Shaping 1,2,4-Triazolium Fluorinated Ionic Liquid Crystals

The synthesis and thermotropic behaviour of some di-alkyloxy-phenyl-1,2,4-triazolium trifluoromethane-sulfonate salts bearing a seven-carbon atom perfluoroalkyl chain on the cation is herein described. The fluorinated salts presenting a 1,2,4-triazole as a core and differing in the length of two alkyloxy chains on the phenyl ring demonstrated a typical liquid crystalline behaviour. The mesomorphic properties of this set of salts were studied by differential scanning calorimetry and polarized optical microscopy. The thermotropic properties are discussed on the grounds of the tuneable structures of the salts. The results showed the existence of a monotropic, columnar, liquid crystalline phase…

Chemistry of Fluorinated Oxadiazoles and Thiadiazoles

A literature survey of the chemistry of fluorinated oxadiazoles and thiadiazoles is presented. The core part on synthetic procedures is given by type of heterocycle and includes recent developments up to the end of 2012. Reactivity is discussed when induced by the presence of the fluorinated moiety. Selected examples of bioactive compounds and applications are illustrated.

Fluorinated heterocyclic compounds. A photochemical synthesis of 3-amino-5-perfluoroaryl-1,2,4-oxadiazoles

Abstract A photochemical methodology for the synthesis of 3-amino- (or 3- N -substituted amino) 5-pentafluorophenyl-1,2,4-oxadiazoles is reported. Irradiation of 3-pentafluorobenzoylamino-4-methyl-1,2,5-oxadiazole (Furazan) at 254 nm in methanol and in the presence of ammonia, primary or secondary aliphatic amines produces 3-amino-, 3-( N -alkylamino)-, 3-( N , N -dialkylamino)-5-pentafluorophenyl-1,2,4-oxadiazoles. The photoreaction follows the fragmentation pattern of the furazan ring with the extrusion of acetonitrile and the formation of a counterpart fragment which the nitrogen nucleophile will capture. Depending on the nature of the reagent, displacement of a fluoride anion at the C(5…

Presence and biodistribution of perfluorooctanoic acid (PFOA) in Paracentrotus lividus highlight its potential application for environmental biomonitoring

AbstractThe first determination of presence and biodistribution of PFOA in ninety specimens of sea urchin Paracentrotus lividus from two differently contaminated sites along Palermo’s coastline (Sicily) is reported. Analyses were performed on the sea urchins’ coelomic fluids, coelomocytes, gonads or mixed organs, as well as on seawater and Posidonia oceanica leaves samples from the collection sites. PFOA concentration ranged between 1 and 13 ng/L in seawater and between 0 and 794 ng/g in P. oceanica. The analyses carried out on individuals of P. lividus from the least polluted site (A) showed PFOA median values equal to 0 in all the matrices (coelomic fluid, coelomocytes and gonads). Conver…

Synthesis of new fluorinated low molecular weight (LMW) gelators

ChemInform Abstract: Photoinduced Molecular Rearrangements. The Photochemistry of Some 1,2, 4-Oxadiazoles in the Presence of Nitrogen Nucleophiles. Formation of 1, 2,4-Triazoles, Indazoles, and Benzimidazoles.

The photochemistry of some 3,5-disubstituted 1,2,4-oxadiazoles in the presence of nitrogen nucleophiles [external, such as added amines or hydrazines, or internal, such as an o-aminophenyl moiety at C(3) of the oxadiazole ring] has been investigated. In the irradiation of 5-amino-(or 5-N-substituted amino) 3-phenyl-1,2,4-oxadiazoles in the presence of aliphatic primary amines (or ammonia), photolytic species arising from heterolytic cleavage of the ring O−N bond capture the nucleophilic reagent to give open-chain intermediates, which develop into 1,2,4-triazolin-5-ones. Similarly, irradiations of 3,5-diphenyl-, 3-methoxy-5-phenyl-, and 5-methyl-3-phenyl-1,2,4-oxadiazoles gave 1,2,4-triazole…

Fluorinated and pegylated polyaspartamide derivatives to increase solubility and efficacy of Flutamide

New fluorinated amphiphilic copolymers based on a biocompatible polyaspartamide have been prepared in order to obtain polymeric micelles useful for delivering anticancer drugs. In particular, α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) has been derivatized with polyethylene glycol (PEG(2000)) and ethylendiamine (EDA). Both these portions form the hydrophilic part of the copolymer, while the hydrophobic moiety is given by 1,2,4-oxadiazoles: 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole (PPOX) or 3-carboxyethyl-5-pentadecafluoroheptyl-1,2,4-oxadiazole (CPOX). Copolymers named PHEA-PEG(2000)-EDA-PPOX and PHEA-PEG(2000)-EDA-CPOX have been prepared with various degrees of derivati…

Photoinduced functionalization of diterpenes: transformation of the C-20 methyl of atractyligenin into a carbomethoxymethyl or carbamoylmethyl group

Abstract Irradiation of the nor-diterpene atractyligenin 1a and of its methyl ester 1b at λ=254 nm in methanol or in methanol in the presence of nitrogen nucleophiles such as ammonia or methylamine gave, besides the decarboxylation product 2, the ester 3a or the amides 3b, 3c, respectively, providing the transformation of the C-20 angular methyl into a carbomethoxymethyl or carbamoylmethyl group. A photochemical pathway involves formation of C-19/C-20 bond in the excited state, followed by a collapse into a ketene intermediate which will capture the nucleophilic reagent.

Heterocyclic photorearrangements. Photoinduced rearrangements of 1,2,4-oxadiazoles substituted by an XYZ side chain sequence

Photoinduced rearrangements of 1,2,4-oxadiazoles substituted by an XYZ side chain sequence at position 3 of the ring have been recognized. Examples taken out from previous results have been emphasized and some other patterns dealing with a 3-phenoxy and 3-enaminoketone sequence have been investigated. An intermediate species derived from photolysis of the ring O-N bond and characterized by a continuous 6π electron system involving the side chain sequence, was suggested to give ring closure to the rearrangement product.

Rearrangements of 1,2,4-Oxadiazole: “One Ring to Rule Them All”

[Figure not available: see fulltext.] 1,2,4-Oxadiazoles are heterocycles characterized by low aromaticity and the presence of a weak O–N bond and are widely studied due to their tendency to rearrange into more stable heterocyclic compounds. This review covers literature from the last fifteen years, highlighting the general features of 1,2,4-oxadiazoles and their applications. Regarding the reactivity, the development of classical reactions (thermal and photochemical rearrangements) is presented in terms of synthetic utility and mechanistic insight. Among the relevant rearrangement reactions, the Boulton–Katritzky Rearrangement (BKR), Migration – Nucleophilic Attack – Cyclization (MN…

Fluorinated Heterocyclic Compounds. A Photochemical Approach to a Synthesis of Polyfluoroaryl-1,2,4-triazoles.

The reaction of some fluorinated 1,2,4-oxadiazoles in the presence of methylamine or propylamine has been investigated. The irradiation in methanol or acetonitrile leads with acceptable yields to the corresponding fluorinated 1- methyl- or 1-propyl-1,2,4-triazole.

New biodegradable hydrogels based on a photo-cross-linkable polyaspartamide and poly(ethylene glycol) derivatives. Release studies of an anticancer drug

The functionalization of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) with glycidyl methacrylate (GMA) gives rise to a water-soluble photosensitive copolymer PHEA-GMA (PHG). Aqueous solutions of PHG alone or in combination with various concentrations of poly(ethylene glycol) dimethacrylate or poly(ethylene glycol) diacrylate (PEGDA) have been exposed to a source of UV rays at 313 nm in order to obtain polymeric networks. All samples have been prepared both as water-swellable microparticles and as gel systems. Microparticles have been characterised by Fourier transform IR spectrophotometry, dimensional analysis and swelling measurements in aqueous media mimicking biological fluids. In vi…

Synthesis of trifluoromethylated 2-benzoyl- and 2-aminoimidazoles from ring rearrangement of 1,2,4-oxadiazole derivatives

Abstract Fluoroalkylated 2-ylamino-imidazoles have been synthesized by reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with fluorinated β-dicarbonyl compounds and subsequent base-induced Boulton–Katritzky Rearrangement (BKR) of the isolated β-enaminocarbonyl intermediate. Alternatively, one-pot reactions performed in the presence of Montmorillonite K10 favoured the condensation at the 3-amino moiety of the oxadiazole and, in some cases, allowed the direct synthesis of 2-benzoylamino-imidazoles. Hydrolysis of 2-benzoylamino-imidazoles easily yielded fluorinated 2-amino-imidazoles targets.

Competing Ring-Photoisomerization Pathways in the 1,2,4-Oxadiazole Series. An Unprecedented Ring-Degenerate Photoisomerization

The irradiation of some 5-alkyl-3-amino-1,2,4-oxadiazoles at lambda = 254 nm in methanol in the presence of triethylamine (TEA) gave ring-photoisomerization both into 2-alkyl-5-amino-1,3,4-oxadiazoles and, unprecedently, into the ring-degenerate 3-alkyl-5-amino-1,2,4-oxadiazoles. The competing ring contraction-ring expansion route and the internal cyclization-isomerization mechanism explain the results.

Trasformazioni eterocicliche di 1,2,4-ossadiazoli fluorurati come substrati dielettrofili

ChemInform Abstract: Synthesis of 4(5)-Phenacyl-imidazoles from Isoxazole Side-Chain Rearrangements.

The reaction must be carried out under nitrogen atmosphere in deoxygenated solvent to prevent the oxidation of the imidazole products.

Photoinduced molecular rearrangements. The photochemistry of 1,2,4-oxadiazoles in the presence of sulphur nucleophiles. Synthesis of 1,2,4-thiadiazoles

Abstract The photochemistry of some 1,2,4-oxadiazoles in the presence of sulphur nucleophiles has been investigated. Irradiation of the 5-amino-3-phenyl- and 3,5-diphenyl-1,2,4-oxadiazole at γ = 254 nm in methanol in the presence of sodium hydrogen sulphide or thiols gave a photo-induced redox reaction at the ring ON bond, leading to the corresponding N -substituted benzamidines. By contrast, irradiation of the 5-amino-3-phenyl-1,2,4-oxadiazole in the presence of thioureas or thiocarbamates, essentially gave 3-phenyl-5-substituted 1,2,4-thiadiazoles, which presume an NS bond formation between the ring-photolytic species and the sulphur nucleophile. In turn, irradiation of the same 5-amino…

Effect of protonation and deprotonation on the gas phase reactivity of fluorinated 1,2,4-triazines

Positive and negative electrospray mass spectrometry (MS), in-time and in-space MS n experiments, high-resolution and accurate mass measurements obtained with an Orbitrap, together with density functional theory calculations have been used to study the gas-phase ion chemistry of a series of fluorinated 1,2,4-triazines. As a result of low-energy collision-induced dissociations, occurring in an ion trap and in a triple quadrupole, their protonated and deprotonated molecules show interesting features depending on the nature and structure of the precursor ions. The occurrence of elimination/hydration reactions produced by positive ions in the ion trap is noteworthy. Decompositions of deprotonat…

Flavouring Extra-Virgin Olive Oil with Aromatic and Medicinal Plants Essential Oils Stabilizes Oleic Acid Composition during Photo-Oxidative Stress

Essential oils (EOs) from medicinal and aromatic plants (MAPs) are well-known as natural antioxidants. Their addition to extra-virgin olive oil (EVOO) can contribute to reducing fat oxidation. The main aim of this study was to improve both food shelf-life and aromatic flavour of EVOO, adding different EOs of Sicilian accessions of common sage, oregano, rosemary and thyme. The morphological and production characteristics of 40 accessions of MAPs were preliminarily assessed. EOs from the most promising accessions of MAPs were analysed by gas-chromatography and mass spectrometry. Photo-oxidative studies of the EOs were carried out and the determination of the EVOO fatty acids obtained from 4 I…

Photochemical synthesis of pyrene perfluoroalkyl derivatives and their embedding in a polymethylmethacrylate matrix: a spectroscopic and structural study

A photochemical, alternative and eco-compatible approach to perfluoroalkyl derivatives of pyrene is presented. The perfluoroalkyl chain is regiospecifically introduced at the 1 position of pyrene. The synthesized products have been embedded in a polymethylmethacrylate matrix by photocuring at 365 nm. Both the photochemical reactions can be considered a “green tool” for the synthetic chemist in order to obtain materials with prospective optoelectronic applications. The so-obtained composites have been the object of a study by UV and fluorescence spectroscopy in order to explore their luminescence properties. The small angle X-ray scattering and the transmission electron microscopy techniques…

Hsp60 Inhibitors and Modulators

In this chapter, we focus on the 60 KDa Heat Shock Protein (Hsp60) and discuss some of its biological, molecular and pathological features. The structural and mechanistic aspect of the Hsp60 folding cycle will be also presented. We further illustrate how Hsp60 may be involved in many diseases and therefore considered as an effective therapeutic or theranostic target. Finally, the state-of-the-art on the development of Hsp60 and bacterial GroEL inhibitors and modulators of their expression will be illustrated. This is discussed in the light of a negative chaperonotherapy, and the consequent development of inhibitors, as well as positive chaperonotherapy, in the event its excessive activity i…

ChemInform Abstract: Heterocyclic Photorearrangements. Photochemical Behaviour of Some 3,5-Disubstituted 1,2,4-Oxadiazoles in Methanol at 254 nm.

Photochemical behaviour of some 3,5-disubstituted 1,2,4-oxadiazoles in methanol at 254 nm has been investigated. Ring photoisomerization to the 1,3,4-oxadiazole heterocycle or formation of open chain compounds involving the nucleophilic solvent was shown to depend on the nature and the position of the substituent. Photoinduced ring closure into the benzimidazole system, involving a 3-N-phenylamino side chain sequence and a photolytic intermediate of the oxadiazole heterocycle, is also reported.

Fluoropolymer Based on a Polyaspartamide containing 1,2,4-Oxadiazole Units: A Potential Artificial Oxygen (O2) Carrier

Abstract In this preliminary work we have prepared a fluorinated polymer capable of solubilizing an appreciable amount of O(2) and, at the same time, maintaining a higher water solubility than perfluoroalkanes investigated as injectable O(2) carriers. In particular, we describe the synthesis and characterization of a new macromolecular conjugate obtained by derivatization of alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) with 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole, called PHEA-F. This new water soluble fluoropolymer was prepared in high yield using a simple procedure. It was characterized by FT-IR and UV-vis spectrophotometry, (19)F-NMR and SEC measurements. O(2) so…

Synthesis of Isoxazoline Derivatives through Boulton–Katritzky Rearrangement of 1,2,4-Oxadiazoles

The base-induced rearrangement of 1,2,4-oxadiazoles into isoxazoline derivatives is reported. This represents the first example of a three-atom side-chain rearrangement that involves a saturated CCO side chain at C-3 of the oxadiazole. Nonaromatic 3-amino-isoxazoline derivatives are obtained in good yields. Interestingly, this reaction occurs through the rearrangement of aromatic oxadiazoles to form less stable bonds than those that are broken.

Trasformazioni eterocicliche di 1,2,4-ossadiazoli fluorurati in reazioni ANRORC-like

Synthesis of fluorinated first generation starburst molecules containing a triethanolamine core and 1,2,4-oxadiazoles

Abstract 5-Pentafluorophenyl-1,2,4-oxadiazoles, differently substituted at C(3), have been synthesized and used to functionalize the aliphatic primary hydroxyl functionalities of triethanolamine, under mild conditions. UV–visible absorption and emission spectra are reported, for both tri- and difunctionalised molecules, showing their potential applications as light-emitters in optoelectronic devices.

ChemInform Abstract: Photoinduced Functionalization of the C-20 Methyl Group of the Nor-diterpene Atractyligenin.

Abstract Irradiation of the nor-diterpene atractyligenin at λ =254 nm in methanol gave, on one hand, the decarboxylation product, and provided, on the other hand, the transformation of the C-20 angular methyl into a methylene-carbomethoxy group. A photochemical pathway involving formation of C-19/C-20 bond is suggested.

Characterization of isomeric 1,2,4-oxadiazolyl-N-methylpyridinium salts by electrospray ionization tandem mass spectrometry.

The mass spectrometric behavior of 1,2,4-oxadiazolyl- N-methylpyridinium salts has been investigated. These substances are of current interest as perspective ionic liquids, compounds used as green solvents for synthesis, and for their catalytic properties. The studies have been developed through electrospray ionization tandem mass spectrometry (ESI-MS/MS) experiments. The obtained results demonstrate a ready distinction between the two isomeric classes, 3- N-methylpyridinium- and 5- N-methylpyridinium-1,2,4-oxadiazoles, is possible through ESI-MS/MS experiments. A deeper investigation on the principal fragmentation pathways of characteristic ions has been also developed.

Characterization of isomeric organic cations by Esi/MS: 3-alkyl-5-(4-N-methylpyridinium)-1,2,4-oxadiazole cations, 5-alkyl-3-(4-N-methylpyridinium)-1,2,4-oxadiazole cations and 3-perfluoroakyl-5-(4-N-methylpyridinium)-1,2,4-oxadiazole cations, 5-perfluoroakyl-3-(4-N-methylpyridinium)-1,2,4-oxadiazole cations

Solvent dependent photochemical reactivity of 3-allyloxy-1,2,4-oxadiazoles

Anrorc rearrangements of fluorinated 1,2,4-oxadiazoles as an expedient route to fluorinated heterocycles

Composti eterociclici fluorurati. Un approccio fotochimico alla sintesi di chinazolin-4-oni

A Generalized Synthesis of 3-Amino-5-aryl-, 3-Amino-5-polyfluorophenyl-, and 3-Amino-5-alkyl-1,2,4-oxadiazoles through Ring-degenerate Rearrangements

A generalized synthesis of 3-amino-5-aryl-, 3-amino-5-poly- fluorophenyl- and 3-amino-5-alkyl-1,2,4-oxadiazoles has been developed starting from the 3-amino-5-methyl-1,2,4-oxadiazole as a common synthon. Aroylation or alkanoylation of this aminooxadiazole, followed by thermally- induced ring-degenerate equilibration of resulting 3-acylamino compounds, and final acid hydrolysis of the 3-acetylamino-5-aryl- (or 5-polyfluorophenyl-), or 3- acetylamino-5-alkyl-1,2,4-oxadiazoles counterpart which is formed, gave the expected 3-amino-5-substituted 1,2,4-oxadiazoles. In the case of some 3- aroylamino compounds, yields of final 3-amino-5-aryloxadiazoles are higher than that expected on the basis of…

A recent portrait of bioactive triazoles

Scientists have extensively explored new synthetic routes in order to obtain 1,2,3- and 1,2,4-triazoles as they represent a very interesting class of compounds due to their wide range of biological activities such as antitumor, antiinflammatory, analgesic, antifungal, antibacterial, antiviral, etc. This mini review reports the synthesis and the biological activities of compounds containing a triazole moiety published since 2007. No attempt is made to provide a comprehensive literature overview, our aim is to highlight some more recent examples of synthetic biological active compounds. In particular, we focus on the applications of “click reactions” that allow the regioselective synthesis of…

Designing fluorous domains. Pyridinium salts bearing a perfluoroalkylated oxadiazole moiety

Perfluorocarbon functionalized hyaluronic acid derivatives as oxygenating systems for cell culture

A set of new hyaluronic acid (HA) derivatives was obtained by binding fluorinated oxadiazole (OXA) moieties to an amino derivative of the polysaccharide (HA-EDA). The obtained HA-EDA-OXA biomaterials are potentially able to improve oxygenation into a scaffold for tissue engineering purposes. The oxygen solubility in aqueous dispersions of the obtained derivatives showed that polymers were able to improve oxygen uptake and maintenance in the medium. The HA-EDA-OXA was employed to form a hydrogel in situ by reaction with a vinyl sulphone derivative of inulin, under physiological conditions. The influence of the presence of OXA moieties on the mechanical properties of the obtained hydrogels as…

Fluorinated Heterocyclic Compounds. An Effective Strategy for the Synthesis of Fluorinated Z-Oximes of 3-Perfluoroalkyl-6-phenyl-2H-1,2,4-triazin- 5-ones via a Ring-Enlargement Reaction of 3-Benzoyl-5-perfluoroalkyl-1,2,4-oxadiazoles and Hydrazine

The reaction of 3-benzoyl-5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine has been investigated, evidencing the possibility of competitive reaction paths. Nucleophilic addition of the hydrazine to the electrophilic C(5) of the 1,2,4-oxadiazole ring, followed by ring opening and ring closure with enlargement, leads with high yield and in very mild experimental conditions to the formation of Z-oximes of 3-perfluoroalkyl-6-phenyl-2H-1,2,4-triazin-5-ones (11a-c) as major products of the reaction. In turn, the hydrazine can attack the electrophilic carbonyl carbon giving 4-perfluoroacylamino-5-phenyl-2H-1,2,3-triazoles (13a-c) through the well-known Boulton-Katritzky rearrangement of the inter…

Composti curcumin-like come agenti neuro-protettori. Interazione con HSP60

La Malattia di Alzheimer rappresenta una sfida fondamentale del XXI secolo per la salute pubblica. Le terapie attualmente utilizzate per la cura dell’Alzheimer si basano sugli aspetti sintomatici della patologia [1]. Un importante ruolo nella malattia è rivestito dalle Heat shock proteins (HSPs), proteine che presiedono al controllo del ripiegamento proteico [2]. Recentemente, è stato dimostrato che HSP60 media la traslocazione del Precursore della Proteina Amiloide (APP) e del Peptide Beta Amiloide (Aβ) nei mitocondri, portando alla perdita della funzionalità dell’organulo [3]. Nel campo degli approcci delle terapie potenziali, la curcumina sta emergendo come lead compound per lo sviluppo …

Synthesis of Tetrasubstituted 4,4'-Biimidazoles

Highly substituted 4,4'-biimidazoles were synthesized, in good to excellent yields, through a multicomponent imidazole ring synthesis by using imidazol-4-yl-ethane-1,2-diones as starting materials. The obtained compounds were preliminarily tested as chromogenic and fluorescent sensors for heavy metals.

Composti eterociclici fluorurati. Sintesi di 2-ammino-pirimidine N-ossido e 1,2,4-triazine

ASYMMETRIC SYNTHESIS OF LINEZOLID THROUGH CATALYZED HENRY REACTION

Linezolid 1 is an antibacterial oxazolidinone approved by FDA in 2000 for the treatment of fastidious bacterial infections.1 The asymmetric synthesis of Linezolid-like molecules make use of the chiral pool approach, through the so-called Manninen reaction.2 This strategy requires the use of BuLi, low temperature and a long elaboration of the acetamide chain. Curiously, the only catalyzed approach toward the asymmetrical synthesis of Linezolid was just recently reported, and belongs to the use of proline-derived catalysts in aldol reactions as the key step.3 This procedure is quite interesting except for the low yield. Here we report a new synthesis of Linezolid, based on a Cu(II)-catalyzed …

Heterocyclic Scaffolds for the Treatment of Alzheimer's Disease

Background: The treatment and diagnosis of Alzheimer’s Disease (AD) are two of the most urgent goals for research around the world. The cognitive decline is generally associated with the elevated levels of extracellular senile plaques, intracellular neurofibril- lary tangles (NFTs), and with a progressive shutdown of the cholinergic basal forebrain neurons transmission. Even if several key targets are under fervent investigation in the cure of AD, till now, the only approved therapeutic strategy is the treatment of symptoms by using cholinesterases inhibitors. It has been demonstrated that both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes are not only responsible of…

Photochemical Functionalization of Allyl Benzoates by C-H Insertion

The photoreactivity of allyl benzoates, containing an electron-rich double bond, has been explored by irradiation at 305 nm in different solvents. Solvent addition products arising from an insertion of the alpha H–C bonds of THF, dioxane, and i-PrOH to the allylic double bond was realized. The observed reactivity depended on reaction conditions and substitution pattern of the substrate. A DFT study on this unusual reaction was performed allowing the formulation of two mechanistic pathways.

Synthesis and characterization of perfluoroalkyl-pyrenes embedded in a polymethylmethacrylate matrix

Photoinduced Molecular Rearrangements. The Photochemistry of Some 1,2,4-Oxadiazoles in the Presence of Nitrogen Nucleophiles. Formation of 1,2,4-Triazoles, Indazoles, and Benzimidazoles

The photochemistry of some 3,5-disubstituted 1,2,4-oxadiazoles in the presence of nitrogen nucleophiles [external, such as added amines or hydrazines, or internal, such as an o-aminophenyl moiety at C(3) of the oxadiazole ring] has been investigated. In the irradiation of 5-amino-(or 5-N-substituted amino) 3-phenyl-1,2,4-oxadiazoles in the presence of aliphatic primary amines (or ammonia), photolytic species arising from heterolytic cleavage of the ring O−N bond capture the nucleophilic reagent to give open-chain intermediates, which develop into 1,2,4-triazolin-5-ones. Similarly, irradiations of 3,5-diphenyl-, 3-methoxy-5-phenyl-, and 5-methyl-3-phenyl-1,2,4-oxadiazoles gave 1,2,4-triazole…

Synthesis, characterization, cellular uptake and interaction with native DNA of a bis(pyridyl)-1,2,4-oxadiazole copper(II) complex

The copper(II) complex of 3,5-bis(2'-pyridyl)-1,2,4-oxadiazole was synthesized and characterized. X-Ray crystallography revealed that the complex consists of a discrete [Cu(3,5-bis(2'-pyridyl)-1,2,4-oxadiazole)(2)(H(2)O)(2)](2+) cation and two ClO(4)(-) anions. The Cu(II) coordination sphere has a distorted octahedral geometry and each ligand chelates the copper ion through the N(4) nitrogen of the oxadiazole ring and the nitrogen of one pyridine moiety. The coordinated water molecules are in cis position and each of them is H-bonded to the 5-pyridyl nitrogen of the oxadiazole ligand and to an oxygen of the perchlorate anion. Biological assays showed that, despite the free ligand not being …

Synthesis, structural characterization, anti-proliferative and antimicrobial activity of binuclear and mononuclear Pt(II) complexes with perfluoroalkyl-heterocyclic ligands

Abstract In this paper we report the synthesis of four Pt(II) complexes with 5-perfluoroalkyl-1,2,4-oxadiazolyl-pyridine and 3-perfluoroalkyl-1-methyl-1,2,4-triazolyl-pyridine ligands. Two binuclear complexes [PtCl(pfibap)2](µ-Cl)2 (1), [Pt2(µ-Cl)2(pfioap)4]Cl2 (2), and two mononuclear [PtCl2(pfptp)] (3), [PtCl2(pfhtp)2] (4), were synthesized with the ligands: 2-(5-perfluoropropyl)-1,2,4-oxadiazole-3yl)-pyridine (pfpop), 2-(5-perfluoroheptyl-1,2,4-oxadiazole-3yl)-pyridine (pfhop), 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp), 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), and were structurally characterized. All complexes were tested in vitro on th…

Recent Advances in 1,2,4-Oxadiazole Chemistry

Heterocyclic rearrangements in constrained media. A zeolite-directed photorearrangement of 1,2,4-oxadiazoles

[reaction: see text] The first intrazeolite-photoinduced rearrangement of a five-membered heterocycle is reported. A completely different behavior compared to solution irradiations has been observed. The zeolite's role in directing the photoreaction of 3-phenyl-1,2,4-oxadiazoles toward the formation of the corresponding 1,3,4-oxadiazoles in a ring contraction-ringexpansion route is discussed.

An ANRORC approach to the synthesis of perfluoroalkylated 1,2,4-triazole-carboxamides

A series of perfluoroalkyl-1,2,4-triazole-carboxamides has been obtained through an ANRORClike rearrangement (Addition of Nucleophile, Ring-Opening and Ring-Closure) of 5- perfluoroalkyl-1,2,4-oxadiazole-3-carboxamides with methylhydrazine or hydrazine. The initial addition of the bidentate nucleophile to the electrophilic C(5) of the 1,2,4-oxadiazole ring, followed by ring opening and ring closure, leads to the formation of triazoles in good yield under mild experimental conditions. In some cases, a competitive ANRORC-enlargement reaction to form 1,2,4-triazin-6-ones was also observed. Obtained carboxamidotriazoles have also been explored as precursors for the synthesis of 3(5)-perfluoroal…

Fluorinated heterocyclic compounds from ring-to-ring transformations of O-N bond containing azoles

Chimica in fase gassosa di ioni radicali, cationi e anioni prodotti da ossime di 1,2,4-triazine fluorurate

ChemInform Abstract: Synthesis of Tetrasubstituted 4,4′-Biimidazoles.

Highly substituted 4,4′-biimidazoles were synthesized, in good to excellent yields, through a multicomponent imidazole ring synthesis by using imidazol-4-yl-ethane-1,2-diones as starting materials. The obtained compounds were preliminarily tested as chromogenic and fluorescent sensors for heavy metals.

On the structure of 3-acetylamino-5-methyl-1,2,4-oxadiazole and on the fully degenerate rearrangements (FDR) of its anion: a stimulating comparison between the results of ‘in-silicon chemistry’ and ‘laboratory chemistry’

An accurate crystal structure determination has provided evidence for a planar conformation for 3-acetylamino-5-methyl-1,2,4-oxadiazole (5), in agreement with quantum-mechanical calculations in the gas phase. In the crystal, a series of strong intermolecular N7H7….O9 hydrogen bonds link the amido groups of different molecules, causing the formation of infinite parallel ordered chains. The effect of the DMSO solvent on the energy and charge distribution of compound 5 and on its relevant 5− anion, involved in a fully degenerate rearrangement (FDR), has been deepened by quantum-mechanical DFT calculations. The calculated energy barrier for the FDR increases in going from in vacuo to DMSO, in a…

On the reaction of some 5-polyfluoroaryl-1,2,4-oxadiazoles with methylhydrazine: synthesis of fluorinated indazoles

The reaction of 5-polyfluoroaryl-1,2,4-oxadiazoles with methylhydrazine has been studied and the synthesis of fluorinated N-methylindazoles has been realized. Rearrangement reactions showed predominantly formation of N(1)-methylindazole regioisomers. Starting compounds were preliminarily functionalized at the polyfluoroaryl moiety through fluorine displacement with nucleophiles (methanol, methylamine, dimethylamine), allowing the obtainment of target indazoles substituted at the C(6) position.

Fluorinated Heterocyclic Compounds− The First Example of an Irreversible Ring-Degenerate Rearrangement on Five-Membered Heterocycles by Attack of an External Bidentate Nucleophile

The reactions of 5-perfluoroalkyl-1,2,4-oxadiazoles 3 with hydroxylamine in DMF give the regioisomeric 3-perfluoroalkyl-1,2,4-oxadiazoles 4 in excellent yields. This process is the first example of ring-degenerate rearrangement (RDR) occurring on five-membered heterocycles by attack of an external bidentate nucleophile, which replaces two heteroatoms of the ring. We suggest that an ANRORC-like mechanism occurs in which the addition of the nucleophilic nitrogen atom (NH2OH) on the C(5) atom of 3 is followed by ring opening and irreversible ring-degenerate closure by attack of the nucleophilic oxygen atom (=NOH) on the C(3) atom of the original ring, realizing an elegant and efficient synthes…

Sintesi e valutazione biologica di 1,2,4-ossadiazoli analoghi del Linezolid

Synthesis of isoxazoline derivatives by Boulton-Katritzky Rearrangements

ChemInform Abstract: Fluoro Heterocycles. A Photochemical Methodology for the Synthesis of 3-Amino- and 3-(N-Alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles.

Abstract A photochemical methodology for the synthesis of perfluoroalkyl-1,2,4-oxadiazoles has been described. 3-Amino- and 3-( N -alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles have been prepared by irradiation of 3-perfluoroalkanoylamino-4-phenyl-1,2,5-oxadiazoles (furazans) at λ =313 nm in methanol and in the presence of ammonia or primary aliphatic amines.

Fluorinated heterocyclic compounds: an assay on the photochemistry of some fluorinated 1-oxa-2-azoles: an expedient route to fluorinated heterocycles

Abstract Photoinduced heterocyclic rearrangements of ON bond-containing azoles have been claimed in the synthesis of target fluorinated heterocyclic compounds. In this context, the photochemical behavior of some fluorinated 1,2,4-oxadiazoles has been investigated. Irradiations of 3-amino-5-perfluoroalkyl-1,2,4-oxadiazoles at λ =313 nm in methanol gave open-chain products arising from a reaction of the nucleophilic solvent with either the first formed ring-photolytic species or with a nitrilimine moiety generated from it. Differently, irradiations in methanol with the presence of triethylamine (TEA) followed competing phototransposition pathways leading to the ring-isomers 2-amino-5-perfluo…

Synthesis of fluorinated 1,2,4-oxadiazin-6-ones through ANRORC rearrangement of 1,2,4-oxadiazoles

Abstract The reaction of 3-ethoxycarbonyl-5-perfluoroalkyl-1,2,4-oxadiazoles with hydroxylamines has been investigated, evidencing the possibility of competitive reaction paths. Nucleophilic addition of hydroxylamine to the electrophilic C(5) of the 1,2,4-oxadiazole ring, followed by ring-opening and ring-closure with enlargement, leads to high yield and in very mild experimental conditions to the formation of 5-hydroxyamino-3-perfluoroalkyl-6 H -1,2,4-oxadiazin-6-ones, one of these presenting water gelation ability. In turn, reactions with N -methylhydroxylamine lead the exclusive formation of 4-perfluoroacylamino-2-methyl-2 H -1,2,5-oxadiazol-3-ones through the well known Boulton–Katritzk…

Synthesis of fluorinated oxadiazoles with gelation and oxygen storage ability

A new family of fluorinated low molecular weight (LMW) gelators has been synthesized through SNAr substitution of 5-polyfluoroaryl-3-perfluoroheptyl-1,2,4-oxadiazoles with glycine ester. The obtained compounds give thermal and pH-sensitive hydrogels or thermo-reversible organogels in DMSO. Oxygen solubility studies showed the ability to maintain high oxygen levels in solution and in gel blend with plate counter agar (PCA).

Sintesi one-pot di N-ossidi di 2-ammino-pirimidine fluorurate. Riarrangiamenti competitivi “four-atom side-chain” di 1,2,4-ossadiazoli

Recent Advances in the Chemistry of 1,2,4-Oxadiazoles

1,2,4-Oxadiazoles experienced an almost 80-year long period of scientific lethargy before they tickled the curiosity of chemists. The study of chemical and photochemical reactivity of 1,2,4-oxadiazoles opened the way to a series of applications in heterocyclic synthesis. Today, 1,2,4-oxadiazoles are known in medicinal chemistry for their use as bioisosters of esters and amides. Furthermore, fluorinated 1,2,4-oxadiazoles have been applied in materials science either by themselves or for the targeted modification of polymers and macromolecules. Overall, the synthesis of 1,2,4-oxadiazoles can be planned to fine-tune their properties for featured applications. Their versatility, either as start…

ChemInform Abstract: Photochemical Functionalization of Allyl Benzoates by C-H Insertion.

The photoreactivity of allyl benzoates, containing an electron-rich double bond, has been explored by irradiation at 305 nm in different solvents. Solvent addition products arising from an insertion of the alpha H–C bonds of THF, dioxane, and i-PrOH to the allylic double bond was realized. The observed reactivity depended on reaction conditions and substitution pattern of the substrate. A DFT study on this unusual reaction was performed allowing the formulation of two mechanistic pathways.

Nuovi Riarrangiamenti Boulton-Katritzky di derivati 1,2,4-ossadiazolici contenenti un atomo di carbonio nucleofilo in catena laterale

Synthesis of Isoxazoline Derivatives through Boulton-Katritzky Rearrangement of 1,2,4-Oxadiazoles

The base-induced rearrangement of 1,2,4-oxadiazoles into isoxazoline derivatives is reported. This represents the first example of a three-atom side-chain rearrangement that involves a saturated CCO side chain at C-3 of the oxadiazole. Nonaromatic 3-amino-isoxazoline derivatives are obtained in good yields. Interestingly, this reaction occurs through the rearrangement of aromatic oxadiazoles to form less stable bonds than those that are broken.

FDA-Approved Fluorinated Heterocyclic Drugs from 2016 to 2022

The inclusion of fluorine atoms or heterocyclic moiety into drug structures represents a recurrent motif in medicinal chemistry. The combination of these two features is constantly appearing in new molecular entities with various biological activities. This is demonstrated by the increasing number of newly synthesized fluorinated heterocyclic compounds among the Food and Drug Administration FDA-approved drugs. In this review, the biological activity, as well as the synthetic aspects, of 33 recently FDA-approved fluorinated heterocyclic drugs from 2016 to 2022 are highlighted.

Photoinduced molecular rearrangements. Some comments on the ring-photoisomerization of 1,2,4-oxadiazoles into 1,3,4-oxadiazoles

The ring-photoisomerization of 3-amino- and 3-methylamino-5-phenyl-1,2,4-oxadiazoles into the corresponding 2-amino- and 2-methylamino-5-phenyl-1,3,4-oxadiazoles has been reinvestigated by examining the effect of a base on the photoreaction. On irradiating at λ = 254 nm in methanol, yields of the ring-photoisomers were found to be significantly enhanced by the addition of triethylamine (TEA) in the photoreaction medium. By contrast, irradiation of the 3-amino-5-phenyloxadiazole in acetonitrile containing TEA gave an almost complete photoreduction into benzoylguanidine, while few percent of the ring photoisomer were detected. Furthermore, the pyrene-sensitized photolysis of 3-amino-5-phenylo…

Design, synthesis, and biological evaluation of a new class of benzo[b]furan derivatives as antiproliferative agents, with in silico predicted antitubulin activity

A new series of 3-benzoylamino-5-(1H-imidazol-4-yl)methylaminobenzo[b]furans were synthesized and screened as antitumor agents. As a general trend, tested compounds showed concentration-dependent antiproliferative activity against HeLa and MCF-7 cancer cell lines, exhibiting GI50 values in the low micromolar range. In most cases, insertion of a methyl substituent on the imidazole moiety improved the antiproliferative activity. Therefore, methyl-imidazolyl-benzo[b]furans compounds were tested in cell cycle perturbation experiments, producing cell cycle arrest with proapoptotic effects. Their core similarity to known colchicine binding site binders led us to further study the structure featur…

Sintesi di nuovi bent-core LC fluorurati

Ammonium formate-Pd/C as a new reducing system for 1,2,4-oxadiazoles. Synthesis of guanidine derivatives and reductive rearrangement to quinazolin-4-ones with potential anti-diabetic activity

1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH4CO2H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us to obtain differently substituted acylamidine, acylguanidine and diacylguanidine derivatives. The proposed system is also effective for the achievement of a reductive rearrangement of 5-(2′-aminophenyl)-1,2,4-oxadiazoles into 1-alkylquinazolin-4(1H)-ones. The alkaloid glycosine was also obtained with this method. The obtained compounds were preliminarily tested for their biological activity in terms of their cytotoxicity, induce…

Heterocyclic photorearrangements. Photoinduced rearrangement of 3-styryl-1,2,4-oxadiazoles

The photochemical behaviour of 3-styryl-5-phenyl-(5-methyl)-1,2,4-oxadiazoles in methanol at 254 nm has been investigated. A photoinduced rearrangement to the quinoline system has been pointed out and explained as proceeding through an initial photolysis of the ring ON bond, followed by a six membered ring closure reaction involving the styryl moiety.

Hsp60, a Novel Target for Antitumor Therapy: Structure-Function Features and Prospective Drugs Design

Heat shock protein 60 kDa (Hsp60) is a chaperone classically believed to be involved in assisting the correct folding of other mitochondrial proteins. Hsp60 also plays a role in cytoprotection against cell stressors, displaying for example, antiapoptotic potential. Despite the plethora of studies devoted to the mechanism of Hsp60's function, especially in prokaryotes, fundamental issues still remain unexplored, including the definition of its role in cancer. Key questions still unanswered pertain to the differences in structure-function features that might exist between the well-studied prokaryotic GroEL and the largely unexplored eukaryotic Hsp60 proteins. In this article we discuss these …

One-pot synthesis of fluorinated 2-amino-pyrimidine-N-oxides. Competing pathways in the four-atom side-chain rearrangements of 1,2,4-oxadiazoles

Abstract Trifluoromethylated 2-amino-pyrimidine N-oxides have been synthesized by reaction of the 3-amino-5-methyl-1,2,4-oxadiazole with trifluoromethyl-β-diketones in the presence of perchloric acid, followed by hydrolysis. In this ring-to-ring transformation an initial formation of (unisolated) 1,2,4-oxadiazole-pyrimidinium salts, and subsequent ring-opening at the oxadiazole moiety occurs. Isolation of 2-(hydroxyamino)-pyrimidine from the reaction mixture evidenced the presence of a competing pathway where the N(4) nitrogen of the oxadiazole is involved in the formation of a regioisomeric pyrimidinium salt. The effect of the trifluoromethyl group on the product distribution is discussed.…

Fluorescent Hg2+ Sensors: Synthesis and Evaluation of a Tren-Based Starburst Molecule Containing Fluorinated 1,2,4-Oxadiazoles.

A new tren-based starburst molecule containing fluorinated 1,2,4-oxadiazoles as fluorophores has been synthesized and its sensing behavior toward several metal cations has been investigated by UV/Vis, fluorescence, 1 H NMR and 19 F NMR spectroscopy. Selective sensing for Hg 2+ ions through a PET-based mechanism was evidenced, suggesting application as fluorescent sensor for Hg 2+ of the off-on type.

Theoretical study of degenerate Boulton-Katritzky rearrangements. Semiempirical and ab initio procedures

Abstract A theoretical study of degenerate Boulton–Katritzky rearrangements concerning the anions of the 3-formylamino-1,2,4-oxadiazole, 3-formylmethyl-isoxazole and 3-hydroxy-iminomethyl-1,2,5-oxadiazole has been carried out by using semiempirical MNDO and ab initio Hartree–Fock procedures. Different transition structures and reactive pathways were obtained in the two cases. Semiempirical treatment shows asymmetrical transition states and non-concerted processes via symmetrical intermediates. By contrast, ab initio procedures describe concerted and synchronous processes involving symmetrically-located transition states. Some comments and criticisms on the theoretical treatment of these typ…

Ionic self assembly in the design of fluorinated ionic liquid crystals (ILCs)

Ionic liquid crystals are a class of compounds containing anions and cations, that combine the properties of liquid crystals and ionic liquids[1]. In the conventional design of ionic liquid crystalline compounds, an ionic core is connected with mesogenic groups via chemical covalent bonding . Alternatively, in ionic compounds, strong electrostatic interactions between cation and anion can be used to build up liquid crystalline order at supramolecular level. This general approach, called ionic self-assembly (ISA), allows one to create ionic phases and mesophases with highly organized supramolecular order [2]. In this context, a new series of fluorinated ionic liquids (ILs) and ionic liquid c…

ChemInform Abstract: LEAD TETRAACETATE OXIDATION OF PHENYLHYDRAZONES OF 3-BENZOYLAZOLES. SYNTHESIS OF AZOACETATES AND THEIR CONVERSION INTO INDAZOLES

Lead tetraacetate (LTA) oxidation of (E)- and (Z)-phenylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole, 3-benzoyl-5-phenylisoxazole, and 3-benzoyl-4-methyl-1,2,5-oxadiazole has been studied. Conversion of azoacetate products into 3-(azol-3-yl)-substituted indazoles has been achieved by reacting them with aluminium chloride in benzene at room temperature.

ChemInform Abstract: Synthesis of Isoxazoline Derivatives Through Boulton-Katritzky Rearrangement of 1,2,4-Oxadiazoles.

This is the first report of the rearrangement of 1,2,4-oxadiazole with saturated C—C—O side chains and an unusual example of an irreversible rearrangement that allows the formation of nonaromatic heterocycles.

Heterocyclic rearrangements. Synthesis of 1,2,4-oxadiazolo[2,3-a]pyrimidinium systems and their ring opening into pyrimidineN-oxides

Reaction des methyl- et phenyl-5 amino-3 oxadiazoles-1,2,4 avec l'acetylacetone ou la benzoylacetone en presence d'acide perchlorique: obtention de methyl- et phenyl-2 methyl- et phenyl-5 methyl-7 oxadiazolo [2,3-a] pyrimidiniums-4 qui se decyclisent ensuite en oxydes-1 d'acylamino-2- et amino-2 methyl-4 methyl- et phenyl-6 pyrimidines

ChemInform Abstract: Fluorinated Heterocyclic Compounds. A Photochemical Synthesis of 3-Amino-5-perfluoroaryl-1,2,4-oxadiazoles.

Abstract A photochemical methodology for the synthesis of 3-amino- (or 3- N -substituted amino) 5-pentafluorophenyl-1,2,4-oxadiazoles is reported. Irradiation of 3-pentafluorobenzoylamino-4-methyl-1,2,5-oxadiazole (Furazan) at 254 nm in methanol and in the presence of ammonia, primary or secondary aliphatic amines produces 3-amino-, 3-( N -alkylamino)-, 3-( N , N -dialkylamino)-5-pentafluorophenyl-1,2,4-oxadiazoles. The photoreaction follows the fragmentation pattern of the furazan ring with the extrusion of acetonitrile and the formation of a counterpart fragment which the nitrogen nucleophile will capture. Depending on the nature of the reagent, displacement of a fluoride anion at the C(5…

ChemInform Abstract: Synthesis of Trifluoromethylated 2-Benzoyl- and 2-Aminoimidazoles from Ring Rearrangement of 1,2,4-Oxadiazole Derivatives.

Abstract Fluoroalkylated 2-ylamino-imidazoles have been synthesized by reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with fluorinated β-dicarbonyl compounds and subsequent base-induced Boulton–Katritzky Rearrangement (BKR) of the isolated β-enaminocarbonyl intermediate. Alternatively, one-pot reactions performed in the presence of Montmorillonite K10 favoured the condensation at the 3-amino moiety of the oxadiazole and, in some cases, allowed the direct synthesis of 2-benzoylamino-imidazoles. Hydrolysis of 2-benzoylamino-imidazoles easily yielded fluorinated 2-amino-imidazoles targets.

ChemInform Abstract: Exploiting the CNC Side Chain in Heterocyclic Rearrangements: Synthesis of 4(5)-Acylamino-imidazoles.

A new variation on the Boulton-Katritzky reaction is reported, namely, involving use of a CNC side chain. A novel Montmorillonite-K10 catalyzed nonreductive transamination of a 3-benzoyl-1,2,4-oxadiazole afforded a 3-(alpha-aminobenzyl)-1,2,4-oxadiazole, which was condensed with benzaldehydes to afford the corresponding imines. In the presence of strong base, these imines underwent Boulton-Katritzky-type rearrangement to afford novel 4(5)-acylaminoimidazoles.

Heterocyclic Rearrangements: An Expedient Route to the Synthesis of Fluorinated Heterocyclic Compounds‡‡Financial support through the Italian MIUR and University of Palermo within the National Research Project “Fluorinated Compounds: New Materials for Advanced Applications”.

Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60,…

SYNTHESIS AND EVALUATION OF CURCUMIN ANALOGUES AS NEURO-PROTECTIVE AGENTS FOR THE ALZHEIMER'S DISEASE

The Alzheimer's disease (AD) is the most common form of senile dementia.1 The most important role in AD is played by the aggregation process of beta-amyloid peptide (Aß), responsible for the cytotoxic effects.2 In this context, the purpose of this study was to synthesize new dicarbonyl compounds 1 structurally related to curcumin3, with anti-aggregation activity against Aß.Parallel studies involve the synthesis of heterocyclic-based curcumin-like molecules that are currently under investigation by means of in silico protocols in order to rationalize the ligand-biological target interactions.

New biodegradable hydrogels based on a photocrosslinkable modified polyaspartamide: synthesis and characterization

Abstract α,β-Poly( N -2-hydroxyethyl)- dl -aspartamide (PHEA), a synthetic water-soluble biocompatible polymer, was derivatized with glycidyl methacrylate (GMA), in order to introduce in its structure chemical residues having double bonds and ester groups. The obtained copolymer (PHG) contained 29 mol% of GMA residues. PHG aqueous solutions at various concentrations ranging from 30 to 70 mg/ml were exposed to a source of UV rays at λ 254 nm in the presence or in the absence of N , N ′-methylenebisacrylamide (BIS); the formation of compact gel phases was observed beginning from 50 mg/ml. The obtained networks were characterized by FT-IR spectrophotometry and swelling measurements which evide…

ChemInform Abstract: Photoinduced Molecular Rearrangements. Some Comments on the Ring-Photoisomerization of 1,2,4-Oxadiazoles into 1,3,4-Oxadiazoles.

The ring-photoisomerization of 3-amino- and 3-methylamino-5-phenyl-1,2,4-oxadiazoles into the corresponding 2-amino- and 2-methylamino-5-phenyl-1,3,4-oxadiazoles has been reinvestigated by examining the effect of a base on the photoreaction. On irradiating at λ = 254 nm in methanol, yields of the ring-photoisomers were found to be significantly enhanced by the addition of triethylamine (TEA) in the photoreaction medium. By contrast, irradiation of the 3-amino-5-phenyloxadiazole in acetonitrile containing TEA gave an almost complete photoreduction into benzoylguanidine, while few percent of the ring photoisomer were detected. Furthermore, the pyrene-sensitized photolysis of 3-amino-5-phenylo…

ChemInform Abstract: Tandem Reactions of 1,2,4-Oxadiazoles with Allylamines.

Two novel thermal rearrangements are presented: the addition of allylamine (II) to oxadiazoles proceeds via ring-opening followed by cycloaddition.

What's Curcumin's mind? The potential role of Curcuminoids in the treatment of Alzheimer's disease

Neurodegenerative diseases (NDs) are one of major public health problems and their impact is continuously growing. Curcumin has been proposed for the treatment of several of these pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to the ability of this molecule to reduce inflammation and aggregation of involved proteins. Nevertheless, the poor metabolic stability and bioavailability of curcumin reduce the possibilities of its practical use. In this review will be highlighted recent results on curcumin and curcuminoids in the search of new effective therapeutic agents against NDs, with particular emphasis on AD.

Experimental and DFT Studies on Competitive Heterocyclic Rearrangements. A Cascade Isoxazole-1,2,4-Oxadiazole-Oxazole Rearrangement

The thermal rearrangements of 3-acylamino-5-methylisoxazoles 1 have been investigated under basic and neutral conditions and interpreted with the support of computational data. The density functional theory (DFT) study on the competitive routes available for the base-catalyzed thermal rearrangement of isoxazoles 1 showed that the Boulton-Katritzky (BK) rearrangement, producing the less stable 3-acetonyl- 1,2,4-oxadiazoles 5, is a much more favored process than either the migration-nucleophilic attack-cyclization (MNAC) or the ring contraction-ring expansion (RCRE). In turn, an increase in reaction temperature will promote the MNAC of oxadiazoles 5, producing the more stable 2-acylaminooxazo…

Theoretical study of photoinduced ring-isomerization in the 1,2,4-oxadiazole series

Abstract A theoretical study of photoinduced ring-isomerization of 3-amino-5-methyl- and 3-amino-5-phenyl-1,2,4-oxadiazoles is reported. The results well agree with the reported experimental data: in particular, they explain the ring-photoisomerization into the corresponding 2-amino-1,3,4-oxadiazoles through a ring contraction-ring expansion route; moreover, the occurrence of competing pathways involving both the ring contraction and the internal cyclization–isomerization mechanism during irradiation of the 5-alkyl substituted substrates in the presence of a base has been also substantiated.

Hydration/elimination reactions of trapped protonated fluoroalkyl triazines

ChemInform Abstract: Photoinduced Single Electron Transfer on 5-Aryl-1,2,4-oxadiazoles: Some Mechanistic Investigations in the Synthesis of Quinazolin-4-ones.

The photochemistry of some 5-aryl-3-methoxy- (or 5-aryl-3-phenyl-) 1,2,4-oxadiazoles irradiated in the presence of different sensitizers [such as diphenylacetylene (DAC), 9,10-diphenylanthracene (DAN), or triphenylene (TPH)] or ground-state donors such as triethylamine (TEA) has been investigated. Intermediates arising from breaking of the ring O-N bond develop both into quinazolin-4-ones (by a heterocyclization reaction involving the aryl at the C-5 of the oxadiazole nucleus) and into open-chain products (corresponding to a reduction at the ring O-N bond), in different ratios depending on their structures and photoreaction conditions. A reasonable explanation considers sensitization by pho…

Polyfluoroalkyl viologen-based Ionic Liquid Crystals

Can phthalates move into the eggs of the loggerhead sea turtle Caretta caretta? The case of the nests on the Linosa Island in the Mediterranean Sea

During the monitoring of Caretta caretta nests on the island of Linosa, 30 unhatched eggs from four nests were collected to study the presence of phthalates in their three components (shell, yolk, and albumen). Four phthalates, namely diethyl (DEP), dibutyl (DBP), di-(2-ethylhexyl) (DEHP), and dioctyl (DOTP) phthalic acid esters (PAE), which are widely used as additives in plastics, were detected in all egg components. The most frequently found phthalate was DBP, followed by DEHP in eggshell and yolk. Dimethyl- (DMP) and butylbenzyl-phthalate (BBP) were below the limits of detection for all samples. The high total phthalate recorded in the yolk suggests that contamination could arise by vit…

Photooxidations of Alkenes in Fluorinated Constrained Media:  Fluoro-organically Modified NaY as Improved Reactors for Singlet Oxygen “Ene” Reactions

Creating a stationary fluorinated environment inside the zeolite cavity can increase the reactivity observed for intrazeolite photooxidation of alkenes. Exchanging the zeolite with fluorinated organic cations is a much more effective strategy than simply using a fluorinated solvent for slurry irradiations. Use of cations containing C-F bonds is also more efficient than use of deuterated cations for creation of a singlet oxygen friendly environment where the quenching processes are slowed down. Doping the zeolite with fluoro-organic cation 4 resulted in an increase in the singlet oxygen lifetime to 12 micros.

Studio dell’effetto dei sostituenti sul riarrangiamento fotoindotto di diaril-1,2,4-ossadiazoli in zeolite NaY

ChemInform Abstract: Heterocyclic Rearrangements. Synthesis of 1,2,4-Oxadiazolo(2,3-a)pyrimidinium Systems and Their Ring Opening into Pyrimidine N-Oxides.

Reaction des methyl- et phenyl-5 amino-3 oxadiazoles-1,2,4 avec l'acetylacetone ou la benzoylacetone en presence d'acide perchlorique: obtention de methyl- et phenyl-2 methyl- et phenyl-5 methyl-7 oxadiazolo [2,3-a] pyrimidiniums-4 qui se decyclisent ensuite en oxydes-1 d'acylamino-2- et amino-2 methyl-4 methyl- et phenyl-6 pyrimidines

Fluoro heterocycles. A photochemical methodology for the synthesis of 3-amino- and 3-(N-alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles

Abstract A photochemical methodology for the synthesis of perfluoroalkyl-1,2,4-oxadiazoles has been described. 3-Amino- and 3-( N -alkylamino)-5-perfluoroalkyl-1,2,4-oxadiazoles have been prepared by irradiation of 3-perfluoroalkanoylamino-4-phenyl-1,2,5-oxadiazoles (furazans) at λ =313 nm in methanol and in the presence of ammonia or primary aliphatic amines.

Asymmetric synthesis and biological evaluation of 1,2,4-Oxadiazoles analogues of Linezolid

Oxazolidinones are a class of antibacterial agents which displayed activity againist a variety of gram-positive pathogens and are highly potent against multidrug-resistant bacteria. Linezolid is the first oxazolidinone antibiotic approved for clinical use but linezolid resistance began to appear. 1,2,4 – Oxadiazoles are known bioactive heterocycles whose activity has been often associated to their bioisosterism with amide or ester functionalities [1]. As results of a research project on the molecular design of heterocycle – based antibacterials to contrast Multi-Drug Resistance (MDR) [2], we report the synthesis of 1,2,4 - Oxadiazole analogues of Linezolid. The synthesis has been achieved b…

Synthesis of trifluoromethylated 2-benzoyl- and 3-aminoimidazoles from ring rearrangement of 1,2,4-oxadiazole derivative

Fluoroalkylated 2-ylamino-imidazoles have been synthesized by reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with fluorinated b-dicarbonyl compounds and subsequent base-induced BoultoneKatritzky Rearrangement (BKR) of the isolated b-enaminocarbonyl intermediate. Alternatively, one-pot reactions performed in the presence of Montmorillonite K10 favoured the condensation at the 3-amino moiety of the oxadiazole and, in some cases, allowed the direct synthesis of 2-benzoylamino-imidazoles. Hydrolysis of 2-benzoylamino-imidazoles easily yielded fluorinated 2-amino-imidazoles targets.

Five-to-Six Membered Ring-rearrangements in the Reaction of 5-Perfluoroalkyl-1,2,4-oxadiazoles with Hydrazine and Methylhydrazine

The hydrazinolysis reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine or methylhydrazine as bidentate nucleophiles has been investigated. The reaction occurred through the addition of the bidentate nucleophile to the C(5)-N(4) double bond of the 1,2,4-oxadiazole followed by ring-opening and ring-closure (ANRORC) involving the second nucleophilic site of the reagent. This ring-closure step could involve either the original C(3) of the 1,2,4-oxadiazole (giving a five-to-five membered ring rearrangement) or an additional electrophilic center linked to it (exploiting a five-to-six membered ring rearrangement). An alternative initial nucleophilic attack may involve the additional elec…

Lower rim arylation of calix[n]arenes with extended perfluorinated domains

Abstract Exhaustive O-arylation of p-tert -butylcalix[ n ]arenes 2 ( n  = 4–8) with an excess of 3-pentadecafluoroheptyl-5-pentafluorophenyl-1,2,4-oxadiazole 3 and K 2 CO 3 in refluxing acetonitrile provides an easy entry to a new family of perfluorinated calix[ n ]arenes 1 . The cyclic tetramer furnishes a mixture of cone , partial cone , and 1,2-alternate conformers, while the larger macrocycles afford single products. The structures of all new compounds are substantiated by NMR techniques and MALDI-TOF mass spectral data. Single-crystal X-ray diffraction studies on the pentamer derivative 1b reveal a distorted cone-in conformation of the calixarene cup.

Mononuclear Perfluoroalkyl-Heterocyclic Complexes of Pd(II): Synthesis, Structural Characterization and Antimicrobial Activity

Two mononuclear Pd(II) complexes [PdCl2(pfptp)] (1) and [PdCl2(pfhtp)] (2), with ligands 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), were synthesized and structurally characterized. The two complexes showed a bidentate coordination of the ligand occurring through N atom of pyridine ring and N4 atom of 1,2,4-triazole. Both complexes showed antimicrobial activity when tested against both Gram-negative and Gram-positive bacterial strains.

Photochemical cyclization of some aldehyde thiosemicarbazones

The photochemical behaviour of some substituted aldehyde thiosemicarbazones 1a-k has been investigated in methanol at 254 nm. Thiosemicarbazones of glyoxil methyl ester 1a-f cyclized to furnish the 3-thioxo- 1,2,4-triazin-5-one 2 ring system. The remaining thiosemicarbazones 1g-j gave 1,2,4-triazoline 4 derivatives.

Klebsiella pneumoniae Lipopolysaccharides Serotype O2afg Induce Poor Inflammatory Immune Responses Ex Vivo

Currently, Klebsiella pneumoniae is a pathogen of clinical relevance due to its plastic ability of acquiring resistance genes to multiple antibiotics. During K. pneumoniae infections, lipopolysaccharides (LPS) play an ambiguous role as they both activate immune responses but can also play a role in immune evasion. The LPS O2a and LPS O2afg serotypes are prevalent in most multidrug resistant K. pneumoniae strains. Thus, we sought to understand if those two particular LPS serotypes were involved in a mechanism of immune evasion. We have extracted LPS (serotypes O1, O2a and O2afg) from K. pneumoniae strains and, using human monocytes ex vivo, we assessed the ability of those LPS antigens to in…

Synthesis, Reactivity, Biological Activity and Applications of Fluorinated Oxadiazoles and Thiadiazoles

A literature survey of the chemistry of fluorinated oxadiazoles and thiadiazoles is presented. The core part on synthetic procedures is given by type of heterocycle and includes recent developments up to the end of 2012. Reactivity is discussed when induced by the presence of the fluorinated moiety. Selected examples of bioactive compounds and applications are illustrated.

Synthesis and characterization of a series of alkyl-oxadiazolylpyridinium salts as perspective ionic liquids

The synthesis of a series of 1,2,4-oxadiazolyl-N-methylpyridinium salts differing in the length and the position of the alkyl chain in the heterocyclic ring and the counter ions is reported. Some features of this new family of salts as perspective ionic liquids are described and the influence of the varying moieties in the modulation of the properties is discussed.

Synthesis of 4(5)-phenacyl-imidazoles from isoxazole side-chain rearrangements

A novel base-induced rearrangement of isoxazoles into imidazole derivatives is reported. In the isoxazole series, this represents the first example of a three-atom side-chain rearrangement involving a CNC sequence. The reactions are carried out under nitrogen and produced 2-aryl-4(5)-phenacyl-5(4)-phenyl-imidazoles in high yields. In the presence of oxygen, a cascade rearrangement-oxidation reaction sequence was observed and imidazole derivatives bearing an oxidized side-chain were isolated.

SINTESI DI IMIDAZOLI E 4,4’-BISIMIDAZOLI FUNZIONALIZZATI, TRAMITE REAZIONI DI RIARRANGIAMENTO DI ISOSSAZOLI

Photoinduced functionalization of diterpenes: photochemical behaviour of grandifloric acid in methanol and acetonitrile

Abstract Irradiation of grandiflorolic acid (11) at λ=254 nm in acetonitrile gave the two epimers 13 and 14 through a photodecarboxylation reaction of the carboxylic group on C-4. Irradiation of compound 11 in methanol at λ=254 nm provided the transformation of the C-20 angular methyl into a carbomethoxymethyl group. In this case, unlike compounds 13 and 14, only one of the two possible isomers (15) was obtained (equatorial methyl at C-4). A mechanistic approach of this reaction in discussed, and the role of mutual stereochemistry between C-20 methyl and C-19 carboxylic group in determining the course of the reaction is pointed out.

Experimental and DFT Studies on Competitive Heterocyclic Rearrangements. Part 2:1 A One-Atom Side-Chain versus the Classic Three-Atom Side-Chain (Boulton−Katritzky) Ring Rearrangement of 3-Acylamino-1,2,4-oxadiazoles

The experimental investigation of the base-catalyzed rearrangements of 3-acylamino-1,2,4-oxadiazoles evidenced a new reaction pathway which competes with the well-known ring-degenerate Boulton-Katritzky rearrangement (BKR). The new reaction consists of a one-atom side-chain rearrangement that is base-activated, occurs at a higher temperature than the BKR, and irreversibly leads to the corresponding 2-acylamino-1,3,4-oxadiazoles. An extensive DFT study is reported to elucidate the proposed reaction mechanism and to compare the three possible inherent routes: (i) the reversible three-atom side-chain ring-degenerate BKR, (ii) the ring contraction-ring expansion route (RCRE), and (iii) the one-…

Recent development in fluorinated antibiotics

This chapter presents the most recent results in the development of fluorinated antibioticsby taking into consideration modern challenges of multidrug-resistant pathogens. After a brief introduction on the direct and indirect effects of fluorine and fluorinated moieties in regulating biological activity, the chapter is developed in three main subsections discussing the two major classes of fluorinated antibiotics, fluoroquinolones and oxazolidinones, plus an overview of recent research on the antibiotic activity of fluorinated analogs of tetracyclines, peptidomimetics, triazoles, and nucleosides. Discussed aspects include: (1) Synthesis and challenges posed by the introduction of fluorinate…

Synthesis of Heteroaromatics via Rearrangement Reactions

Experimental and DFT Studies on Competitive Heterocyclic Rearrangements. 3. A Cascade Isoxazole−1,2,4-Oxadiazole−Oxazole Rearrangement

The thermal rearrangements of 3-acylamino-5-methylisoxazoles 1 have been investigated under basic and neutral conditions and interpreted with the support of computational data. The density functional theory (DFT) study on the competitive routes available for the base-catalyzed thermal rearrangement of isoxazoles 1 showed that the Boulton-Katritzky (BK) rearrangement, producing the less stable 3-acetonyl-1,2,4-oxadiazoles 5, is a much more favored process than either the migration-nucleophilic attack-cyclization (MNAC) or the ring contraction-ring expansion (RCRE). In turn, an increase in reaction temperature will promote the MNAC of oxadiazoles 5, producing the more stable 2-acylaminooxazol…

Synthesis and biological evaluation of 1,4-oxadiazole analogues of Linezolid

ChemInform Abstract: Heterocyclic Photorearrangements. Photoinduced Rearrangement of 3-Styryl-1,2,4-oxadiazoles.

The photochemical behaviour of 3-styryl-5-phenyl-(5-methyl)-1,2,4-oxadiazoles in methanol at 254 nm has been investigated. A photoinduced rearrangement to the quinoline system has been pointed out and explained as proceeding through an initial photolysis of the ring ON bond, followed by a six membered ring closure reaction involving the styryl moiety.

Photoinduced Single Electron Transfer on 5-Aryl-1,2,4-oxadiazoles:  Some Mechanistic Investigations in the Synthesis of Quinazolin-4-ones

The photochemistry of some 5-aryl-3-methoxy- (or 5-aryl-3-phenyl-) 1,2,4-oxadiazoles irradiated in the presence of different sensitizers [such as diphenylacetylene (DAC), 9,10-diphenylanthracene (DAN), or triphenylene (TPH)] or ground-state donors such as triethylamine (TEA) has been investigated. Intermediates arising from breaking of the ring O-N bond develop both into quinazolin-4-ones (by a heterocyclization reaction involving the aryl at the C-5 of the oxadiazole nucleus) and into open-chain products (corresponding to a reduction at the ring O-N bond), in different ratios depending on their structures and photoreaction conditions. A reasonable explanation considers sensitization by pho…

Sintesi di ossadiazoli fluorurati come nuovi Low molecular weight hydrogelators

Fluorinated Heterocyclic Compounds. A Photochemical Approach to a Synthesis of Fluorinated Quinazolin-4-ones

An efficient and generalized photochemical methodology for the preparation of fluorinated quinazolin-4-ones is described. Depending on the starting substrate, quinazolin-4-ones bearing a perfluoroalkyl- or perfluoroaryl- substituent in position 2 or fluorine atoms on any positions of the benzo-fused moiety can easily be obtained. 5-Aryl-3-perfluoroalkylpentafluorophenyl- or 5-polyfluoroaryl-3-phenyl(methyl)-1,2,4-oxadiazoles, respectively, can be considered as ideal precursors that can be transformed into the target quinazolin-4-ones by irradiation in the presence of triethylamine (TEA) (at λ = 313 nm) or pyrene (at λ = 365 nm) in dry methanol or acetonitrile as solvent. Some mechanistic co…

Extended Investigation of the Aqueous Self-Assembling Behavior of a Newly Designed Fluorinated Surfactant

The physicochemical behavior of the newly synthesized fluorinated 5-hydroxyamino-3-perfluoroheptyl-1,2,4-oxadiazin-6-one (PFHO) surfactant was investigated. Thermal analysis showed that the pure surfactant is thermally stable under an inert atmosphere to 135 degrees C, which is several degrees higher than the melting point (99 degrees C). PFHO is rather active at the water/air interface where it assumes a standing up configuration. It exhibits an enhanced self-assembling behavior; accordingly, the critical micellar concentrations at some temperatures are 2 orders of magnitude lower than those of a similar surfactant having the same phobicity, such as sodium perfluorooctanoate. Even in the d…

Photochemically Produced Singlet Oxygen: Applications and Perspectives

This Review aims to provide early stage researchers with an updated guide to applications of photochemically produced singlet oxygen and, at the same time, widen the experienced researcher's perspectives in a holistic approach to singlet oxygen chemistry. Without being exhaustive, literature between 2010 and early 2018 has been surveyed by focusing on a critical evaluation of new knowledge and applications. After an introductory section concerning singlet oxygen production, detection, and interactions with biological systems, subsequent sections describe current applications of singlet-oxygen-enabled technology. Besides strictly chemical synthesis applications, attention has been given to t…

Synthesis of Amino-1,2,4-triazoles by Reductive ANRORC Rearrangements of 1,2,4-Oxadiazoles

The reaction of various 1,2,4-oxadiazoles with an excess of hydrazine in DMF has been investigated. 3-Amino- 1,2,4-triazoles are produced through a reductive ANRORC pathway consisting of the addition of hydrazine to the 1,2,4-oxadiazole followed by ring-opening, ring-closure, and final reduction of the 3-hydroxylamino-1,2,4-triazole intermediate. The general applicability of 1,2,4-oxadiazoles ANRORC reactivity is demonstrated also in the absence of C(5)-linked electron-withdrawing groups.

Sintesi di Low Molecular Weight Gelators (LMWG) Fluorurati

Photoinduced functionalization of the C-20 methyl group of the nor-diterpene atractyligenin

Abstract Irradiation of the nor-diterpene atractyligenin at λ =254 nm in methanol gave, on one hand, the decarboxylation product, and provided, on the other hand, the transformation of the C-20 angular methyl into a methylene-carbomethoxy group. A photochemical pathway involving formation of C-19/C-20 bond is suggested.

Oxadiazolyl-pyridines and perfluoroalkyl-carboxylic acids as building blocks for protic ionic liquids: crossing the thin line between ionic and hydrogen bonded materials.

A series of 18 samples has been prepared in order to obtain fluorinated materials as Protic Ionic Liquids (PILs). These were synthesized by appropriately mixing 1,2,4-oxadiazoles derivatised with two pyridines, or one pyridine and a fluorinated chain, and perfluoroalkyl-carboxylic acids, either mono- or dicarboxylic, leading to symmetric and non-symmetric materials. Many of them showed low melting points. However, the possibility of classifying the synthesized materials as PILs is discussed in terms of effective ionicity of the systems by the combination of Density Functional Theory (DFT) calculation and IR spectroscopy. The important outcome of our investigation is that the complete proton…

Microreattori fluorurati. Studio della reazione "ene" con ossigeno singoletto in zeolite NAY modificata con cationi fluoroorganici

Synthesis of Fluorinated Bent-Core Mesogens (BCMs) Containing the 1,2,4-Oxadiazole Ring

New fluorinated bent-core mesogens containing the 1,2,4-oxadiazole or 1,2,4-triazole nucleus have been synthesized taking advantage of the ANRORC (Addition of Nucleophile, Ring-Opening, Ring-Closure) reactivity of 5-perfluoroalkyl-1,2,4-oxadiazoles. Physical state changes of the obtained compounds were characterized through DSC, POM, and SAXS. Besides the formation of a smectic mesophase, a novel behavior as organic molecular glass was evidenced for some 1,2,4-oxadiazole derivatives.

Molecular rearrangements of 1-oxa-2-azoles as an expedient route to fluorinated heterocyclic compounds

Molecular rearrangements of O-N bond-containing azoles (1-oxa-2- azoles) represent a wide class of reactions by which various heterocycle-to- heterocycle transformations can be performed as alternative synthetic methodologies. The material presented in this review is an extensive survey of both thermal and photochemical methodologies that have been applied to fluorinated oxadiazoles, and shows how molecular rearrangements can be an alternative and in some cases the most convenient route for the synthesis of several fluorinated heterocycles.

Synthesis and characterization of a new set of protic ionic liquids

Designing fluorous domains. Synthesis of a series of pyridinium salts bearing a perfluoroalkylated azole moiety

The synthesis of a series of N-methylpyridinium salts bearing a perfluoroalkylated 1,2,4-oxadiazole or 1,2,4-triazole moiety is reported. X-Ray structures of representative perfluoroalkyl-triazolylpyridine (15) and methyl- pyridinium iodide salt (5a) are reported. Their crystal packing clearly shows segregation between the aromatic and parallel double layer fluorinated regions.

Synthesis of Fluorinated Indazoles Through ANRORC-Like Rearrangement of 1,2,4-Oxadiazoles with Hydrazine.

A series of 6-substituted fluorinated indazoles has been obtained through an ANRORC-like rearrangement (Addition of Nucleophile, Ring-Opening and Ring-Closure) of 5-tetrafluorophenyl-1,2,4-oxadiazoles with hydrazine. The initial addition of the bidentate nucleophile to the electrophilic C(5) of the 1,2,4-oxadiazole ring, followed by ring opening and ring closure, leads to the formation of fluorinated indazoles in high yield under mild experimental conditions. Functionalization of the C(6) in the final indazole nucleus was preliminarily achieved through a nucleophilic aromatic substitution on the starting 5-pentafluorophenyl-1,2,4-oxadiazole.

Fluoroarylation of hydroxylated molecules with 5-pentafluorophenyl-1,2,4-oxadiazoles

Study on the thermotropic properties of highly fluorinated 1,2,4-oxadiazolylpyridinium salts and their perspective applications as ionic liquid crystals

A new series of fluorinated salts, iodides and trifluoromethanesulfonates, was synthesized from perfluoroalkylated 1,2,4-oxadiazolylpyridines. Their thermotropic properties were investigated by combined temperature resolved small angle and wide angle X-ray scattering, differential scanning calorimetry and polarised optical microscopy. The UV–visible and photoluminescence properties were studied for all compounds. The results showed for two compounds the existence of an enantiotropic mesomorphic smectic liquid crystal phase. All iodides showed thermochromism phenomena suggesting prospective applications in optoelectronics.

Synthesis and characterization of new azoles as building blocks for functional ionic systems

The Binding Mechanism of Epolactaene to Hsp60 Unveiled by in Silico Modelling

Molecular Dynamics (MD) simulations and DFT/MM calculations were performed in order to rationalize available experimental results and to provide structural details on the binding mechanism of Epolactaene (EPO) to the 60 KDa Heat Shock Protein (Hsp60). The available crystal structure of Hsp60 represents the last step of the chaperone folding cycle, while the Hsp60-EPO complex was obtained by using a homology model of Hsp60, in order to simulate a state related to the beginning of the folding cycle (Rs1). The results of MD simulations point out that EPO shows the highest binding affinity for the empty ATP binding site. The presence of ATP opens a channel that allows the entrance of both EPO d…

Experimental and DFT studies on competitive heterocyclic rearrangements. part 2: A one-atom side-chain versus the classic three-atom side-chain (Boulton-Katritzky) ring rearrangement of 3-acylamino-1,2,4-oxadiazoles

The experimental investigation of the base-catalyzed rearrangements of 3-acylamino-1,2,4-oxadiazoles evidenced a new reaction pathway which competes with the well-known ring-degenerate Boulton- Katritzky rearrangement (BKR). The new reaction consists of a one-atom side-chain rearrangement that is base-activated, occurs at a higher temperature than the BKR, and irreversibly leads to the corresponding 2-acylamino-1,3,4-oxadiazoles. An extensive DFT study is reported to elucidate the proposed reaction mechanism and to compare the three possible inherent routes: (i) the reversible three-atom side-chain ring-degenerate BKR, (ii) the ring contraction-ring expansion route (RCRE), and (iii) the one…

The synthesis of fluorinated heteroaromatic compounds. Part 1. Five-membered rings with more than two heteroatoms. A review

(2005). THE SYNTHESIS OF FLUORINATED HETEROAROMATIC COMPOUNDS. PART 1. FIVE-MEMBERED RINGS WITH MORE THAN TWO HETEROATOMS. A REVIEW. Organic Preparations and Procedures International: Vol. 37, No. 5, pp. 447-506.

Tandem Reactions of 1,2,4-Oxadiazoles with Allylamines

A reaction of 3-chloro-1,2,4-oxadiazoles with allylamine and diallylamine has been investigated. 3,3a,4,5-Tetrahydroisoxazolo[3,4-d]pyrimidines are produced through a tandem ANRORC/[3 + 2]cycloaddition pathway consisting of the addition of allylamine to the 1,2,4-oxadiazole, followed by ring opening, nitrone formation, and finally cycloaddition. 3-N-Allylamino-1,2,4-oxadiazoles were also obtained as minor products through a classical SNAr. Conversely, a reaction with diallylamine produces 3-N,N-diallylamino-1,2,4-oxadiazole and imidazoline through tandem SNAr/aziridination and nucleophilic ring opening.

ChemInform Abstract: 1,2,4-Oxadiazole Rearrangements Involving an NNC Side-Chain Sequence.

The thermal rearrangement of N-1,2,4-oxadiazol-3-yl-hydrazones into 1,2,4-triazole derivatives is reported. This represents the first example of a three-atom side-chain rearrangement involving an NNC sequence linked at the C(3) of the oxadiazole. The reactions carried out under solvent-free conditions produced good to high yields of the final products.

Heterocyclic rearrangements.N,N-diphenylhydrazones, oximes andO-methyloximes of 3-benzoyl-5-phenyl-1,2,4-oxadiazole

The behaviour of (E)- and (Z)-N,N-diphenylhydrazones and O-Methyloximes of 3-benzoyl-5-phenyl-1,2,4-oxadiazole has been studied. When refluxed in benzene, or in dioxane-water (1:1), the (Z)-N,N-diphenylhydrazone 8Z gave the indazole 11 or the substituted semicarbazide 12, respectively. The O-methyloxime 14Z did not give any rearrangement. A criticism of the oximation reaction of 3-benzoyl-5-phenyl-1,2,4-oxadiazole is also reported.

ChemInform Abstract: Photochemical Cyclization of Some Aldehyde Thiosemicarbazones.

The photochemical behaviour of some substituted aldehyde thiosemicarbazones 1a-k has been investigated in methanol at 254 nm. Thiosemicarbazones of glyoxil methyl ester 1a-f cyclized to furnish the 3-thioxo- 1,2,4-triazin-5-one 2 ring system. The remaining thiosemicarbazones 1g-j gave 1,2,4-triazoline 4 derivatives.

1,2,4-Oxadiazole rearrangements involving an NNC side-chain sequence.

The thermal rearrangement of N-1,2,4-oxadiazol-3-yl-hydrazones into 1,2,4-triazole derivatives is reported. This represents the first example of a three-atom side-chain rearrangement involving an NNC sequence linked at the C(3) of the oxadiazole. The reactions carried out under solvent-free conditions produced good to high yields of the final products.

Fotochimica organica in zeolite: dalle fotoossidazioni ai riarrangiamenti eterociclici

Linear free energyortho-correlations in the thiophene series. Part IX . Kinetics of esterification with diazodiphenylmethane of some 3-, 4-, and 5-substituted thiophene-2-carboxylic acids in methanol

The rate constants for the esterification of some 3-, 4-, and 5-substituted thiophene-2-carboxylic acids with diazodiphenylmethane in methanol at 25° have been measured. The reactivity of some para- and ortho-substituted benzoic acids has also been determined. Logarithmic kinetic constants for ortho-, meta-, and para-like substituted thiophene-2-carboxylic acids furnish an excellent linear free energy relationship when plotted versus Δpka (β 0.89, r 0.989, C.L. > 99.9%, n 18, i 0.04), thus confirming the peculiar behaviour of five-membered ring derivatives. The correlation with σH values offers an additional proof of the hyper-ortho character of the 2,3-relation in thiophene derivatives. pa…

Photochemical reactivity of 6α-hydroxy, 7-keto neoclerodane diterpenoids

Abstract The photochemical reactivity, in methanol at λ  = 254 nm, of two 6α-hydroxy-7-keto neoclerodane, isoeriocephalin ( 1 ) and teucrolivin B ( 2 ) was evaluated. From the first compound, two new products were obtained: the 6β-hydroxy epimer ( 3 ) and the ɛ-lactone ( 4 ). The second one yielded exclusively the new spiro γ-lactone ( 5 ). The formation of these new products can be explained by the well-known radical mechanism Norrish type I.

Applications of ring rearrangements involving a participating side chain for the synthesis of five-membered heterocycles

FLUORINATED DERIVATIVES OF A POLYASPARTAMIDE BEARING POLYETHYLENE GLYCOL CHAINS AS OXYGEN CARRIERS

Abstract In this paper the synthesis and characterization of new fluorinated polymers based on a polyaspartamide bearing polyethylene glycol (PEG) chains, are reported. The starting material was the α,β-poly(N-2-hydroxyethyl)- dl -aspartamide (PHEA), a water soluble and biocompatible polymer, that has been derivatized with both polyethylene glycol (with a molecular weight of 2000 Da) and 5-pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole. By varying the amount of the fluorinated oxadiazole, three samples have been prepared and characterized by FT-IR, 1H NMR, 19F NMR and UV–VIS spectroscopy. Size exclusion chromatography analysis of these copolymers revealed the occurrence of a self-asso…

Photochemistry of 1,2,4-oxadiazoles. A DFT study on photoinduced competitive rearrangements of 3-amino- and 3-N-methylamino-5-perfluoroalkyl-1,2,4-oxadiazoles

The photoinduced competitive rearrangements of 5-perfluoroalkyl-3-amino(N-alkylamino)-1,2,4-oxadia- zoles have been investigated by DFT calculations and UV-vis spectroscopy. The observed product selectivity depends on the number of hydrogen atoms present in the amino moiety and involves two or three possible routes: (i) ring contraction-ring expansion (RCRE), (ii) internal-cyclization isomerization (ICI), or (iii) C(3)-N(2) migration-nucleophilic attack-cyclization (MNAC). UV absorption and fluorescence spectra of the reactants, and vertical excitation energy values, calculated by time dependent DFT, support the involvement of a neutral singlet excited state in the photoexcitation process. …

The synthesis of fluorinated heteroaromatic compounds. Part 2. Five-membered rings with two heteroatoms. A review

Fluorinated Heterocyclic Compounds. An Expedient Route to 5-Perfluoroalkyl-1,2,4-triazoles via an Unusual Hydrazinolysis of 5-Perfluoroalkyl-1,2,4-oxadiazoles:  First Examples of an ANRORC-Like Reaction in 1,2,4-Oxadiazole Derivatives

The hydrazinolysis reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles has been investigated. Nucleophilic addition of the reagent to the C(5)-N(4) double bond of the oxadiazole ring, followed by ring-opening and then ring-closure involving the beta-nitrogen atom of the hydrazino moiety and the C(3) of the oxadiazole ring, explains the formation of 5-perfluoroalkyl-1,2,4-triazoles as final products. Useful applications in synthesis of this uncommon hydrazinolysis can be claimed.

Gas phase behavior of radical cations of perfluoroalkyl-1,2,4-triazines: an experimental and theoretical study

Electron ionization mass spectrometry and low-energy collision-induced decomposition reactions occurring in a tridimensional ion trap, together with density functional theory (DFT) calculations on neutrals, even- and odd-electron cations, have been used to study the gas-phase ion chemistry of a series of perfluoroalkyl-1,2,4-triazines. Loss of oxygen, due to thermal degradation occurring before ionization, likely involving the hydroxylamino group, has been observed. Compounds having a carbonyl group at position 6 of the triazine ring fragment in the source by elimination of NO followed by HF or CO. The decomposition pathways occurring due to CID experiments have shown interesting features d…

Antiproliferative Activity Predictor: A New Reliable In Silico Tool for Drug Response Prediction against NCI60 Panel.

In vitro antiproliferative assays still represent one of the most important tools in the anticancer drug discovery field, especially to gain insights into the mechanisms of action of anticancer small molecules. The NCI-DTP (National Cancer Institute Developmental Therapeutics Program) undoubtedly represents the most famous project aimed at rapidly testing thousands of compounds against multiple tumor cell lines (NCI60). The large amount of biological data stored in the National Cancer Institute (NCI) database and many other databases has led researchers in the fields of computational biology and medicinal chemistry to develop tools to predict the anticancer properties of new agents in advan…

Fluorinated heterocycles from 1,2,4-oxadiazole precursors. Synthesis of 3-amino-indazoles

Photochemistry of Fluorinated Heterocyclic Compounds. An Expedient Route for the Synthesis of Fluorinated 1,3,4-Oxadiazoles and 1,2,4-Triazoles

The photochemistry of some 3-N-alkylamino-5-perfluoroalkyl-1,2,4-oxadiazoles in the presence of nitrogen nucleophiles such as ammonia and primary and secondary aliphatic amines has been investigated. The primary photolytic intermediate from the cleavage of the ring O-N bond follows two distinct and competing pathways leading to (i). 5-perfluoroalkyl-1,3,4-oxadiazoles, through the ring contraction-ring expansion photoisomerization route favored by the presence of the base or (ii). 5-perfluoroalkyl-1,2,4-triazoles, through the intervention, as an internal nucleophile, of the exocyclic N-alkylamino moiety of the oxadiazole followed by the attack of the external nitrogen nucleophile and subsequ…

Novel ANRORC rearrangements of 1,2,4-oxadiazoles

Synthesis of tetrasubstituted-4,4'-biimidazoles with perspective heavy-metal sensing ability

Concise asymmetric synthesis of Linezolid through catalyzed Henry reaction

A new asymmetric synthesis of the antibiotic Linezolid was performed through a copper-catalyzed Henry reaction as the key step. The use of camphor-derived aminopyridine ligands helped to improve the yields of the chiral precursor and to obtain Linezolid in good overall yield and enantiomeric excess.

Synthesis of platinum complexes with 2-(5-perfluoroalkyl-1,2,4-oxadiazol-3yl)-pyridine and 2-(3-perfluoroalkyl-1-methyl-1,2,4-triazole-5yl)-pyridine ligands and their in vitro antitumor activity.

Five new mononuclear Pt(II) complexes with 5-perfluoroalkyl-1,2,4-oxadiazolyl-pyridine and 3-perfluoroalkyl-1,2,4-triazolyl-pyridine ligands are reported. The ligands 2-(5-perfluoroheptyl-1,2,4-oxadiazole-3yl)-pyridine (pfhop), 2-(5-perfluoropropyl)-1,2,4-oxadiazole-3yl)-pyridine (pfpop), 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and their complexes [PtCl2(pfhop)(2)]center dot 1.5 DMSO (2a), [PtCl2(pfpop)(2)]center dot 1.5 DMSO (3a), [PtCl2(pfhtp)(2)]center dot 1.5 DMSO (4a), PtCl2(pfhtp) (4b), [PtCl2(PfPtP)(2)]center dot 1.5 DMSO (5a) have been synthesized and structurally characterized. The comple…

Chasing phthalates in tissues of marine turtles from the Mediterranean sea

Tissues from thirteen specimens of marine turtles, one Dermochelys coriacea and twelve Caretta caretta, found dead along the Sicilian coasts in 2016 were analyzed for the presence of phthalates. Four phthalates (DEP, DBP, BBP, and DEHP) were found at different significant concentrations in liver and gonads, while only DBP was found in muscle tissues and at a fourfold lower concentration than other phthalates in Dermochelys coriacea. No traces of DEP were detected in C. caretta tissues where DOTP was also revealed. The presence of phthalates in fat tissue in specimens of C. caretta showed a major prevalence of the most lipophilic phthalates DEHP and DOTP. The total concentration of all analy…

On the photoreaction of some 1,2,4-oxadiazoles in the presence of2,3-dimethyl-2-butene. Synthesis of N-imidoyl-aziridines

Fhe photochemistry of some 3,5-disubstituted 1,2,4-oxadiazoles in the presence of 2,3-dimethyl-2-butene has been investigated. The irradiation in acetonitrile yielded differently substituted N-imidoyl-aziridines through an aziridination reaction involving an acyliminonitrene intermediate. Pyrolysis of N-imidoyl-aziridines produced the corresponding N-allylamidines through a ring opening process.

Heterocyclic photorearrangements. Photochemical behaviour of some 3,5-disubstituted 1,2,4-oxadiazoles in methanol at 254 nm

Photochemical behaviour of some 3,5-disubstituted 1,2,4-oxadiazoles in methanol at 254 nm has been investigated. Ring photoisomerization to the 1,3,4-oxadiazole heterocycle or formation of open chain compounds involving the nucleophilic solvent was shown to depend on the nature and the position of the substituent. Photoinduced ring closure into the benzimidazole system, involving a 3-N-phenylamino side chain sequence and a photolytic intermediate of the oxadiazole heterocycle, is also reported.

ChemInform Abstract: Synthesis of Amino-1,2,4-triazoles by Reductive ANRORC Rearrangements of 1,2,4-Oxadiazoles.

The hydrazinolysis of the oxadiazoles under optimized conditions allows a general synthesis of functionalized aminotriazole products which are of interest due to the biological activity of the heterocyclic system.

Exploiting the CNC Side Chain in Heterocyclic Rearrangements: Synthesis of 4(5)-Acylamino-imidazoles

A new variation on the Boulton-Katritzky reaction is reported, namely, involving use of a CNC side chain. A novel Montmorillonite-K10 catalyzed nonreductive transamination of a 3-benzoyl-1,2,4-oxadiazole afforded a 3-(alpha-aminobenzyl)-1,2,4-oxadiazole, which was condensed with benzaldehydes to afford the corresponding imines. In the presence of strong base, these imines underwent Boulton-Katritzky-type rearrangement to afford novel 4(5)-acylaminoimidazoles.