Aromatic Iodination Research Articles

Elemental Sulfur-Mediated Aromatic Halogenation.

A method for aromatic halogenation using a combination of elemental sulfur (S8) and N-halosuccinimide has been developed. A catalytic quantity of elemental sulfur (S8) with N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) effectively halogenated less-reactive aromatic compounds, such as ester-, cyano-, and nitro-substituted anisole derivatives. No reaction occurred in the absence of S8, underscoring its crucial role in the catalytic activity. This catalytic system was also applicable to aromatic iodination with 1,3-diiodo-5,5-dimethylhydantoin.

Cyclic Diaryliodonium Salts: Eco‐Friendly and Versatile Building Blocks for Organic Synthesis

AbstractCyclic diaryliodoniums are an important class of high‐valent aromatic iodine reagents for the synthesis of various axially chiral biaryls and biaryl compounds. Moreover, transition‐metal‐catalyzed annulation has been established for the construction of various heterocyclic rings and ladder‐type π‐conjugated polycyclic aromatic hydrocarbons with readily available cyclic diaryliodoniums as the starting materials. As halogen‐bonding donors, cyclic aryliodoniums have been explored as organocatalysts in a variety of organic reactions. In this review, the application progress of cyclic diaryliodoniums has been systematically outlined, which highlights recent developments in the application reactions of cyclic diaryliodoniums, including synthetic application, limitations and reaction mechanisms in representative cascade reactions to provide insights for the development prospects of cyclic diaryliodoniums.magnified image

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.

Eco-friendly and Green Procedure for Iodination of Reactive Aromatics Using PEG 400-I2/HIO3 Combination

Background: Iodination of organic substrate is an important reaction for synthesis of pharmacological active molecules. Methods: In view of these concerns, we reported the convenient procedure for synthesis of iodo compounds using iodine and iodic acid in PEG-400.We have reported the eco-friendly procedure for preparation of aromatic iodo compounds using iodine and iodic acid in green reaction media as polyethylene glycol (PEG-400). Results: The iodination of some aromatic compounds such as benzaldehydes, acetophenones, phenols, amines and heterocyclic compounds carried out using iodine, iodic acid and PEG-400. The synthesized substituted aromatic iodo compounds were confirmed based on spectral characterization and mixed melting points. Conclusion: The method comprises several advantages such as simple reaction procedure, easy isolation, quantitative yields, and purity of iodo products.

NCBSI/KI: A Reagent System for Iodination of Aromatics through In Situ Generation of I-Cl.

In situ iodine monochloride (I-Cl) generation followed by iodination of aromatics using NCBSI/KI system has been developed. The NCBSI reagent requires no activation due to longer bond length, lower bond dissociation energy, and higher absolute charge density on nitrogen. The system is adequate for mono- and diiodination of a wide range of moderate to highly activated arenes with good yield and purity. Moreover, the precursor N-(benzenesulfonyl)benzenesulfonamide can be recovered and transformed to NCBSI, making the protocol eco-friendly and cost-effective.

Application of Electrochemical Processes to Classical Iodocyclisation: Utility for Selectivity and Mechanistic Insight

AbstractThe hazards and difficulties of handling elemental halogens such as I2 can be circumvented through the electrochemical generation of these species in situ and ‘on‐demand’. Advantages of this approach include the halogen being introduced into the reaction mixture at a steady rate, ensuring low concentrations to prevent halogenation of reactive aromatic rings. We also demonstrate that the Lewis acid required to promote this reaction, a Zn(II) salt, can also be generated in situ from a zinc‐coated graphite electrode in a clean and energy‐efficient manner. Mechanistic studies indicate an unusual pathway, which provides selectivity for the iodocyclisation without the often‐problematic electrophilic aromatic iodination of the aryl ring.

Iodine biofortification through expression of HMT, SAMT and S3H genes in Solanum lycopersicum L.

The uptake process and physiological reaction of plants to aromatic iodine compounds have not yet been documented. The aim of this research was to compare uptake by tomato plants of KI and KIO3, as well as of organic iodine compounds – 5-ISA (5-iodosalicylic acid), 3,5-diISA (3,5-diiodosalicylic acid), 2-IBeA (2-iodobenzoic acid), 4-IBeA (4-iodobenzoic acid) and 2,3,5-triIBeA (2,3,5-triiodobenzoic acid). Only 2,3,5-triIBeA had a negative influence on plant development. All organic iodine compounds were taken up by roots and transported to leaves and fruits. Among all the compounds applied, the most efficiently transferred iodine was 2-IBeA – to fruits, and 4-IBeA – to leaves. The order of iodine accumulation in fruit cell compartments was as follows: organelles > cell walls > soluble portions of cells; for leaf and root cells, it was: organelles > cell walls or soluble portions, depending on the compound applied. The compounds studied influence iodine metabolism through expression of the HMT gene which encodes halide ion methyltransferase in leaves and roots. Also, their influence on modification of the activity of the SAMT and S3H genes that encode salicylic acid carboxyl methyltransferase and salicylic acid 3-hydroxylase was established. It was discovered that exogenously applied 5-ISA, 3,5-diISA, 2-IBeA and 4-IBeA are genuinely (endogenously) synthesised in tomato plants; to date, this has not been described for the tomato, nor for any other species of higher plant.

Iodotriflamdation vs. Electrophilic Aromatic Iodination in the Reaction of N‐Phenyltriflamide with Alkenes

AbstractReaction of N‐phenyltriflamide with styrene, p‐chlorostyrene, vinylcyclohexane and α‐methylstyrene in oxidative system (t‐BuOCl + NaI) gives three types of products: (i) of aromatic iodination of the reagent – N‐(4‐iodophenyl)triflamide and N‐(2,4‐diiodophenyl)triflamide; (ii) of oxidative addition of the iodinated reagent to the substrate with different regioselectivity – N‐[2‐iodo‐1‐(aryl)ethyl]‐N‐(4‐iodophenyl)triflamides or N‐(2‐cyclohexyl‐2‐iodoethyl)‐N‐(4‐iodophenyl)triflamide; (iii) of chloro(oxy)iodination of the substrate – 2‐iodo‐1‐phenylethanol, 1‐chloro‐4‐(1‐chloro‐2‐iodoethyl)benzene, 1‐cyclohexyl‐2‐iodoethanol and 1‐iodo‐2‐phenylpropan‐2‐ol. Different regioselectivity of iodosulfonamidation for different alkenes and the competition between electrophilic aromatic iodination and iodotriflamidation are explained and the mechanism is proposed based on the results of quantum chemical calculations and the NBO analysis.

Syntheses, structures, and stabilities of aliphatic and aromatic fluorous iodine(I) and iodine(III) compounds: the role of iodine Lewis basicity.

The title molecules are sought in connection with various synthetic applications. The aliphatic fluorous alcohols RfnCH2OH (Rfn = CF3(CF2)n–1; n = 11, 13, 15) are converted to the triflates RfnCH2OTf (Tf2O, pyridine; 22–61%) and then to RfnCH2I (NaI, acetone; 58–69%). Subsequent reactions with NaOCl/HCl give iodine(III) dichlorides RfnCH2ICl2 (n = 11, 13; 33–81%), which slowly evolve Cl2. The ethereal fluorous alcohols CF3CF2CF2O(CF(CF3)CF2O)xCF(CF3)CH2OH (x = 2–5) are similarly converted to triflates and then to iodides, but efforts to generate the corresponding dichlorides fail. Substrates lacking a methylene group, RfnI, are also inert, but additions of TMSCl to bis(trifluoroacetates) RfnI(OCOCF3)2 appear to generate RfnICl2, which rapidly evolve Cl2. The aromatic fluorous iodides 1,3-Rf6C6H4I, 1,4-Rf6C6H4I, and 1,3-Rf10C6H4I are prepared from the corresponding diiodides, copper, and RfnI (110–130 °C, 50–60%), and afford quite stable RfnC6H4ICl2 species upon reaction with NaOCl/HCl (80–89%). Iodinations of 1,3-(Rf6)2C6H4 and 1,3-(Rf8CH2CH2)2C6H4 (NIS or I2/H5IO6) give 1,3,5-(Rf6)2C6H3I and 1,2,4-(Rf8CH2CH2)2C6H3I (77–93%). The former, the crystal structure of which is determined, reacts with Cl2 to give a 75:25 ArICl2/ArI mixture, but partial Cl2 evolution occurs upon work-up. The latter gives the easily isolated dichloride 1,2,4-(Rf8CH2CH2)2C6H3ICl2 (89%). The relative thermodynamic ease of dichlorination of these and other iodine(I) compounds is probed by DFT calculations.

Magnesiate Addition/Ring-Expansion Strategy To Access the 6-7-6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids.

A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6-7-6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C-N bond formation and subsequent elaboration.

N‐Iodosuccinimide (NIS) in Direct Aromatic Iodination

N‐Iodosuccinimide (NIS) in pure trifluoroacetic acid (TFA) offers a time‐efficient and general method for the iodination of a wide range of mono‐ and disubstituted benzenes at room temperature, as demonstrated in this paper. The starting materials were generally converted into mono‐iodinated products in less than 16 hours at room temperature, without byproducts. A few deactivated substrates needed addition of sulfuric acid to increase the reaction rate. Another exception was methoxybenzenes that preferentially were iodinated by NIS in acetonitrile with only catalytic amounts of TFA.

Selective Claisen rearrangement and iodination for the synthesis of polyoxygenated allyl phenol derivatives

Allyl aryl ethers and allyl phenol derivatives were prepared starting from commercial or synthetized phenols. Either Williamson reaction or Et2AlCl catalyzed Claisen rearrangement was performed to obtain the polyoxygenated molecules. The pivotal allyl phenols were then modified by methylation, iodocyclization or electrophilic aromatic iodination to afford the polyoxygenated derivatives in good to excellent yields. Additionally, their antibacterial properties were also investigated against Gram-positive and Gram-negative bacteria.

Tuning transthyretin amyloidosis inhibition properties of iododiflunisal by combinatorial engineering of the nonsalicylic ring substitutions.

Two series of iododiflunisal and diflunisal analogues have been obtained by using a two step sequential reaction solution-phase parallel synthesis. The synthesis combined an aqueous Suzuki-Miyaura cross-coupling and a mild electrophilic aromatic iodination step using a new polymer-supported iodonium version of Barluenga's reagent. From a selected set of 77 noniodinated and 77 iodinated diflunisal analogues, a subset of good transthyretin amyloid inhibitors has been obtained with improved turbidimetry inhibition constants, high binding affinity to transthyretin, and good selectivity for TTR compared to other thyroxine binding proteins.

125I-Labelled 2-Iodoestrone-3-sulfate: synthesis, characterization and OATP mediated transport studies in hormone dependent and independent breast cancer cells

IntroductionOrganic Anion Transporting Polypeptides (OATP) are a family of membrane associated transporters that facilitate estrone-3-sulphate (E3S) uptake by hormone dependent, post-menopausal breast cancers. We have established E3S as a potential ligand for targeting hormone dependent breast cancer cells, and in this study sought to prepare and investigate radioiodinated E3S as a tool to study the OATP system. Methods2- and 4-Iodoestrone-3-sulfates were prepared from estrone via aromatic iodination followed by a rapid and high yielding sulfation procedure. The resulting isomers were separated by preparative HPLC and verified by 1H NMR and analytical HPLC. Transport studies of 2- and 4-[125I]-E3S were conducted in hormone dependent (i.e. MCF-7) and hormone independent (i.e. MDA-MB-231) breast cancer cells in the presence or absence of the specific transport inhibitor, bromosulfophthalein (BSP). Cellular localization of OATP1A2, OATP2B1, OATP3A1 and OATP4A1 were determined by immunofluorescence analysis using anti-Na+/K+ ATPase-α (1:100 dilution) and DAPI as plasma membrane and nuclear markers, respectively. ResultsSignificantly (p<0.01) higher total accumulation of 2-[125I]-E3S was observed in hormone dependent MCF-7 as compared to hormone independent MDA-MB-231 breast cancer cells. In contrast 4-[125I]-E3S did not show cellular accumulation in either case. The efficiency of 2-[125I]-E3S transport (expressed as a ratio of Vmax/Km) was 2.4 times greater in the MCF-7 as compared to the MDA-MB-231 breast cancer cells. OATP1A2, OATP3A1 and OATP4A1 expression was localized in plasma membranes of MCF-7 and MDA-MB-231 cells confirming the functional role of these transporters in radioiodinated E3S cellular uptake. ConclusionAn efficient method for the preparation of 2- and 4-[125I]-E3S was developed and where the former demonstrated potential as an in vitro probe for the OATP system. The new E3S probe can be used to study the OATP system and as a platform to create radiopharmaceuticals for imaging breast cancer.

An in situ acidic carbon dioxide/glycol system for aerobic oxidative iodination of electron-rich aromatics catalyzed by Fe(NO3)3·9H2O

An environmentally benign CO2/glycol reversible acidic system was developed for the iron(III)-catalyzed aerobic oxidative iodination of electron-rich aromatics without the need for any conventional acid additive or organic solvent. Notably, moderate to high isolated yields (up to 97%) of the aryl iodides were attained with comparable regioselectivity when ferric nitrate nonahydrate was used as the catalyst with molecular iodine under 1 MPa of CO2.

2-Methoxyethanol: A remarkably efficient and alternative reaction medium for iodination of reactive aromatics using iodine and iodic acid

Remarkably effective iodination of reactive aromatics carried out using iodine and iodic acid in 2-methoxyethanol as an efficient and alternative reaction medium. The comparison has been made by carrying out iodination reaction in acetic acid and ethanol. The 2-methoxyethanol is found to be excellent reaction solvent in terms of clean reaction conditions, short reaction time giving quantitative yields of product and no need of further purification .

Investigation of 3′-debenzoyl-3′-(3-([124I]-iodobenzoyl))paclitaxel analog as a radio-tracer to study multidrug resistance in vivo

A study was carried out to identify a suitable radioactive paclitaxel analog and to use it to investigate tumor multidrug resistance in vivo. 3′-Debenzoyl-3′-(3-([124I]-iodobenzoyl))paclitaxel was prepared by aromatic iodination of 3′-debenzoyl-3′-(3-trimethylstannylbenzoyl)paclitaxel. Uptake of the labeled paclitaxel analog in nude mice bearing tumor with the paclitaxel sensitive cancer cell lines MCF7 and MDA-435/LCC6(WT), and multidrug resistant cell lines NCI/ADR-RES and MDA-435/LCC6(MDR), was studied. There was no difference in drug level between the sensitive and resistant MDA-435/LCC6 tumors at 6h post-injection. However, at 6h, there was a significant increase in drug level for the MCF7 tumor as compared with the NCI/ADR-RES tumor, presumably due to increased drug retention. At 24h, drug uptake/retention was significantly higher in both sensitive tumor cell lines as compared to their drug resistant counterparts. Pretreatment of mice with MDR transport modulators, Cyclosporine or tRA 96029, did not increase the level of labeled paclitaxel analog in the drug resistant MDA-435/LCC6(MDR) tumor. On the other hand, at 24h Cyclosporine apparently increased analog level in the drug sensitive MDA-435/LCC6(WT) tumor, aiding drug imaging studies.

Undesired Synthetic Outcomes During a Project-Based Organic Chemistry Laboratory Experience

While project-based chemistry laboratories are effective at providing second-year organic students with simulated research experience, there can be unexpected consequences when students carry out literature procedures. During an organic synthesis project, students accidentally added reagents for an aromatic iodination reaction in an incorrect order, resulting in the synthesis of nitrogen triiodide and the evacuation of the laboratory. A brief discussion of the events leading up to the reaction and steps taken to remediate the situation identify potential pitfalls in developing project-based chemistry laboratories.

ChemInform Abstract: Aromatic Iodination Using N‐Iodosaccharin in Room Temperature Ionic Liquids.

AbstractThe process can be applied to various arenes including those which are only modestly activated.

Aromatic iodination using N-iodosaccharin in room temperature ionic liquids

More reactive iodination conditions have been developed that combine the use of room temperature ionic liquids with N-iodosaccharin. Using these reaction conditions, even very modestly activated arenes such as toluene can be iodinated in good yield under very mild conditions.