Catalyst/Metal/Solvent-Free Markovnikov Hydrothiolation of Unactivated Alkenes with Dithiocarbamic Acids.

Catalyst-free Markovnikov-selective hydrothiolation of unactivated alkenes still remains a great challenge. Herein, we develop a catalyst/metal/solvent-free methodology for the Markovnikov hydrothiolation of unactivated alkenes with in situ prepared dithiocarbamic acids, providing a wide array of alkyl dithiocarbamates. A variety of terminal, internal, cyclic, and acyclic unactivated alkenes were applied successfully in this protocol. This three-component thiol-ene reaction can be considered as a new family of click reactions.

Bromination of endo-7-norbornene derivatives revisited: failure of a computational NMR method in elucidating the configuration of an organic structure.

Previously we reported on the bromination of endo-7-bromonorbornene at different temperatures yielding mixtures of addition products. The structural elucidations of the formed compounds were achieved by NMR spectroscopy. Particularly, the γ-gauche effect and long-range couplings were instrumental in assigning the stereochemistry of the adducts. However, in a recent paper, Novitskiy and Kutateladze claimed that based on an applied machine learning-augmented DFT method for computational NMR that the structure of the product, (1R,2R,3S,4S,7s)-2,3,7-tribromobicyclo[2.2.1]heptane was wrong. With the aid of their computational method, they revised a number of published structures, including ours, and assigned our product the structure (1R,2S,3R,4S,7r)-2,3,7-tribromobicyclo[2.2.1]heptane. To fit their revised structure, they proposed an alternative mechanism featuring a skeletal rearrangement without the intermediacy of a carbocation. Herein, we are not only confirming the structure originally assigned by us through crucial NMR experiments, we also present the ultimate structural proof by means of X-ray crystallography. Moreover, we disprove the mechanism proposed by the aforementioned authors based on sound mechanistic reasoning and point to an oversight by the authors that led them to an erroneous mechanistic pathway.

Design, synthesis, characterization, and anticancer activity of a novel series of O-substituted chalcone derivatives.

A new series of O-substituted chalcone derivatives bearing an/a allyl-, prenyl- or propargyl-substituent at different positions of rings A and B and their derivatives as drug leads, was designed, synthesized, and characterized. The chalcone derivatives were synthesized via base catalyzed Claisen-Schmidt condensation in MeOH or EtOH solutions of appropriately substituted aromatic ketones with O-allyl, and O-propargylvanillin, respectively. The intermediates O-substituted phenylketone derivatives were firstly synthesized by nucleophilic substitution reaction. All the newly synthesized compounds were characterized by IR, NMR spectral data and elemental analyses. A preliminary cytotoxicity was performed with the compounds (1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a-f, 6a-d, 7a-d) and the positive control, doxorubicin towards CCRF-CEM leukemia cells. Amongst them, compounds 1a, 2a, 5b-d, 6b, 7a, 7c and doxorubicin displayed IC50 values below 20 µM while other compounds were less or not active at up to 50 µM. Remarkably interesting cytotoxic effects, with IC50 values below 1 µM were recorded with 5c against HCT116 p53-/- colon adenocarcinoma cells, 5e against CCRF-CEM cells and MDA-MB-231-BCRP breast adenocarcinoma cells, and 6b against HCT116 p53+/+ cells and HCT116 p53-/- cells.

Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles.

The synthesis of novel polycyclic π-conjugated dihydropyridazines, pyridazines, and pyrroles was studied. Dihydropyridazine dyes were synthesized by inverse electron-demand Diels-Alder cycloaddition reactions between a dibenzosuberenone and tetrazines that bear various substituents. The pyridazines were synthesized in high yields by oxidation of dihydropyridazine-appended dibenzosuberenones with PIFA or NO. p-Quinone derivatives of pyridazines were also obtained by H-shift isomerization following the inverse electron-demand Diels-Alder reaction of tetrazines with p-quinone dibenzosuberenone. Then these pyridazines were converted to the corresponding pyrroles by reductive treatment with zinc. It was observed that all the dihydropyridazines obtained gave absorbance and emission at long wavelengths.

Transition Metal-Free Heteroarylation of Quinoxaline: Construction of Heteroaryl-Fused Phenazines by Oxidative Coupling.

A concise method for the construction of heteroaryl-fused phenazines was developed via PIFA-BF3·Et2O-mediated oxidative coupling of di-heteroarylated quinoxalines for the first time. Synthesis of mono- and di-heteroarylation of quinoxaline was performed effectively using only LiTMP reagent under transition metal-free conditions and without the use of halogen-containing starting compounds. In addition, nonsymmetrical di-heteroarylated quinoxalines were synthesized through reheteroarylation of mono-heteroarylated quinoxalines in the same way. Oxidation of the saturated compounds formed after heteroarylation was easily accomplished with iodine. The UV-vis absorption and fluorescence features of some compounds were examined.

One hundred years of benzotropone chemistry.

This review focuses on the chemistry of benzo-annulated tropones and tropolones reported since the beginning of the 20th century, which are currently used as tools by the synthetic and biological communities.

Twisted baskets.

A preparative procedure for obtaining a pair of twisted molecular baskets, each comprising a chiral framework with either right ((P)-1syn) or left ((M)-1syn) sense of twist and six ester groups at the rim has been developed and optimized. The racemic (P/M)-1syn can be obtained in three synthetic steps from accessible starting materials. The resolution of (P/M)-1syn is accomplished by its transesterification with (1R,2S,5R)-(-)-menthol in the presence of a Ti(IV) catalyst to give diastereomeric 8(P) and 8(M). It was found that dendritic-like cavitands 8(P) and 8(M), in CD2Cl2, undergo self-inclusion ((1)H NMR spectroscopy) with a menthol moiety occupying the cavity of each host. Importantly, the degree of inclusion of the menthol group was ((1)H NMR spectroscopy) found to be greater in the case of 8(P) than 8(M). Accordingly, it is suggested that different folding characteristic of 8(P) and 8(M) ought to affect the physicochemical characteristics of the hosts to permit their effective separation by column chromatography. The absolute configuration of 8(P)/8(M), encompassing right- and left-handed "cups", was determined with the exciton chirality method and also verified in silico (DFT: B3LYP/TZVP). Finally, the twisted baskets are strongly fluorescent due to three naphthalene chromophores, having a high fluorescence quantum yield within the rigid framework of 8(P)/8(M).

Trapping of organophosphorus chemical nerve agents in water with amino acid functionalized baskets.

We prepared eleven amino-acid functionalized baskets and used (1) H NMR spectroscopy to quantify their affinity for entrapping dimethyl methylphosphonate (DMMP, 118 Å(3) ) in aqueous phosphate buffer at pH=7.0±0.1; note that DMMP guest is akin in size to chemical nerve agent sarin (132 Å(3) ). The binding interaction (Ka ) was found to vary with the size of substituent groups at the basket's rim. In particular, the degree of branching at the first carbon of each substituent had the greatest effect on the host-guest interaction, as described with the Verloop's B1 steric parameter. The branching at the remote carbons, however, did not perturb the encapsulation, which is important for guiding the design of more effective hosts and catalysts in future.

Oxidation of cyanobenzocycloheptatrienes: Synthesis, photooxygenation reaction and carbonic anhydrase isoenzymes inhibition properties of some new benzotropone derivatives.

The oxidation of some cyanocycloheptatrienes with CrO3 and pyridine was investigated and a few new nitrile functionalised benzotropone derivatives were obtained. Photooxygenation reaction of these products was also studied. The structures of the formed products were determined on the basis of NMR spectroscopy and the formation mechanism of unusual products was discussed. Human carbonic anhydrase isoenzymes I, and II (hCA I and hCA II) inhibition properties of nitrile functionalized new benzotropone derivatives were also studied. Both CA isozymes were inhibited in the low micromolar range by these nitrile functionalized benzotropone analogues. The newly synthesized benzotropone derivatives showed inhibition constants in the sub-micromolar range (2.51-4.06µM). The best hCA I inhibition was observed in 5H-benzocycloheptene-7-carbonitrile (Ki: 2.88±0.86µM). On the other hand, 5-oxo-5H-benzocycloheptatriene-7-carbonitrile showed the powerful inhibitory effect against hCA II (Ki: 2.51±0.34µM).

Fluorometric and colorimetric sensor for selective detection of cyanide anion by dibenzosuberenone-based dihydropyridazine in aqueous solution.

A new chemosensory based on deprotonation and intramolecular charge transfer (ICT) was developed to detect cyanide in food samples. Deprotonation was facilitated by increasing the acidity of the NH proton in the dibenzosuberenone-based dihydropyridazine chemosensor Pz3 with -CN substituents. Addition of cyanide to acetonitrile and aqueous acetonitrile solution (1/9) of Pz3 resulted in their significant color change from colorless to purple in visible light, accompanied by a strong red shift in the absorption spectrum. Meanwhile, the near-infrared (NIR) emission (ex. 525 nm, em. 670 nm) of Pz3- resulting from deprotonation showed fluorescence switching behavior to detect the cyanide anion. While the acidic NH protons interact with basic anions as F-, CN-, OAc- and H2PO4- in organic solution (MeCN), just CN ions interact with in aqueous organic solutions (H2O-MeCN 1/9 HEPES pH 7.4). The limit of detection of cyanide from the fluorescence spectrum is 80 nM, which is well below the value determined for drinking water by World Health Organization (WHO). The interference effect of cations and anions showed that Pz3 could play an important role in the determination of waste NaCN. In addition, Pz3 successfully carried out the selective detection of cyanide in food samples such as bitter almonds and sprouting potatoes.

Nucleophilic substitution of bromonorbornenes and derivatives by electron transfer reactions.

The photoinitiated substitution reactions of anti-7-bromobenzonorbornadiene (5), its syn isomer 6, exo-anti-13-bromobenzocyclobutanorbornene (7), syn-7-bromonorbornene (8) and bromonorbornane (9) with Me(3)Sn(-) and Ph(2)P(-) anions, in liquid ammonia, are here informed to occur with good yields of substitution. The stereochemical outcome is discussed in terms of calculations with the B3LYP functional and the 6-31+G* basis set; the solvent being included as a continuum through the PCM model. The experimental relative chemical reactivity of pairs of substrates toward a given anion is also presented.

A molecular claw: a dynamic cavitand host.

Up for grabs: A modular receptor comprises a hexaazatriphenylene "platform" and three imide residues on its concave side carrying flexible alkane chains. The chains not only populate the host's cavity but can also extend and can grab an appropriately sized and shaped guest in solution.

Selectfluor and TBAX (Cl, Br) Mediated Oxidative Chlorination and Bromination of Olefins.

Herein, we report the first metal-free and molecular halogen reagent-free dihomohalogenation methodology by using Selectfluor as an oxidant and tetrabutylammonium bromide/chloride salts as a halogen source. This effective strategy provides various fluorine-free halogenated products easily in quantitative yields from alkenes, alkynes, and natural products.

Dibenzosuberenone-Based Photo- and Thermochromic Switches, a Transformation: Rearrangement of Dibenzosuberenones to Spiro Anthrones.

In this study, a new class of photo- and thermochromic compounds was discovered. Fluorescent dihydropyridazine-appended dibenzosuberenone derivatives with central seven-membered rings were converted to colorless spiro anthrones with central six-membered rings by thermal isomerization or visible-light (420 nm) irradiation. Under UV light (350 nm), the spiro anthrones converted back to benzosuberenones. The chemical structures of the spiro anthrones were determined by NMR, UV-vis spectroscopy, and HRMS analyses. It was also observed that the dibenzosuberenone derivatives were oxidized on exposure to UV irradiation for a long time.

Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols.

The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with a series of phenol derivatives was investigated by using the esterase assay, with 4-nitrophenyl acetate as substrate. 2,6-Dimethylphenol, 2,6-diisopropylphenol (propofol), 2,6-di-t-butylphenol, butylated hydroxytoluene, butylated hydroxyanisole, vanillin, guaiacol, di(2,6-dimethylphenol), di(2,6-diisopropylphenol), di(2,6-di-t-butylphenol), and acetazolamide showed K(I) values in the range of 37.5-274.5 microM for hCA I and of 0.29-113.5 microM against hCA II, respectively. All these phenols were non-competitive inhibitors with 4-nitrophenylacetate as substrate. Some antioxidant phenol derivatives investigated here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide acetazolamide, and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents.

Synthesis and Diels-Alder cycloaddition reaction of norbornadiene and benzonorbornadiene dimers.

Dimeric forms of norbornadiene and benzonorbornadiene were synthesized starting with known monobromide derivatives. The Diels-Alder cycloaddition reaction of dimers with TCNE and PTAD was investigated and new norbornenoid polycyclics were obtained. All compounds were characterized properly using NMR spectroscopy.

Novel eugenol derivatives: Potent acetylcholinesterase and carbonic anhydrase inhibitors.

Eugenol was used as starting material to obtain some phenolic compounds. The synthesis of these phenolic compounds was performed in a two-step procedure. The structures of the formed products (novel eugenol derivatives 1-6) have been determined on the basis of NMR spectroscopy and other spectroscopic methods. The compounds were tested in terms of carbonic anhydrase (CA) inhibition potency. Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, which catalyse the reaction between carbon dioxide (CO2) and water (H2O), to generate bicarbonate (HCO3-) and protons (H+). CO2, HCO3- and H+ are essential molecules and ions for many important physiologic processes occurring in all living organisms. Acetylcholinesterase (AChE, E.C.3.1.1.7) is found in high concentrations in the red blood cells and brain. Novel eugenol derivatives (1-6) were tested for the inhibition of two cytosolic CA isoforms I, and II (hCA I, and II) and AChE. These compounds demonstrated effective inhibitory profiles with Ki values in ranging of 113.48-738.69nM against hCA I, 92.35-530.81nM against hCA II, and 90.10-379.57nM against AChE, respectively. On the other hand, acetazolamide clinically used as CA inhibitor, shoed Ki value of 594.11nM against hCA I, and 120.68nM against hCA II, respectively. Also, AChE was inhibited by tacrine as an AChE inhibitor at the 71.18nM level.

Synthesis of an F-BODIPY [2]catenane using the chemistry of bis(dipyrrinato)metal complexes.

ML2 type complexes of an olefin terminated 5H-dipyrrin ligand can be subjected to twofold ring closing metathesis to give bis(dipyrrinato)copper(ii) and bis(dipyrrinato)zinc(ii) [2]catenates. Demetalation of the copper(ii) [2]catenate with KCN/N2H4·H2O gave the corresponding bis(dipyrrin) [2]catenand. The boron difluoride complex of this bis(dipyrrin) was obtained as the first fluorescent F-BODIPY [2]catenane.

Effective bromo and chloro peroxidation catalysed by tungsten(vi) amino triphenolate complexes.

Amino triphenolate tungsten(vi) complexes have been prepared and they proved to be efficient catalysts in haloperoxidation reactions using hydrogen peroxide as a terminal oxidant and inorganic sources of halides. In particular, interesting results have been obtained in the challenging chloroperoxidation reactivity (catalyst loading down to 0.05% with TONs up to 900). A comparison among three different metal complexes bearing the same ligand (vanadium(v), molybdenum(vi) and tungsten(vi)) showed much better performances of the last complex both on bromo and chloro peroxidations.