Letters in Organic Chemistry - Volume 13, Issue 8, 2016

Background: Thiosemicarbazones containing mono- or disaccharide moieties reveal several various remarkable biological activities; therefore these compounds have been focused in organic syntheses. Sydnone ring is the potential basic pharmacodynamic nucleus, which has been reported to possess a wide variety of biological activities such as antitumor, anticancer, anti-inflammatory, antiviral, and scavenging activities. The connection of monosaccharide moiety to sydnone ring could initiate the new activities. Methods: The synthetic reaction of different substituted 3-phenyl-4-formylsydnone N-(tetra-O-acetyl-β- D-galactopyranosyl)thiosemicarbazones was carried out under microwave-assisted heating conditions. The structures of obtained thiosemicarbazones were confirmed by IR, NMR and mass spectra. All obtained thiosemicarbazones were screened for DPPH radical scavenging ability. Results: Some different substituted 3-formyl-4-phenylsydnones were prepared by Vilsmeier-Haacks formylation reaction. These substituted 4-formylsydnones were converted into corresponding thiosemicarbazones by condensation with N-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)thiosemicarbazide. Some of these thiosemicarbazones showed remarkable DPPH radical scavenging ability. Conclusion: The efficient synthesis of 3-phenyl-4-formylsydnone N-(tetra-O-acetyl-β-D-galactopyranosyl) thiosemicarbazones under microwave-assisted refluxing conditions has been reported. Reaction yields were 40-80%. Obtained results showed that the compounds 4f and 4g have high antioxidant activity.

Background: Amide functionality is an important in many areas of chemistry, including peptide, polymer, and complex molecule synthesis. Furthermore, Morita-Baylis-Hillman (MBH) reaction is well known efficient and economical carbon-carbon bond forming reaction which affords densely functionalized scaffolds. δ-Lactams are important constituents of natural products and have widespread applications from pharmaceuticals to synthetic organic chemistry. To the best of our knowledge, MBH adducts of nitro alkenes and their further oxidized products have not been utilized to construct the target molecule of present investigation. With aim to incorporate nitro group in pyridin-2-ones, we wished to prepare MBH adduct of nitroalkenes, which would be a novel scaffold that can be utilized for synthesis of diverse molecules. Methods: A flame-dried round bottom flask was charged with benzimidazolium salt, α- nitrocinnamaldehyde, phenacyl bromide, and amine in THF/ButOH under positive pressure of nitrogen followed by addition of DBU. The resulting pale yellow solution was stirred for 12-14 h at room temperature and finally after work-up we isolated the desired amide. Then, a mixture of prepared amide and molecular iodine in dichloromethane was stirred at room temperature for 4.5-6 h yields the target lactams. Results: [E]-α-Nitrocinnamaldehydes, prepared from Morita-Baylis-Hillman adduct of nitoalkenes, were converted into functionalized amides (81-95%) under the catalysis of N-heterocyclic carbenes. The reaction proceeds via d3 nucleophile of homoenolate and involves three components coupling strategy. A probe to utilized the prepared amide scaffold for construction of pyridin-2-one was also performed and the reactions gave excellent yields (82-93%) of pure products with highly diastereoselective (>92%) in favor of trans isomer. Conclusion: We have documented an original NHC-catalyzed direct synthesis of α-nitro amides with diverse functionalities, which opens up a new aspect for the utility of MBH adducts of nitroalkenes in organic synthesis. We have also disclosed a new anti-selective synthesis of 3-nitropyridin-2-ones from the prepared amide scaffold. Thus, the envisaged atom-economic strategy for the synthetically important functionalized amides and pharmaceutically important 2-pyridones would be a practical alternative to the existing procedures for their preparations.

Background: Ferulic acid salts of nicotine and cotinine chalcogen analogs (thionicotine and selenonicotine) were characterized by spectroscopic methods. Antioxidant properties of all compounds prepared were evaluated. The obtained results indicated that thionicotine salt with ferulic acid was the most efficient to prevent the induced-oxidative haemolysis. Methods: The structure of salts was determined by ESI-MS and NMR methods. The antioxidant properties of all compounds prepared were evaluated by their reducing power, free radical scavenging activity and chelating capacity. Antioxidant and protective activities of compounds tested were compared with butylated hydroxytoluene (BHT) and Trolox, as standards. The capacity of all compounds to protect in vitro human erythrocytes from oxidative damage induced by 2,2'-azobis (2-methylpropionamidine) dihydrochloride (APPH) or tert-butyl hydroperoxide (t-BuOOH) was also estimated. Results: Ferulic acid forms the 1:1 salts with thionicotine and selenonicotine while 2:1 salt is formed with nicotine. Thionicotine salt with ferulic acid was the most efficient antioxidant (61.4% DPPH scavenging activity), as effective as standard Trolox (63%), and two times more effective than BHT (32.1%) at 1 mg/mL. Neither nicotine alkaloids and ferulic acid alone nor their salts, did not induce modification in the RBC shape or in their cell membrane permeability up to the concentration 1 mg/mL after 60 min or 24 h incubation Thionicotine salt with ferulic acid was the most potent inhibitor, as effective as Trolox and about 4 times more efficient than BHT at 1 mg/mL. Conclusion: Nicotine alkaloids salts with ferulic acid characterize an antioxidative potential and protect erythrocytes against oxidative-damage, therefore, they can be take into account for the further structureactivity studies in searching for new effective antioxidants.

Background: The fungi have been a wealthy source of secondary metabolites with novel structures and diverse pharmacological activities. Aspergillus a large diversified genus, is one of the main contributors to bioactive metabolites originated from fungal source. Former phytochemical study of A. aegyptiacus isolated cotton textile resulted in the isolation and characterization of pyrrolidine alkaloids and ophiobolin sesterterpenoids. Method: The fungus was cultivated and the broth and mycelium were segregated by filtration. The concentrated EtOAc extract of the fungal broth was submitted to Sephadex LH-20, SiO2, and HPLC CC to get four compounds. UV, IR, NMR, and MS spectral analyses as well as molecular modelling were utilized for structure elucidation of these compounds. Cytotoxic activity of 1-4 was evaluated towards MCF7, A549, HeLa, HCT116, and PC12 cancer cell lines using MTT assay. Results: A new oxepane derivative namely, aegyoxepane (3), along with (22E,24R)-stigmasta-5,7,22- trien-3-β-ol (1), variculanol (2), and 1-methylimidazolidin-2-one (4) were separated from the EtOAc extract of A. aegyptiacus. Compounds 2 and 4 exhibited significant cytotoxic activities towards HeLa and HCT116 cell lines with IC50 values 3.97 and 4.51 μM and 2.89 and 2.91 μM, respectively compared to adriamycin. Conclusion: Aspergillus aegyptiacus has been proven to be a rich source of diverse classes of chemical constituents. The chromatographic treatment of the EtOAc of A. aegyptiacus produced four compounds, one of them was new (3) and other (4) was isolated for the first time from natural origin. They exhibited strong to moderate cytotoxic potential towards MCF7, HCT116, and HeLa cell lines.

Background: Azaspirocycles are important frameworks in biologically active natural products and are an emerging pharmacophore in drug design. We prepared ten novel zwitterionic azaspirocyclic hydantoins along with their ring-opened and nitro-group reduced analogues. Methods: Zwitterionic azaspirocyclic hydantoins were synthesized in high yield from 2,4- dinitrobenzoic acid and a range of carbodiimides in dichloromethane as solvent. These novel molecules were purified by reverse-phase medium pressure (flash) chromatography and fully characterized. Some molecules were evaluated in the NIH NCI-60 anti-cancer screen. Results: Intense red zwitterionic azaspirocyclic hydantoins were fashioned from an electron-deficient benzoic acid, 2,4-dinitrobenzoic acid, in a dearomatizing intramolecular ipso-spiroannulation using 1,3- disubstituted carbodiimides. Our proposed reaction mechanism invokes a rearrangement to an N-acylurea intermediate that spontaneously ipso-spirocyclizes under our reaction conditions in a 100% atom efficient manner. A broad survey of available carbodiimides revealed that only molecules with sterically undemanding N-alkyl groups on this N-acylurea precursor were able to form the most stable products. A diagnostic analytical pattern was observed in tandem MS in ESI- mode that revealed an unusual degradation by way of R-NCO neutral fragment loss. Catalytic hydrogenation gave quantitative conversion to the ring-opened 2,4-diaminoaromatic N-acylurea. Stable structures were tested for anticancer activity, yet without success. Conclusion: We have presented an efficient and atom-economical synthetic approach to zwitterionic azaspirocyclic hydantoins using the in situ intramolecular dearomatization of electrophilic N-acylureas.

Background: There are numerious work on thiacrown ethers that are utilized for binding metal ions. Usually, relative binding ratios have been reported for few selected cations in these works. This study aims to develop a new method to explain cation binding properties by using the hardness parameters for ligands and metal ions, heteroatom rate (S/O) for ligands and extraction percentages. Methods: In this work, complexation constants and selectivity factors of a previously synthesized mixed donor soft bases of thia-oxacrown ethers with metal salts hard Lewis acids (Mg2+, Ca2+, Cr3+), intermediate Lewis acids (Zn2+, Pb2+, Fe3+, Co2+), and soft Lewis acid (Ag+) were determined in a chloroformdichloromethane by using a liquid-liquid ion pairs metal extraction method. Results: The synthesized compounds were 1,10-dithia-18-crown-6 (B1), 1,7-dithia-15-crown-5 (B2), 1,7-dithia-12-crown-4 (B3), 1,7-dithia-18-crown-6 (B4), 1,10-dithia-21-crown-7 (B5) and 1,4-dithia-12- crown-4 (B6). Based on various experiments using the aforementioned extraction method, following results have been observed: first, calcium ion has been the most extractable ion for all ligands in chloroform. At the same time, the most selective ligands for Zn+2, Mg2+, Ca2+, Fe3+, Cr3+, Co2+ and Pb2+in dichloromethane are B1, B1, B1, B1, B5, B5, B4-B5, respectively. Besides these results, in competitive liquid-liquid ion pairs metal extraction studies, all of the ligands have exhibited a large selectivity for iron and zinc ions. Conclusion: In the light of results, one can conclude that the increase in the heteroatom rate in thiacrown ethers softens the ligands; therefore, the ligands complex with soft metals selectively.

Coumarin constitutes one of the major classes of naturally occurring compounds. In the well-known family of coumarin derivatives, dimeric coumarins (also called biscoumarins) occupy an interesting position. Although some types of these compounds could be isolated from plants and interest in its chemistry because of its usefulness as biologically active agents. It also represents the core structure of several molecules of pharmaceutical importance. Coumarin has been reported to serve as anti-cancer, anti-microbial, anti-inflammatory, anticoagulant agents. These pharmacological properties of coumarin arised our interest in synthesizing some coumarin derivatives. Methods: Aldehydes, 4-hydroxycoumarin, H2O and Fe3O4@SiO2@KIT-6 were stirred at room temperature. After completion the reaction, we extracted the product with CHCl3/H2O. After completion of the reaction, the Fe3O4@SiO2@KIT-6 magnetic nanoparticles were easily separated from the reaction medium by a magnet (1.4 T), and the reaction mixture filtered off. Then, 5 mL distilled water was added into the beaker and the obtained precipitate was filtered off. Finally, the crude products were recrystallized by ethanol to give pure products. The identity and purity of the products were confirmed by IR, 1H NMR, 13C NMR and elemental analysis. Results: As part of our going interest for the development of efficient and environmentally friendly procedures for the synthesis of heterocyclic and pharmaceutical compounds, an efficient, facile and solvent free procedure was introduced for the synthesis of bis coumarinylmethane by the reaction of one equivalent of synthesized aldehyde and two equivalent of 4-hydroxycoumarin using Fe3O4@SiO2@KIT-6. Although, synthesis of bis coumarins using ionic liquids was reported, However, most of these reported methods suffer from environmental pollution, expensive reagents or catalysts, long reaction time, severe conditions, unsatisfactory yields and complicated operations. In order to make this reaction simple and green, herein, we used Fe3O4@SiO2@KIT-6 to synthesis of bis coumarinylmethanes by the one-pot reaction of 4-hydroxycoumarin and various benzaldehydes at room temperature. Conclusion: In conclusion, we have investigated the Fe3O4@SiO2@KIT-6 as a mild and efficient catalyst for the synthesis of substituted bis coumarin compounds. The remarkable advantages offered by this method are: catalyst is inexpensive, non-toxic, easy handling and reusable, simple work-up procedure, short reaction time, high yields of product with better purity and green aspect by avoiding toxic catalyst and hazardous solvent. To the best of our knowledge this is the first report on synthesis of bis coumarin compounds using Fe3O4@SiO2@KIT-6.

Background: The isoniazid has been a key compound in first-line tuberculosis (TB) treatment, usually in combination with other drugs. Following on from the use of isoniazid itself, various derivatives of isoniazid have also been investigated as anti-TB agents and other diseases. This work aims to synthesize, multigram scale, salicylaldehyde isonicotinoyl hydrazone from isoniazid and salicylaldehyde, using ultrasound. Additionally, we have been interested in establishing a general, smaller-scale, ultrasonic driven synthesis of arylaldehyde isoniazid N-acylhydrazones, particularly for use in our biological studies. Methods: A Multiwave Eco-Sonics QR750 ultrasonic generator (20 KHz, 750 W) equipped with a converter/ transducer, and titanium oscillator (horn, diameter = 4 mm) was used for the ultrasonic irradiantion. Compounds were characterized by melting points, infrared spectra, mass spectra (CG/MS), electron microscopy, X-ray powder diffraction, solid-state 13C and solution NMR spectra. Results: This work describes a green chemistry protocol, multigram scale (ca 4 mole) and highly efficient synthesis utilizing ultrasonic irradiation of salicylaldehyde isonicotinoyl hydrazone, a widely used compound in biological studies. With a short reaction time of 30 min, and a facile work up, involving washing with water, the important bioactive product was obtained in a high yield, 98.7%, and in a high purity 99.43%. Also prepared using ultrasonic irradiation with short reaction times, in high yields and high purities, but on smaller scales, were a series arylaldehyde isoniazid N-acylhydrazones, all of which exhibit promising activity against cancer and tuberculosis. Comparisons with the classical procedures indicate advantages in the ultrasonic irradiated methodology. Conclusion: We report the high yielding ultrasonic synthesis of pure salicylaldehyde isonicotinoyl hydrazone on a 4 mole scale. In addition, a series of ten isoniazid N-acylhydrazone derivatives has been obtained using ultrasonic irradiation. The ultrasonic procedures are simple, safe, with short reaction times, and produce high yields.

Background: Several steroid derivatives have been prepared using different protocols; however some require special reagents and conditions. The aim of the study involved the synthesis of three steroid-tetraone derivatives using testosterone as building block. Methods: Steroid-tetraone derivatives were prepared by a series of reactions that involve; 1) synthesis of testosterone derivatives (steroid-carbazol or phenylhydrazono-androstanol or steroid-diazepinol) via different conditions; 2) reaction of testosterone derivatives with 3,5-dinitrobenzoic acid in basic medium to form three steroid-ether-nitrobenzoic acid derivatives; 3) synthesis of some steroid-esternitrobenzoic acid derivatives analogs by the reaction of steroidether-nitrobenzoic acid derivatives with 4-hydroxybenzoic acid in presence of DCC; 4) reduction of nitro group with sodium borohydride to form three amino-steroid derivatives; 5) preparation of carboxypropamido-steroid analogs by the reaction of amino-steroid with succinic acid using boric acid as catalyst; and 6) synthesis of steroid-tetraone derivatives by reaction of carboxypropamido-steroid with ethylenediamine in presence of boric acid. The chemical structure of compounds was determined by spectroscopic and spectrometric methods. Results: The 1H NMR spectrum showed signals at 5.50 (CH2-NHCO), 5.68 (Ph-NHCO) and 8.50 ppm (Ph-CONH) for the steroid-tetraone derivatives. Conclusions: In this study were prepared three steroid-tetraone derivatives using several chemical techniques, that they are simple and easy procedures of handling.

Background: 1,2,4-triazole and its derivatives are known to have various biological activities such as antifungal, antiviral, antidepressant, antitumor, anti-inflammatory, antitubercular, antimigrain and anti-cancer. Computational chemistry plays an important role in determining structural and chemical properties of chemical compounds. There are many studies on computational studies of triazole derivatives. The aim of this study is to prepare new triazole derivative having potent of bio-active material and to investigate the computational properties. Methods: The molecular geometry of compound 2 was optimized by using X-ray structural parameters at the DFT calculations with a hybrid functional B3LYP (Becke’s three parameter hybrid functional using the LYP correlation functional) with the 6-31G (d,p), were performed with the Gaussian 03W software package. Results: In this work, title compound was synthesized and characterized by IR and NMR techniques. The compound was crystallized in ethanol and single crystal which suitable for X-ray analysis was obtained. The geometric optimization was studied and obtained through computational data compared with crystallographic data. Vibrational data, 1H-NMR and 13CNMR chemical shifts were calculated and compared with experimental ones. Spectral results are in agreement with each other. TD-DFT was computed and important transitions were assigned. Conclusion: Spectral results are in agreement with each other. TD-DFT was computed and important transitions were assigned. In addition, electrostatic potential map were obtained computationally. While triazole nitrogens have electrophilic character, amine groups have nucleophilic character. Moreover, natural bond orbital analysis were calculated computationally. The interactions of LP(N1) Ц#159;* (C2-N2), LP(N3) σ* (C1-O2), LP(O2) σ* (C1-N1), LP(N6) Ц#159;*(C12-N5), LP(O1) Ц#159;* (C15-C16), LP(N9) Ц#159;* (C21-N8) provide the extra stabilization energy to the molecule. The most important σ σ* interaction was obtained as σ (C3-H) σ* (C2-N1), σ (N2-N3) σ* (C2-C3), σ (N6-H) σ* (C12- S1), σ (C19-H) σ* (C20-S2), σ (N9-H) σ* (C21-S2).