Electrophilic Halogenation Research Articles

Cover Picture: Enantioselective halogenation via asymmetric phase‐transfer catalysis (BKCS 07/2022)

Chiral phase‐transfer catalyst brings insoluble ionic halogenating reagents into the solution and mediates enantioselective halogenations by forming highly ordered asymmetric environments through ion pairing and/or hydrogen‐bonding interactions with the substrate and the reagent. Such approaches have been enormously successful in both nucleophilic and electrophilic halogenations. In this review, the remarkable examples over the past decade are surveyed with brief mechanistic discussions. image

Interception of enamine intermediates in reductive functionalization of lactams by sodium hydride: Synthesis of 2-cyano-3-iodo piperidines and pyrrolidines

Facile conversion of 2-piperidones and 2-pyrrolidones into 2-cyano-3-iodo piperidines or pyrrolidines has been accomplished by the sequence of 1) controlled hydride reduction of lactams using sodium hydride (NaH) in the presence of sodium iodide (NaI); 2) silylation of anionic hemiaminal intermediates to facilitate deoxygenation to form an equilibrium mixture of iminium cations and enamines-silanol pair; 3) interception of enamine intermediates by electrophilic iodination to generate iodonium ions; 4) nucleophilic cyanation of the resultant iminium cations. The overall transformation proceeded in highly diastereoselective fashion. The resultant 2-cyano-3-iodo piperidines were converted into 2-cyanotetrahydropyridines, which could be used for [2 + 2]-annulation or ring-expansion reactions with reactive benzyne or alkyne species, respectively.

Iridium-Catalyzed Hydroiodination and Formal Hydroamination of Olefins with N-Iodo Reagents and Molecular Hydrogen: An Umpolung Strategy.

We herein report a convenient method to convert olefins to organic iodides and amines using an Ir/ZhaoPhos catalyst, molecular hydrogen, and an electrophilic iodine(I) reagent. High yields and regioselectivities were obtained under mild conditions. In addition, basic workup with potassium carbonate leads to C-N products. Control experiments and DFT calculations tentatively excluded the pathway involving the in situ formation of HI. Instead, a catalytic cycle involving the hydrogenation of the haliranium ion intermediate was proposed.

Synthesis of 5‐Alkynyl and 2,5‐Dialkynyl‐L‐histidines

AbstractSynthesis of previously unknown 5‐alkynyl‐L‐histidines and 2,5‐dialkynyl‐L‐histidines is reported. Fully protected 5‐iodo‐ and 2,5‐diiodo‐L‐histidines obtained upon electrophilic iodination underwent cross‐coupling alkynylation reaction with terminal alkynes in the presence of palladium‐copper co‐catalytic system to afford ring‐modified histidines in 62–85 % yield. The method is also successfully utilized to late‐stage alkynylate a 5‐iodohistidine residue containing peptide.

HFIP-promoted halo-carbocyclizations of N- and O-tethered arene-alkene substrates to access all halo (X = Br, I, Cl)-functionalized tetrahydroquinoline and chroman cores.

A new method for the stereoselective metal-, additive- and oxidant-free Friedel-Crafts-type halo-carbocyclization of N- and O-tethered arene-olefin substrates is reported, involving reaction with a suitable electrophilic halogenating reagent (NXS/DCDMH) in hexafluoroisopropanol. All halo (X = Br, I, Cl)-functionalized tetrahydroquinolines and chromans were obtained in excellent yields and with high levels of diastereocontrol (dr = >99 : 1), and these products were successfully transformed into synthetically useful compounds such as dihydroquinolines and partial or full azahelicene compounds.

Electrophilic halogenations of propargyl alcohols: paths to α-haloenones, β-haloenones and mixed β,β-dihaloenones.

The Meyer–Schuster rearrangement of propargyl alcohols or alkynols leading to α,β-unsaturated carbonyl compounds is well known. Yet, electrophilic halogenations of the same alkynols and their alkoxy, ester and halo derivatives are inconspicuous. This review on the halogenation reactions of propargyl alcohols and derivatives intends to give a perspective from its humble direct halogenation beginning to the present involving metal catalysis. The halogenation products of propargyl alcohols include α-fluoroenones, α-chloroenones, α-bromoenones and α-iodoenones, as well as β-haloenones and symmetrical and mixed β,β-dihaloenones. They are, in essence, tri and tetrasubstituted alkenes carrying halo-functionalization at the α- or β-carbon. This is a potential stepping stone for further construction towards challenging substituted alkenones via Pd-catalysed coupling reactions.

DABCO as a practical catalyst for aromatic halogenation with N-halosuccinimides.

A simple and practical synthetic approach for synthesis of aromatic halides is developed. Simple Lewis base, DABCO, is used as the catalyst. This arene halogenation process proceedes conveniently and efficiently at ambient conditions, providing the desired products in good to excellent yields and selectivity.

Synthesis and Evaluation of 3-Halobenzo[b]thiophenes as Potential Antibacterial and Antifungal Agents

The global health concern of antimicrobial resistance has harnessed research interest to find new classes of antibiotics to combat disease-causing pathogens. In our studies, 3-halobenzo[b]thiophene derivatives were synthesized and tested for their antimicrobial activities using the broth microdilution susceptibility method. The 3-halo substituted benzo[b]thiophenes were synthesized starting from 2-alkynyl thioanisoles using a convenient electrophilic cyclization methodology that utilizes sodium halides as the source of electrophilic halogens when reacted along with copper(II) sulfate. This environmentally benign methodology is facile, uses ethanol as the solvent, and results in 3-halo substituted benzo[b]thiophene structures in very high yields. The cyclohexanol-substituted 3-chloro and 3-bromobenzo[b]thiophenes resulted in a low MIC of 16 µg/mL against Gram-positive bacteria and yeast. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) properties of the compounds were determined. The compounds with the lowest MIC values showed excellent drug-like properties with no violations to Lipinski, Veber, and Muegge filters. The time-kill curve was obtained for cyclohexanol-substituted 3-chlorobenzo[b]thiophenes against Staphylococcus aureus, which showed fast bactericidal activity at MIC.

Organic Compound with Potential for X-ray Imaging Applications.

A radiopaque compound, namely, 4,4-bis(4-hydroxy-3,5-diiodophenyl)pentanoic acid, was synthesized by the electrophilic aromatic iodination of 4,4-bis(4-hydroxyphenyl)pentanoic acid using sodium iodide and sodium hypochlorite. The active iodines created by hypochlorite were selectively bound to the ortho positions of the diphenolic acid and obtained a tetraiodo compound. Characterization of this iodinated compound was accomplished by routine methods such as Fourier transform infrared (FTIR) spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, energy-dispersive X-ray spectroscopy, mass spectroscopy, UV–Vis spectroscopy, and thermogravimetry. The iodine content in the compound was as high as 64% by weight and therefore expected to possess substantial radiopacity. A 5% solution of the compound in dimethyl sulfoxide exhibited radiopacity of 885 ± 7 Hounsfield Units when tested with computed tomography (CT) scanner. In vitro cytotoxicity test performed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that the compound was noncytotoxic to L929 fibroblast cells up to the level of 0.8 mg/mL concentration. Overall results indicate that this highly radiopaque compound has the potential to be used for X-ray imaging in the clinical scenario.

The Influence of Secondary Interactions on the [N-I-N]+ Halogen Bond.

[Bis(pyridine)iodine(I)]+ complexes offer controlled access to halonium ions under mild conditions. The reactivity of such stabilized halonium ions is primarily determined by their three‐center, four‐electron [N−I−N]+ halogen bond. We studied the importance of chelation, strain, steric hindrance and electrostatic interaction for the structure and reactivity of halogen bonded halonium ions by acquiring their 15N NMR coordination shifts and measuring their iodenium release rates, and interpreted the data with the support of DFT computations. A bidentate ligand stabilizes the [N−I−N]+ halogen bond, decreasing the halenium transfer rate. Strain weakens the bond and accordingly increases the release rate. Remote modifications in the backbone do not influence the stability as long as the effect is entirely steric. Incorporating an electron‐rich moiety close by the [N−I−N]+ motif increases the iodenium release rate. The analysis of the iodine(I) transfer mechanism highlights the impact of secondary interactions, and may provide a handle on the induction of stereoselectivity in electrophilic halogenations.

Cyclic Haloiodanes: Syntheses, Applications and Fundamental Studies

AbstractHypervalent iodine reagents are powerful tools in contemporary organic synthesis. They have found numerous applications in modern oxidative transformations. The unique reactivity of hypervalent iodine allows access to unconventional electrophilic synthons. For example, electrophilic halogenation chemistry has been greatly expanded by the study of various haloiodanes. Cyclic λ3‐haloiodanes are versatile reagents which can promote reactions such as halogenations, halocyclizations and oxidations. Their peculiar reactivity sets them apart from traditional sources of electrophilic halogens. Furthermore, they offer a broad range of reactivities which have been exploited in more diversified transformations. This review summarizes the different syntheses and derivatives of these cyclic haloiodanes, their applications and mechanistic insights as well as the relevant computational, structural and kinetic studies.

Oxoammonium salts are catalysing efficient and selective halogenation of olefins, alkynes and aromatics

Electrophilic halogenation reactions have been a reliable approach to accessing organohalides. During the past decades, various catalytic systems have been developed for the activation of haleniums. However, there is still a short of effective catalysts, which could cover various halogenation reactions and broad scope of unsaturated compounds. Herein, TEMPO (2,2,6,6-tetramethylpiperidine nitroxide) and its derivatives are disclosed as active catalysts for electrophilic halogenation of olefins, alkynes, and aromatics. These catalysts are stable, readily available, and reactive enough to activate haleniums including Br+, I+ and even Cl+ reagents. This catalytic system is applicable to various halogenations including haloarylation of olefins or dibromination of alkynes, which were rarely realized in previous Lewis base catalysis or Lewis acid catalysis. The high catalytic ability is attributed to a synergistic activation model of electrophilic halogenating reagents, where the carbonyl group and the halogen atom are both activated by present TEMPO catalysis.

Synthesis of Long-Chain Alkanoyl Benzenes by an Aluminum(III) Chloride-Catalyzed Destannylative Acylation Reaction.

This paper describes the facile synthesis of haloaryl compounds with long-chain alkanoyl substituents by the destannylative acylation of haloaryls bearing tri-n-butyltin (Bu3Sn) substituents. The method allows the synthesis of many important synthons for novel functional materials in a highly efficient manner. The halo-tri-n-butyltin benzenes are obtained by the lithium-halogen exchange of commercially available bis-haloarenes and the subsequent reaction with Bu3SnCl. Under typical Friedel-Crafts conditions, i.e., the presence of an acid chloride and AlCl3, the haloaryls are acylated through destannylation. The reactions proceed fast (<5 min) at low temperatures and thus are compatible with aromatic halogen substituents. Furthermore, the method is applicable to para-, meta-, and ortho-substitution and larger systems, as demonstrated for biphenyls. The generated tin byproducts were efficiently removed by trapping with silica/KF filtration, and most long-chain haloaryls were obtained chromatography-free. Molecular structures of several products were determined by X-ray single-crystal diffraction, and the crystal packing was investigated by mapping Hirshfeld surfaces onto individual molecules. A feasible reaction mechanism for the destannylative acylation reaction is proposed and supported through density functional theory (DFT) calculations. DFT results in combination with NMR-scale control experiments unambiguously demonstrate the importance of the tin substituent as a leaving group, which enables the acylation.

Impacts of diphenylamine NSAID halogenation on bioactivation risks

Diphenylamine NSAIDs are highly prescribed therapeutics for chronic pain despite causing symptomatic hepatotoxicity through mitochondrial damage in five percent of patients taking them. Differences in toxicity are attributed to structural modifications to the diphenylamine scaffold rather than its inherent toxicity. We hypothesize that marketed diphenylamine NSAID substituents affect preference and efficiency of bioactivation pathways and clearance. We parsed the FDA DILIrank hepatotoxicity database and modeled marketed drug bioactivation into quinone-species metabolites to identify a family of seven clinically relevant diphenylamine NSAIDs. These drugs fell into two subgroups, i.e., acetic acid and propionic acid diphenylamines, varying in hepatotoxicity risks and modeled bioactivation propensities. We carried out steady-state kinetic studies to assess bioactivation pathways by trapping quinone-species metabolites with dansyl glutathione. Analysis of the glutathione adducts by mass spectrometry characterized structures while dansyl fluorescence provided quantitative yields for their formation. Resulting kinetics identified four possible bioactivation pathways among the drugs, but reaction preference and efficiency depended upon structural modifications to the diphenylamine scaffold. Strikingly, diphenylamine dihalogenation promotes formation of quinone metabolites through four distinct metabolic pathways with high efficiency, whereas those without aromatic halogen atoms were metabolized less efficiently through two or fewer metabolic pathways. Overall metabolism of the drugs was comparable with bioactivation accounting for 4–13% of clearance. Lastly, we calculated daily bioload exposure of quinone-species metabolites based on bioactivation efficiency, bioavailability, and maximal daily dose. The results revealed stratification into the two subgroups; propionic acid diphenylamines had an average four-fold greater daily bioload compared to acetic acid diphenylamines. However, the lack of sufficient study on the hepatotoxicity for all drugs prevents further correlative analyses. These findings provide critical insights on the impact of diphenylamine bioactivation as a precursor to hepatotoxicity and thus, provide a foundation for better risk assessment in drug discovery and development.

Photoredox Catalyzed Dealkylative Aromatic Halogen Substitution with Tertiary Amines.

A reaction of aromatic halides bearing electron-withdrawing groups with tertiary amines in the presence of an iridium catalyst under blue light irradiation is described. Products of the aromatic substitution of the halide by the dialkylamino fragment are obtained. The interaction of aryl radicals with tertiary amines to generate zwitterionic radical species is believed to be the key factor responsible for the reaction efficiency.

Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

Halocyclization of alkenes is a powerful bond-forming tool in synthetic organic chemistry and a key step in natural product biosynthesis, but catalyzing halocyclization with high enantioselectivity remains a challenging task. Identifying suitable enzymes that catalyze enantioselective halocyclization of simple olefins would therefore have significant synthetic value. Flavin-dependent halogenases (FDHs) catalyze halogenation of arene and enol(ate) substrates. Herein, we reveal that FDHs engineered to catalyze site-selective aromatic halogenation also catalyze non-native bromolactonization of olefins with high enantioselectivity and near-native catalytic proficiency. Highly selective halocyclization is achieved by characterizing and mitigating the release of HOBr from the FDH active site using a combination of reaction optimization and protein engineering. The structural origins of improvements imparted by mutations responsible for the emergence of halocyclase activity are discussed. This expansion of FDH catalytic activity presages the development of a wide range of biocatalytic halogenation reactions.

Structural Variations among Marketed Diphenylamine NSAIDs Determine Preference and Efficiency for Four Possible Bioactivation Pathways

Diphenylamine NSAIDs are highly prescribed therapeutics for chronic pain despite causing symptomatic hepatotoxicity through mitochondrial damage in roughly five percent of the patients taking them. Studies attribute differences in toxicities to minor structural modifications to the diphenylamine scaffold rather than inherent toxicity of diphenylamine itself. We hypothesize that substituents of marketed diphenylamine NSAIDs determine the preference and efficiency of bioactivation pathways relative to overall drug clearance. We tested the hypothesis through a novel integration of bioinformatic, computational, and experimental approaches. Initially, we parsed the FDA DILIrank database containing liver toxicity information on marketed drugs and modeled their potential bioactivation into quinones to identify a family of seven clinically relevant diphenylamine NSAIDs including the well-studied diclofenac. These drugs fell into two subgroups, i.e. acetic acid and propionic acid diphenylamines, varying in hepatotoxicity risks and modeled bioactivation propensities. Next, we carried out novel steady-state kinetic studies to assess bioactivation pathways by trapping quinones with dansyl glutathione. Analysis of the glutathione adducts by MS characterized structures while dansyl fluorescence provided quantitative yields for their formation over time. The resulting kinetics identified four possible bioactivation pathways among the drugs, but the preference and efficiency of reactions depended upon structural modifications to the diphenylamine scaffold. Strikingly, diphenylamine dihalogenation promotes the formation of quinone metabolites through four distinct metabolic pathways with high efficiency, whereas those without aromatic halogen atoms were metabolized less efficiently through two or fewer metabolic pathways. Despite differences in bioactivation, overall metabolism of the drugs was comparable with bioactivation accounting for 4 to 13% of clearance. Lastly, we calculated daily bioload exposure from the quinone metabolites based on bioactivation efficiency, drug bioavailability, and maximal daily dose. The results revealed stratification into the two diphenylamine subgroups; propionic acid diphenylamines had a nearly four-fold greater daily bioload on average compared to acetic acid diphenylamines. However, the lack of sufficient study on the corresponding liver toxicities for all drugs prevented a more correlative analysis. Future work will identify responsible enzymes to understand the role of these structural modifications in metabolic clearance and bioactivation and subsequent drug-induced liver injury. These findings will provide critical insights on the impact of diphenylamine bioactivation as a precursor to DILI and thus, provide a foundation for better risk assessment in drug discovery and development.

A novel approach for the detection and identification of sulfur mustard using liquid chromatography-electrospray ionization-tandem mass spectrometry based on its selective oxidation to sulfur mustard monoxide with N-iodosuccinimide.

A new derivatization strategy for the detection and identification of sulfur mustard (HD) via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) is developed. The method incorporates selective oxidation of the sulfide group by the electrophilic iodine reagent N-iodosuccinimide (NIS) to produce sulfur mustard monoxide (HDSO). The derivatization reaction efficiencies were evaluated with acetonitrile extracts of soil, asphalt, cloth, Formica, and linoleum spiked with HD at concentrations of 50-5000 pg/ml and found to be similar to that with pure acetonitrile. The current derivatization approach is the first to preserve the identity of chloride groups and support HD regulation and evidentiary findings.

Ni–NiO heterojunctions: a versatile nanocatalyst for regioselective halogenation and oxidative esterification of aromatics

Herein, we report a facile method for the synthesis of Ni–NiO heterojunction nanoparticles, which we utilized for the nuclear halogenation reaction of phenol and substituted phenols usingN-bromosuccinimide (NBS).

Halogen bond-induced electrophilic aromatic halogenations.

In recent years, there has been increasing interest in utilising halogen bonds in organic synthesis, especially in aromatic halogenation reactions. N-Halosuccinimides and 1,3-dihalo-5,5-dimethylhydantoins are popular sources of halonium ions due to their ease of handling and low toxicities. Traditionally, these N-haloimides are activated by electrophiles, namely Brønsted and Lewis acids. The recent discovery of possible activation by nucleophilic Lewis base catalysts led to a paradigm shift in aromatic halogenation. Active functional motifs in Lewis base catalysts such as CS, R-S-R1, Ar-S-S-Ar, SO, Ar-NH2, and R2NH+Cl- form halogen bonds with the positively charged σ-hole of the halogen atoms: an essential interaction to produce halonium ions. This review highlights the evolution of the two modes of activation. Evidence of halogen bond formation from mechanistic studies of nucleophilic activation is also discussed herein.