypervalent iodine reagent as an organocatalyst from iodoarene by anodic oxidation. This mild desulfurizative amination presents ample substrate scope and good functional group tolerance without the use of extra stoichiometric chemical oxidants. As only electrons serve as the oxidation reagents, this method offers a straightforward and sustainable manner towards versatile N‐heterocyclic amines, including late‐stage functionalization of pharmaceutically relevant molecules.

Hypervalent iodine catalysis enabled iterative multi-fluorination: not just a simple alternative for the electrochemical approach.

Unlike the well-established fluoroalkylation, the direct incorporation of multiple fluorine atoms into small molecules via iterative fluorinations has been much less investigated. Herein, we report a hypervalent iodine catalytically selective multi-fluorination in which the fluorination degree is controlled by the delicate balance between the HF/amine ratios. The pros and cons of hypervalent iodine catalysis and the previously established electrochemical approach in the iterative multi-fluorinations are also provided.

Synthesis and Characterization of Novel 2,4-Diaryloctahydro-2H-Chromene Derivatives with Four Stereocenters

Chromene derivatives are among the natural compounds and they can also be easily obtained synthetically. They are one of the most commonly used skeletons in heterocyclic chemistry. Chromene derivatives are used in the cosmetic and pigment industries as well as having a wide spectrum of biological activity. Synthesis of chromene derivatives and their application areas is a current topic. In this study, it is aimed to synthesis and characterization of new chromene derivatives by catalysis of molecular iodine starting from 1,5-diol derivatives with chiral centers. In this context, 8 new 2,4-diaryloctahydro-2H-chromene derivatives were synthesized in high yields and their structure determinations were made by spectroscopic methods (1H-NMR, 13C-NMR, 2D-NMR, GCMS and FTIR) and their stereochemistry was determined.

Enynes Difluorination via Iodine(I/III) Catalysis

Enynes Difluorination via Iodine(I/III) Catalysis

Nucleophilic aromatization of monoterpenes from isoprene under nickel/iodine cascade catalysis

As a large number of organic compounds possessing two isoprene units, monoterpenes and monoterpenoids play important roles in pharmaceutical, cosmetic, agricultural, and food industries. In nature, monoterpenes are constructed from geranyl pyrophosphate (C10) via various transformations. Herein, the bulk C5 chemical—isoprene, is used for the creation of various monoterpenoids via a nucleophilic aromatization of monoterpenes under cascade catalysis of nickel and iodine. Drugs and oil mixtures from conifer and lemon can be convergently transformed to the desired monoterpenoid. Preliminary mechanistic studies are conducted to get insights about reaction pathway. Two types of cyclic monoterpenes can be respectively introduced onto two similar heterocycles via orthogonal C–H functionalization. And various hybrid terpenyl indoles are programmatically assembled from abundant C5 or C10 blocks. This work not only contributes a high chemo-, regio-, and redox-selective transformation of isoprene, but also provides a complementary approach for the creation of unnatural monoterpenoids.

Regioselective, catalytic 1,1-difluorination of enynes.

Fluorinated small molecules are prevalent across the functional small-molecule spectrum, but the scarcity of naturally occurring sources creates an opportunity for creative endeavour in developing routes to access these important materials. Iodine(I)/iodine(III) catalysis has proven to be particularly well-suited to this task, enabling abundant alkene substrates to be readily intercepted by in situ-generated λ3-iodanes and processed to high-value (di)fluorinated products. These organocatalysis paradigms often emulate metal-based processes by engaging the π bond and, in the case of styrenes, facilitating fluorinative phenonium-ion rearrangements to generate difluoromethylene units. Here we demonstrate that enynes are competent proxies for styrenes, thereby mitigating the recurrent need for aryl substituents, and enabling highly versatile homopropargylic difluorides to be generated in an operationally simple manner. The scope of the method is disclosed, together with application in target synthesis (>30 examples, up to >90% yield).

Efficient Metal-Free Oxidative C–H Amination for Accessing Dibenzoxazepinones via μ-Oxo Hypervalent Iodine Catalysis

Dibenzoxazepinones exhibit unique biological activities and serve as building blocks for synthesizing pharmaceutical compounds. Despite remarkable advancements in organic chemistry and recent developments in synthetic approaches to dibenzoxazepinone motifs, there is a strong demand for more streamlined synthesis methods. The application of the catalytic C–H amination strategy, which enables the direct transformation of inert aromatic C–H bonds into C–N bonds, offers a rapid route to access dibenzoxazepinone frameworks. Hypervalent-iodine-catalyzed oxidative C–H amination has the potential to become an effective approach for synthesizing dibenzoxazepinones. In this study, we present our method of employing μ-oxo hypervalent iodine catalysis for intramolecular oxidative C–H amination of O-aryl salicylamides, facilitating the synthesis of target dibenzoxazepinone derivatives bearing various functional groups in a highly efficient manner.

Regioselective benzylation of imidazo[1,5-a]pyridines and indoles via iodine catalyzed reaction using alcohols - An approach to crystal structure prediction, DFT studies and Hirshfeld surface analysis

Iodine catalysed, regioselective C-1 benzylation of imidazo[1,5-a] pyridines and C-3 benzylation of indoles with diphenylmethanol has been developed. This new protocol provides an efficient protocol in the synthesis of the benzylation methodology as it targets exclusively CH bonds, even in presence of reactive NH bonds and variety of benzyl substituted indoles and imidazo[1,5-a] pyridines are synthesized with broad range of functionalities leads to the elegant formation of new CC bond under metal free conditions. This report represents a mild protocol for the synthesis of tris(heteroaryl/aryl) methanes from solid bench stable diarylmethanols. The products formed are interesting for their potential biological applications. The crystal structure of the compound 3k was determined by single crystal X-ray diffraction studies. The compound crystallized in triclinic crystal system with P-1 space group. The molecular structure is stabilized by short intermolecular interactions and intramolecular CH⋯N hydrogen bond interactions. The crystal structure also exhibits intermolecular CH⋯π, CCl⋯π and π⋯π stacking interactions. The intermolecular interactions are quantified through Hirshfeld surface analysis using fingerprint plots. The surface properties were analysed using 3D Hirshfeld surfaces. Further, the density functional theory calculations were carried to calculate the electronic properties of the molecule. The HOMO-LUMO energy gap is found to be 4.0981 eV. Finally, the chemically active sites on the molecule are identified by analysing the molecular electrostatic potential map.

Recent Progress of Iodine Catalysis Directed toward Environmentally more Benign and Sustainable Chemistry

Recent Progress of Iodine Catalysis Directed toward Environmentally more Benign and Sustainable Chemistry

Synthesis and Biological Evaluation of Substituted Fused Dipyranoquinolinones

New methyl-substituted, and diphenyl-substituted fused dipyranoquinolinones are prepared in excellent yields via the triple bond activation and 6-endo-dig cyclization of propargyloxycoumarin derivatives by gold nanoparticles supported on TiO2 in chlorobenzene under microwave irradiation. In the absence of gold nanoparticles, the methyl-substituted propargyloxycoumarin derivatives resulted in fused furopyranoquinolinones through Claisen rearrangement and 5-exo-dig cyclization. The intermediate propargyloxy-fused pyridocoumarins are prepared by propargylation of the corresponding hydroxy-fused pyridocoumarins. The methyl-substituted derivatives of the latter are synthesized in excellent yield by the three-component reaction of amino hydroxycoumarin with n-butyl vinyl ether under iodine catalysis. The diphenyl-substituted derivatives of hydroxy-fused pyridocoumarins are obtained, also, by the three-component reaction of amino hydroxycoumarin with benzaldehyde and phenyl acetylene catalyzed by iron (III) chloride. Preliminary biological tests of the title compounds indicated lipoxygenase (LOX) (EC 1.13.11.12) inhibitory activity (60–100 μM), whereas compound 28a, with IC50 = 10 μM, was found to be a potent LOX inhibitor and a possible lead compound. Only compounds 10b and 28b significantly inhibited lipid peroxidation.

Iodanyl Radical Catalysis.

ConspectusHypervalent iodine reagents find application as selective chemical oxidants in a diverse array of oxidative transformations. The utility of these reagents is often ascribed to (1) the proclivity to engage being selective two-electron redox transformations; (2) facile ligand exchange at the three-centered, four-electron (3c-4e) hypervalent iodine-ligand (I-X) bonds; and (3) the hypernucleofugacity of aryl iodides. One-electron redox and iodine radical chemistry is well-precedented in the context of inorganic hypervalent iodine chemistry─for example, in the iodide-triiodide couple that drives dye-sensitized solar cells. In contrast, organic hypervalent iodine chemistry has historically been dominated by the two-electron I(I)/I(III) and I(III)/I(V) redox couples, which results from intrinsic instability of the intervening odd-electron species. Transient iodanyl radicals (i.e., formally I(II) species), generated by reductive activation of hypervalent I-X bonds, have recently gained attention as potential intermediates in hypervalent iodine chemistry. Importantly, these open-shell intermediates are typically generated by activation of stoichiometric hypervalent iodine reagents, and the role of the iodanyl radical in substrate functionalization and catalysis is largely unknown.Our group has been interested in advancing the chemistry of iodanyl radicals as intermediates in the sustainable synthesis of hypervalent I(III) and I(V) compounds and as novel platforms for substrate activation at open-shell main-group intermediates. In 2018, we disclosed the first example of aerobic hypervalent iodine catalysis by intercepting reactive intermediates in aldehyde autoxidation chemistry. While we initially hypothesized that the observed oxidation was accomplished by aerobically generated peracids via a two-electron I(I)-to-I(III) oxidation reaction, detailed mechanistic studies revealed the critical role of acetate-stabilized iodanyl radical intermediates. We subsequently leveraged these mechanistic insights to develop hypervalent iodine electrocatalysis. Our studies resulted in the identification of new catalyst design principles that give rise to highly efficient organoiodide electrocatalysts that operate at modest applied potentials. These advances addressed classical challenges in hypervalent iodine electrocatalysis related to the need for high applied potentials and high catalyst loadings. In some cases, we were able to isolate the anodically generated iodanyl radical intermediates, which allowed direct interrogation of the elementary chemical reactions characteristic of iodanyl radicals. Both substrate activation via bidirectional proton-coupled electron transfer (PCET) reactions at I(II) intermediates and disproportionation reactions of I(II) species to generate I(III) compounds have been experimentally validated.This Account discusses the emerging synthetic and catalytic chemistry of iodanyl radicals. Results from our group have demonstrated that these open-shell species can play a critical role in sustainable synthesis of hypervalent iodine reagents and play a heretofore unappreciated role in catalysis. Realization of I(I)/I(II) catalytic cycles as a mechanistic alternative to canonical two-electron iodine redox chemistry promises to open new avenues to application of organoiodides in catalysis.

Iodine-Catalyzed Claisen-Rearrangements of Allyl Aryl Ethers and Subsequent Iodocyclizations.

Iodine can be considered as the simplest halogen-bond donor. Previous investigations have revealed its remarkable catalytic effect in various reactions. The catalytic activity of iodine can often even compete with that of traditional Lewis acids. So far, iodine was typically used to activate carbonyl derivatives like Michael acceptors. We now demonstrate that iodine can also be used to activate allyl aryl ethers in Claisen rearrangements. The formed ortho-allylic phenols rapidly undergo iodocyclizations to afford dihydrobenzofurans, which are important building blocks for medicinal applications. A comparison with different catalysts further highlights the potential of iodine catalysis for this reaction. Computational and mechanistic investigations provide deeper insights into the underlying non-covalent interactions and their role for the catalysis.

Aqueous C-H aminomethylation of phenols by iodine catalysis.

A transition-metal-free strategy regarding an iodine-sodium percarbonate catalysis to achieve the ortho-aminomethylation of phenols in aqueous media has been developed. This method can effectively broaden a wide range of phenols, tolerate sensitive functional groups, and achieve the late-stage functionalization of ten functional molecules that contain phenolic structures.

Recent Advances of Green Catalytic System I2/DMSO in C–C and C–Heteroatom Bonds Formation

Developing a green, practical and efficient method for the formation of C–C and C–Heteroatom bonds is an important topic in modern organic synthetic chemistry. In recent years, the I2/DMSO catalytic system has attracted wide attention because of its green, high efficiency, atomic economy, low cost, mild reaction conditions and it is environment-friendly, which is more in line with the requirements of sustainable chemistry. Heteroatom-containing compounds have shown lots of important applications in pharmaceutical synthesis, agrochemicals, material chemistry and organic dyes. At present, the I2/DMSO catalytic system has been successfully applied to the synthesis of various heteroatom-containing compounds. The C–C and C–Heteroatom bonds have been formed efficiently, which has been proved to be a green and mild catalytic system. In this review, the research achievements of the I2/DMSO catalytic system in the formation of C–C and C–Heteroatom bonds from 2015 to date are described, and the research area is prospected. This review attempts to reveal the general law of iodine catalysis and lay a foundation for the design of new reactions.

Cyclopropene activation via I(I)/I(III) catalysis: Proof of principle and application in direct tetrafluorination

Preliminary validation of cyclopropene activation by an I(I)/I(III) catalysis manifold is disclosed to enable the direct tetrafluorination of 3,3-diarylcyclopropenes. This transformation occurs through the in situ generation of ArI(III)F2, with inexpensive iodobenzene, amine·HF complexes and Selectfluor® serving as catalyst, fluoride source and oxidant, respectively. Leveraging this approach, it has been possible to generate four C(sp3)-F bonds in a single operation (up to 44%). A Hammett study revealed that the reaction has a very narrow tolerance window with respect to the p-substituent of the aryl groups. Through a process of reaction deconstruction, a mechanism involving two discrete catalytic processes is proposed. Whereas the first cycle results in the ring opening fluorination of the 3,3-diarylcyclopropene, the second proceeds via a fluorination/phenonium ion rearrangement to liberate a tetrafluorinated diarylethane. This study adds hypervalent iodine catalysis to the plenum of strategies that facilitate cyclopropene activation.

Stereocontrolled Synthesis of Fluorinated Isochromans via Iodine(I)/Iodine(III) Catalysis.

The success of saturated, fluorinated heterocycles in contemporary drug discovery provides a stimulus for creative endeavor in main group catalysis. Motivated by the ubiquity of isochromans across the bioactive small molecule spectrum, the prominence of the anomeric effect in regulating conformation, and the metabolic lability of the benzylic position, iodine(I)/iodine(III) catalysis has been leveraged for the stereocontrolled generation of selectively fluorinated analogs. To augment the current arsenal of fluorocyclization reactions involving carboxylic acid derivatives, the reaction of readily accessible 2‐vinyl benzaldehydes is disclosed (up to >95 : 05 d.r. and 97 : 03 e.r.). Key stereoelectronic interactions manifest themselves in the X‐ray crystal structures of the products, thereby validating the [CH2‐CHF] fragment as a stereoelectronic mimic of the [O‐CH(OR)] acetal motif.