Iodine Reagents Research Articles

Regioselective C(sp2)-H halogenation of pyrazolo[1,5-a]pyrimidines facilitated by hypervalent iodine(iii) under aqueous and ambient conditions.

An efficient and mild approach has been developed for the regio-selective direct C3 halogenation of pyrazolo[1,5-a]pyrimidines employing readily available potassium halide salts and a hypervalent iodine(iii) reagent at ambient temperature. The protocol is both practical and environmentally friendly, utilizing water as a green solvent, potassium halides as an inexpensive and bench stable halogen source and PIDA as a non-toxic reagent, enabling clean and efficient halogenation at room temperature. The procedure yields a range of C3 halogenated pyrazolo[1,5-a]pyrimidines in good to excellent yields. Mechanistic studies suggest the involvement of electrophilic substitution mechanism in the halogenation process.

Metal-free photoinduced generation and alkynylation of carbamoyl radicals: a facile synthesis of alkynyl amides.

A metal-free photoinduced alkynylation of carbamoyl radicals with hypervalent iodine(III) reagents for a facile synthesis of alkynyl amides is described. This protocol features good functional group tolerance and a broad substrate scope for direct synthesis of alkynyl amide derivatives in good to excellent yields under mild and redox-neutral reaction conditions. The synthetic application is demonstrated by the late-stage installation of alkynyl amides into natural products and active pharmaceutical relevant molecules. The mechanistic studies indicated the simultaneous existence of photoredox catalytic and direct photoexcited processes, and the quantum yields confirmed the occurrence of the radical chain propagation process.

Peptide coupling using recyclable bicyclic benziodazolone.

We report a greener peptide coupling using bicyclic benziodazolone and triarylphosphine as coupling reagents. Bicyclic benziodazolone also works as a base and can be recovered as the corresponding iodine(I) compound after use, which can be converted to the original iodine(III) reagent by electrolytic oxidation.

Site-selective benzylic C-H hydroxylation in electron-deficient azaheterocycles.

Benzylic C-H bonds can be converted into numerous functional groups, often by mechanisms that involve hydrogen atom transfer as the key bond breaking step. The abstracting species is most often an electrophilic radical, which makes these reactions best suited to electron-rich C-H bonds to achieve appropriate polarity matching. Thus, electron deficient systems such as pyridine and pyrimidine are relatively unreactive, and therefore underrepresented in substrate scopes. In this report, we describe a new method for heterobenzylic hydroxylation-essentially an unknown reaction in the case of pyrimidines-that makes use of an iodine(III) reagent to afford very high selectivity towards electron-deficient azaheterocycles in substrates with more than one reactive position and prevents over-oxidation to carbonyl products. The identification of key reaction byproducts supports a mechanism that involves radical coupling in the bond forming step.

Predicting bond dissociation energies of cyclic hypervalent halogen reagents using DFT calculations and graph attention network model.

Although hypervalent iodine(III) reagents have become staples in organic chemistry, the exploration of their isoelectronic counterparts, namely hypervalent bromine(III) and chlorine(III) reagents, has been relatively limited, partly due to challenges in synthesizing and stabilizing these compounds. In this study, we conduct a thorough examination of both homolytic and heterolytic bond dissociation energies (BDEs) critical for assessing the chemical stability and functional group transfer capability of cyclic hypervalent halogen compounds using density functional theory (DFT) analysis. A moderate linear correlation was observed between the homolytic BDEs across different halogen centers, while a strong linear correlation was noted among the heterolytic BDEs across these centers. Furthermore, we developed a predictive model for both homolytic and heterolytic BDEs of cyclic hypervalent halogen compounds using machine learning algorithms. The results of this study could aid in estimating the chemical stability and functional group transfer capabilities of hypervalent bromine(III) and chlorine(III) reagents, thereby facilitating their development.

Light promoted metal-free regio- and stereoselective isoperfluoropropylation of unactivated alkenes with an i-C3F7-iodine(iii) reagent

A visible light promoted eco-friendly regio- and stereo-selective isoperfluoropropylation of various terminal alkenes and alkynes with an i-C3F7-iodine(iii) (PFPI) reagent.

A decade of lessons in the activation of ArIL2 species.

Hypervalent iodine(iii) compounds of the general structure ArIL2 are widely used as oxidizing agents for a variety of applications across both organic and inorganic chemistry. Considerable work has been done on the activation of these compounds by tuning the ligands at the iodine centre. This perspective summarises the work of our and other groups on rectification of historically misidentified iodine(iii) reagents of this class, and the syntheses of activated species. Recent advances focusing on increasing the oxidative capacity of I(iii) moieties using Lewis and Brønsted acids and Lewis bases as well as the activation of halogens with I(iii) are discussed.

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes.

Iminoiodinanes comprise a class of hypervalent iodine reagents that is often encountered in nitrogen-group transfer (NGT) catalysis. In general, transition metal catalysts are required to effect efficient NGT to unactivated olefins because iminoiodinanes are insufficiently electrophilic to engage in direct aziridination chemistry. Here, we demonstrate that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) activates N-arylsulfonamide-derived iminoiodinanes for the metal-free aziridination of unactivated olefins. 1H NMR and cyclic voltammetry (CV) studies indicate that hydrogen-bonding between HFIP and the iminoiodinane generates an oxidant capable of direct NGT to unactivated olefins. Stereochemical scrambling during aziridination of 1,2-disubstituted olefins is observed and interpreted as evidence that aziridination proceeds via a carbocation intermediate that subsequently cyclizes. These results demonstrate a simple method for activating iminoiodinane reagents, provide analysis of the extent of activation achieved by H-bonding, and indicate the potential for chemical non-innocence of fluorinated alcohol solvents in NGT catalysis.

Iodide-umpolung catalytic system for non-traditional amide coupling from nitroalkanes and amines.

An N-iodosuccinimide (NIS) catalyst was developed for use in the non-traditional synthesis of amide derivatives from nitroalkanes and amines. In contrast to traditional oxidative catalysis, this catalytic system involves reversing the polarities of two catalytic components (umpolung) by means of a hypervalent iodine reagent. A variety of functional groups were tolerated in the reaction, suggesting that they have the potential for use in other types of oxidative catalytic reactions.

Unexpected dearomatization of N-protected 5-aminopyrazoles at ambient temperature: a simple route to highly functionalized pyrazolines.

We present a new strategy for the dearomatized hydroxylation of 5-aminopyrazoles using a hypervalent iodine reagent at room temperature. This method produces a series of 4-hydroxy-5-iminopyrazolines with good to excellent yields within 2 hours. Additionally, we demonstrate a domino reaction for the synthesis of 4-hydroxy-pyrazolones. Mechanistic studies indicate that the dearomatization proceeds through a cationic intermediate.

Synthesis of 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one and Skeleton construction of a type D spirobisnaphthalene structure via dearomatization by a high-valence iodine reagent and Diels–Alder reaction

The core skeleton syntheses of 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-2,5-dien-4-one 3 were explored. Then, two key skeleton molecules (5ah and 6d) were successfully constructed in 78% and 39% overall yields.

Isoxazole group directed Rh(III)-catalyzed alkynylation using TIPS-EBX.

A highly effective isoxazole directed ortho C-H alkynylation has been developed. Rhodium(III) catalyzed direct di-(and/or mono) alkynylation using a hypervalent iodine reagent (TIPS-EBX) is reported. The reaction proceeds with a wide substrate scope under benign conditions. Preliminary mechanistic studies support this chelation assisted C-H alkynylation.

Electrochemistry of Chelation-Stabilized Hypervalent Bromine(III) Compounds

Compared to hypervalent iodine(III) reagents, the bromine(III) counterparts provide attractive features such as higher electrophilicity, better nucleofugality of the bromanyl unit, and more driving force for oxidation processes.[1] Unprecedented synthetic transformations such as the Hofmann rearrangement of sulfonamides to the corresponding N-arylsulfamoyl fluorides,[2] oxidative coupling of alkynes and primary alcohols to conjugated enones,[3] regioselective C-H functionalization of non-activated alkanes[4] and a rare Bayer-Villinger-type oxidation of open-chain aliphatic aldehydes[5] show the great potential for hypervalent bromine(III). Unfortunately, conventional bromine(III) reagents are associated with poor stability, resulting in difficult-to-control reactivity and low compatibility with functional groups. Moreover, difficult preparation protocols, almost exclusively starting from the highly toxic and corrosive BrF3 precursor, currently limit the accessibility.[1b] In a previous study, we demonstrated chelation-stabilized hypervalent bromine(III) compounds possessing enhanced stability through the coordinating hexafluoro-2-hydroxypropanyl substituents, prepared through mild synthesis via an electrochemical approach (see Figure A). Anodic oxidation of bromoarene precursor 1 under galvanostatic conditions in an undivided cell leads to a benchtop-stable series of para-substituted derivatives of λ3-bromanes 2 that showed flexibly tunable redox potentials in a range from 1.86 V to 2.60 V vs. Ag/0.01 M AgNO3 making it possible to adjust the mediator to the substrate of interest. Based on electroanalytical, spectroscopic, and quantum chemical studies, mechanistic insights into the electrochemical generation and the reactivity of chelation-stabilized bromine(III) were obtained (Figure B),[6] which will be discussed in the present contribution.The utility of 2 was demonstrated with several synthetic applications, including C(sp 3)-H amidation of anilines to yield adduct 3 and oxidative coupling of anisoles yielding symmetric biaryls 4 (see Figure C). However, through the high stability of doubly chelated structure of bromanes, the number of synthetic applications remains relatively limited. In this context, we currently investigate the electrochemistry and reactivity of benzbromoxoles which are stabilized by only one chelating hexafluoro-2-hydroxypropanyl substituent.[7] The results of the mechanistic studies will be presented in this contribution.[1] (a) K. Miyamoto, M. Saito, S. Tsuji, T. Takagi, M. Shiro, M. Uchiyama, M. Ochiai, J. Am. Chem. Soc. 2021, 143, 9327-9331; (b) T. Wirth, T. Patra, B. Winterson, Synthesis 2021, 54, 1261-1271.[2] M. Ochiai, T. Okada, N. Tada, A. Yoshimura, K. Miyamoto, M. Shiro, J. Am. Chem. Soc. 2009, 131, 8392-8393.[3] M. Ochiai, A. Yoshimura, T. Mori, Y. Nishi, M. Hirobe, J. Am. Chem. Soc. 2008, 130, 3742-3743.[4] M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi, W. Nakanishi, Science 2011, 332, 448-451.[5] M. Ochiai, A. Yoshimura, K. Miyamoto, S. Hayashi, W. Nakanishi, J. Am. Chem. Soc. 2010, 132, 9236-9239.[6] N. Mohebbati, I. Sokolovs, P. Woite, M. Lokov, E. Parman, M. Ugandi, I. Leito, M. Roemelt, E. Suna, R. Francke, Chem. Eur. J. 2022, 28, e202200974.[7] I. Sokolovs, E. Suna, Org. Lett. 2023. Figure 1

Iodine(III)‐Aluminum or ‐Ammonium Salts for the Oxidative Aromatic Inorganic Functionalization

AbstractStrategies for introducing halogens and other inorganic groups in aromatic systems, usually involve non‐general and strong oxidative protocols which resulted in poor functional group compatibility. Iodine(III) reagents have emerged as an excellent alternative for the aromatic inorganic functionalization due to their low toxicity and strong oxidative character. In this context, the synergistic combination of different iodine(III) reagents and aluminum or ammonium salts including AlCl3, AlBr3, Al(NO3)3, NH4Cl, NH4Br and NH4I have recently demonstrated a great versatility for introducing the chlorine, bromine, iodine and nitro groups in aromatic systems, mainly phenols, anilines and some heterocycles. Using these common salts, their anions are softly oxidated by iodine(III) reagents, allowing the in situ formation of non‐described halogenating and nitrating species and in consequence, the introduction of these inorganic groups under an umpolung reactivity as chemical electrophilic synthons.

HTIB as an Efficient and Convenient Reagent for Oxidative Cleavage of C=N in Pyrimidinyl Hydrazones

This study is aimed to explore the efficiency of [hydroxy(tosyloxy)iodo]benzene (HTIB) in the oxidative cleavage of some pyrimidinyl hydrazones. The protocol involves stirring the hydrazone derivatives with HTIB in dichloromethane at room temperature. The oxidative cleavage of C = N in pyrimidinyl hydrazones regenerated parent ketones in high yields. The methodology has advantage of preventing over oxidation of carbonyl functionality.. KEYWORDS :[Hydroxy(tosyloxy)iodo]benzene, Hydrazone, Hypervalent iodine reagent, Oxidative cleavage, Pyrimidine.

A machine learning approach for predicting the reactivity power of hypervalent iodine compounds

The knowledge of chemical reactivity of substrates is a prerequisite to accurately design a chemical reaction; however, it has been a challenging task due to the slow trial-and-error experimental approaches and the high computational cost associated with in silico investigations. Artificial intelligence techniques could serve as an alternative to efficiently determine the relative reactivity of chemical entities. In the context of this research, we propose an artificial neural network model to predict the bond dissociation energies of hypervalent iodine reagents. An open-source cheminformatics package, namely, Mordred, was employed for calculating various 1D, 2D and topological descriptors. The approach utilizes a dataset of more than 1000 hypervalent iodine reagents, and the bond dissociation energies can be predicted with a remarkable accuracy, as suggested by an R2 score of 0.97 and a mean absolute error of 1.96 kcal/mol. Owing to the low cost and high efficiency, this machine learning approach can provide an alternative to the theoretical/experimental approaches to rationally design a chemical reaction and without having to go through the hassle of high-throughput experimentation to reach the desired reaction outcome. In an effort to make the model interpretable, a feature importance algorithm was applied, which identified descriptors contributing most to the development of the model. Features describing electronegativity and polarizability are some of the important contributors to the model’s training.

Metal‐Free Synthesis of 4‐Bromoisocoumarins through Brominative Annulation of 2‐Alkynylaryloate Esters Using In Situ Generated Transient Bromoiodane

AbstractHerein, we report a facile and proficient protocol for the synthesis of 4‐bromoisocoumarins through brominative annulation of 2‐alkynylaryloate esters with in situ generated bromoiodane using a simple hypervalent iodine reagent as mild oxidant and potassium bromide as the halogen source. Using this method, a broad range of valuable halogenated isocoumarins can be obtained in excellent yields at room temperature. Also, this reaction takes place in the absence of any metal catalyst and exhibits high functional group tolerance. Besides, the reaction can also be extended to the gram scale, and a catalytic approach was also demonstrated. Additionally, the prepared 4‐bromoisocoumarins were further transformed into important synthetic compounds.

Direct Access to Quinazolines and Pyrimidines from Unprotected Indoles and Pyrroles through Nitrogen Atom Insertion.

Recent advances in single-atom insertion reactions have opened up new synthetic approaches for molecular diversification. Developing innovative strategies to directly transform biologically relevant molecules, without any prefunctionalization, is key to further expanding the scope and utility of such transformations. Herein, the direct access to quinazolines and pyrimidines from the corresponding unprotected 1H-indoles and 1H-pyrroles is reported, relying on the implementation of lithium bis(trimethylsilyl)amide (LiHMDS) as a novel nitrogen atom source in combination with commercially available hypervalent iodine reagents. Further application of this strategy in late-stage settings demonstrates its potential in lead structure diversification campaigns.

Advancing Gold Redox Catalysis: Mechanistic Insights, Nucleophilicity-Guided Transmetalation, and Predictive Frameworks for the Oxidation of Aryl Gold(I) Complexes.

Gold redox catalysis, often facilitated by hypervalent iodine(III) reagents, offers unique reactivity but its progress is mainly hindered by an incomplete mechanistic understanding. In this study, we investigated the reaction between the gold(I) complexes [(aryl)Au(PR3 )] and the hypervalent iodine(III) reagent PhICl2 , both experimentally and computationally and provided an explanation for the formation of divergent products as the ligands bonded to the gold(I) center change. We tackled this essential question by uncovering an intriguing transmetalation mechanism that takes place between gold(I) and gold(III) complexes. We found that the ease of transmetalation is governed by the nucleophilicity of the gold(I) complex, [(aryl)Au(PR3 )], with greater nucleophilicity leading to a lower activation energy barrier. Remarkably, transmetalation is mainly controlled by a single orbital - the gold dx 2 -y 2 orbital. This orbital also has a profound influence on the reactivity of the oxidative addition step. In this way, the fundamental mechanistic basis of divergent outcomes in reactions of aryl gold(I) complexes with PhICl2 was established and these observations are reconciled from first principles. The theoretical model developed in this study provides a conceptual framework for anticipating the outcomes of reactions involving [(aryl)Au(PR3 )] with PhICl2 , thereby establishing a solid foundation for further advancements in this field.

Divergent Transformation of Carboxylic Acids through Photocatalytic Decarboxylation with Hypervalent Iodine Reagents

Divergent Transformation of Carboxylic Acids through Photocatalytic Decarboxylation with Hypervalent Iodine Reagents