Letters in Organic Chemistry - Volume 13, Issue 2, 2016

Background: The pyrano[2,3-c]pyrazoles have various biological properties such as antiinflammatory, anti-cancer, antifongical, analgesics and have a potential inhibitor for human ChK1 kinase. For these reasons several synthetic methods are reported. For our part we want to propose a method which respects the environment. Method: To achieve our study we used as a model the condensation reaction of hydrazine hydrate, ethyl acetoacetate, benzaldehyde and malononitrile in the respective proportions of 1/1/1/1 and in the presence of Triphenylphosphine in various concentrations and different solvents. Results: We found that the optimal conditions for this reaction are 10 mol% of catalyst in refluxed H2O. Given these results and to show the generality of the procedure, we applied the optimized reaction conditions for the synthesis of various dihydropyrano[2,3-c]pyrazoles from a range of substituted aromatic and heteroaromatic aldehydes. We have also applied these conditions by changing hydrazine by phenylhydrazine. The desired products are obtained in good to excellent yields. Conclusion: We describe a simple, efficient and benign method for the dihydropyrano[2,3-c]pyrazoles synthesis by a four-component condensation between hydrazine (or phenylhydrazine), ethyl acetoacetate, malononitrile and a variety of aromatic and heteroaromatic aldehydes, catalyzed by Triphenylphosphine.

Background: Thiosemicarbazone derivatives containing mono- or disaccharide moieties have remarkable anti-microorganism and antioxidant activities both in vivo and in vitro, therefore thiosemicarbazone derivatives containing simultaneously monosaccharide or disaccharide moieties have been synthesized. The conventional catalysts used in reactions of aldehydes or ketones with amines in general involve only several typically organic and mineral acids, such acetic acid or hydrochloric acid. The use of strong acidic catalysts in carbohydrate chemistry often have some disadvantages associated with prolonged reaction times, harsh and harmful reaction conditions, and sometimes, the difficulty in product separations. This problem needs to be resolved in synthesis of carbohydrate derivatives because of their susceptibility towards the strong acids. Therefore, we are especially interested in developing the use of inexpensive, simple and efficient catalysts in the synthesis of thiosemicarbazones having peracetylated mono- and disaccharide moieties. Methods: The synthesis of some substituted benzaldehyde N-(hepta-O-acetyl-β-D-lactosyl)thiosemicarbazones using different acidic and basic catalysts. The synthetic reaction was carried out under conventional and microwave-assisted heating conditions. The antibacterial activity of these thiosemicarbazones against some typical bacteria screened by using the MIC evaluation method. Results: Reaction conditions, including catalysts (piperidine, hydrochloric and acetic acids) and heating methods (such as conventional and microwave-assisted ones), have been investigated for the synthesis of benzaldehyde N-(hepta-O-acetyl- β-D-lactosyl)thiosemicarbazones. Based on optimal conditions found in the synthesis of benzaldehyde N-(hepta-O-acetyl- β-D-lactosyl)thiosemicarbazone, the other substituted thiosemicarbazones were synthesized by condensation reactions of N-(hepta-O-acetyl-β-D-lactosyl)thiosemicarbazide with corresponding different substituted benzaldehydes. Almost all obtained thiosemicarbazones exhibited remarkable antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Enterobacter and Escherichia coli. Conclusion: The optimal conditions were found for synthesis of thiosemicarbazones having β-lactose moiety under conventional and microwave-assisted heating conditions. Almost all quantitative yields, simple isolation and purification procedures of these products made it to become a useful procedure for the synthesis of these compounds. Almost all synthesized thiosemicarbazones exhibited the remarkable antibacterial activity.

Background: A depsipeptide is a molecule that has both peptide and ester linkages in proximity in the same amino acid-containing small molecule or chain. Many depsipeptides show very promising biological activities, including anticancer, antibacterial, anticancer, antiviral, antifungal, anti-inflammatory, and anti-clotting or anti-antherogenic properties. The aim of this paper is to apply ionic liquid as a green media for the synthesis of new α-thiazolodepsipeptide derivatives via a four-component reaction. Methods: Thiazole-containing depsipeptides were produced easily in one step by a four-component Condensation/ Passerini tandem reaction of thiourea carboxylic acid derivatives, phenacyl bromides, ketones and isocyanides in 1-methyl-3- pentylimidazolium bromide as new solvent. Results: As shown in Scheme 1, the reaction of thiourea carboxylic acid 1, phenacyl bromide or its derivatives 2, alkyl isocyanides 3 and ketones 4 in an ionic liquid at 50°C produce depsipeptide derivatives 5 in good yield. The products were characterized by 1H NMR, 13C NMR, Mass ,and IR spectroscopy. This reaction carried out based on combination of cyclization and passerini reactions. Conclusion: In summary the reaction of thiourea carboxylic acid, phenacyl bromide or its derivatives, alkyl isocyanides and ketones in ionic liquid at 50°C produce depsipeptide derivatives in good yields. The advantage of the present procedure is that all four substrates were mixed in ionic liquid as a one-pot reaction without any catalyst and without the need for separation of intermediates.

Bakcground: The antioxidant activity of quercetin has been linked to many factors including its chemical structure. Studies about the process of quercetin oxidation have related the formation of dimers through a dioxane linkage, which could result from Diels-Alder cycloaddition. To evaluate the impact of microwave irradiation on the quercetin dimers formation, Diels-Alder reactions of quercetin with 3,5-di-tert-butyl-o-quinone were investigated, and heterodimer isolation and structural determination was performed. Methods: Reactions of quercetin with 3,5-di-tert-butyl-o-benzoquinone were completed under conventional heating conditions as well as microwave irradiation. 1D/2D NMR experiments allowed the identification and quantification of the major isomer, and the energy of the most stable conformer was obtained by DFT calculations at M06-2X/6-31G(d,p) level of theory. Results: Under conventional thermal conditions a reaction time of 10 h allows to obtain a product mixture of isomers in approximately in 2:1 ratio (1H NMR). Although the proportion of product mixture remains similar under microwave irradiation, the complete conversion took 30 min. In addition, a 1:5 molar ratio of quercetin to benzoquinone was found to increase to 75% the formation of the thermodynamic product (DFT) 8,10-di-tert-butyl-5a-(3,4-dihydroxyphenyl)-1,3,11atrihydroxy- 5aH-benzo[5,6][1,4]dioxino[2,3-b]chromen-12(11aH)-one whose identity was established by spectroscopic analyses in conjunction with molecular modeling studies. Conclusion: A quercetin heterodimer was synthesized by Diels-Alder reaction under classical heating and microwave irradiation conditions. The use of microwave flash heating promotes shorter reaction times and a slight improvement in stereochemistry. This synthetic methodology suggest that microwave irradiation approach has a positive impact on the mechanism of cycloaddition.

Background: Tetrazoles are imperative nitrogen rich heterocyclic compounds with a wide range of applications in the field of organic synthesis, coordination chemistry, material sciences, and medicinal chemistry. A most common approach for the synthesis of 5-substituted-1H-tetrazoles is achieved by [3+2] cycloaddition reaction of azides to nitriles. In this paper a new acidic ionic liquid is introduced as a catalyst to promote the mentioned reaction. Methods: Piperazinium dihydrogen sulfate:as a new acidic ionic compound was obtained by treatment of piperazine with sulfuric acid, which is further was applied as a catalyst for the [3+2] cycloaddition reaction of azides to organic nitriles. Results: The [3+2] cycloaddition reaction of sodium azide with structurally different organic nitriles using only 1.5 mol% of the piperazinium dihydrogen sulfate proceeded well at 100°C and 5-substituted-1H-tetrazoles were prepared in good to excellent yields. Herein, piperazinium dihydrogen sulfate has a dual role of catalyst and reaction medium, which circumvents the use of any organic solvent. The catalyst is also recyclable. This method is particularly suitable for benzonitriles carrying deactivating groups which furnished the corresponding products in excellent yields. By this method, mono [3+2] cycloaddition product of dicyanides was obtained. Conclusion: In conclusion, piperazinium dihydrogen sulfate as a new acidic ionic compound was applied to promote synthesis of 5-substituted-1H-tetrazoles through [3+2] cycloaddition reaction of organic nitriles with sodium azide. This new ionic compound can be easily separated from the reaction mixture which resulted to a simple work-up of the products.

Background: Oriented research towards discovery of new antimicrobial agents continues as several microbes develop resistance to currently approved drugs. A selected set of N1-(1-ethyl-4-oxoquinolin- 6-yl)amidrazone-3-carboxylates incorporating N-piperazines or related congeners have been synthesized via interaction of the particular hydrazonoyl chloride, derived from 6-amino-1-ethyl-4-oxoqinoline-3-carboxylate, with the appropriate sec-cyclic amine. Methods: The in vitro antibacterial activity screening of the synthetic compounds was performed against Gram negative Escherichia coli and Gram positive Staphylococcus aureus species. The screening test was performed using Müller Hinton Agar and Müller Hinton Broth medium. The bacterial inoculum turbidity was determined using a 0.5 McFarland standard tube to get 105 cells/ml of bacterial concentration. Bacterial cultures were grown overnight using blood agar medium prior to incubation with the synthetic compounds. 10 mg of each compound was dissolved in 1 ml of dimethyl sulfoxide (DMSO). Results: Compounds having a morpholine appendage, N-ethyl-, N-formyl-, and N-(4-methoxyphenyl)-piperazine residues showed moderate in vitro antibacterial activity against S. aureus (MIC = 10 μg/mL). Higher activity against E. coli was displayed by the morpholino, N-formyl-, and N-(4-methoxyphenyl)piperazine derivatives (MIC = 1 μg/mL), whilst the compound incorporating N-(4-fluorophenyl)piperazin-1-yl grouping exhibited the highest activity with MIC = 0.1 μg/mL. Conclusion: A selected set of quinolone-amidrazone hybrid derivatives were synthesized and tested against Gram negative E. coli and Gram positive S. aureus species. Those hybrids incorporating morpholine, N-(formyl)piperazinyl, N-(4- methoxyphenyl)piperazinyl and N-(4-fluoropheny)piperazinyl moieties exhibited the highest activity (MIC = 1-0.1 μg/mL).

Bacground: Among the class of oxygen heterocycles, the benzoannulated lactone (3H -isobenzofuran- 1-one or phthalide) moiety is found in many natural products. Phthalides possess a wide range of biological activity e.g. (-)-Hidrastine is active at the human opioid receptor known as CCR5, while fuscinarin interferes with HIV entry into cells. Phthalides also represent an important structural subunit in numerous natural products that exhibit a wide range of biological activities, such as antispasmodic, antifungal, vasodilators, and coronary artery dilators. Except their biological activities, phthalides are also versatile starting material for the synthesis of various important organic compounds, including the key intermediates in the synthesis of functionalized naphthalenes and anthracenes, which in turn are used as synthons for tricyclic and tetra cyclic aromatic natural products. The present communication describes a simple but efficient and expedient one pot strategy for the synthesis of phthalides. Methods: Diethyl phthalate was considered initially for the cyclization strategy using different metal hydrides at variable temperatures. The reaction was carried out at -30°C with 2.5 equivalent of DIBAL-H, the phthalide was obtained in ~68% yield along with minor amount of alcohol (~10%) and the unreacted starting material (~12%). In the reaction protocol, other solvents such as tetrahydrofuran, diethyl ether, and chlorobenzene were found to be effective in cyclization at -30°C. But yield of the phthalide was observed to be less compare to CH2Cl2. Further decrease of the reaction temperature up to - 78°C showed no effect on the yield of cyclized product. Use of 3 equivalent of DIBAL-H dramatically decreases the yield of the cyclized product (30%) and increased the amount of reduced product (60%). Results: The promising outcome of the above observations encouraged us to study the general scope and limitations of this protocol for the reduction of different substituted phthalides. It was found that diethyl esters of nitro-, bromo-, 4'- methyl-biphenyl-, 3'-methyl-biphenyl-, 2'-methyl-biphenyl-, biphenyl-, 4-pyrazin-2-yl-, and 4-(4-methyl-thiazol-5-yl)- substituted phthalic acids readily underwent reduction with DIBAL-H to afford the corresponding phthalides in moderate to good yields. Conclusion: We developed a simple, convenient, one step protocol for the synthesis of isobenzofuran-1(3H)-ones (phthalides) from phthalate esters in moderate to good yields. We have also demonstrated a short and effective route to prepare two bioactive butyrolactones, viz., maculalactone A & B. In our opinion, the present approach is general in nature and could be useful to design diverse butyrolactone skeletons.

Background: Xanthenes are an important class of organic compounds and have also received significant attention due to their wide range of pharmacological activities such as antibacterial, antiviral, antiinflammatory activities, antagonists for the paralyzing action of zoxazolamine and efficiency in photodynamic therapy, a well-known method for controlling the localized tumors. Natural sources are also rich of xanthene compounds. Popularly known pigments, santalin have been isolated from plant species. Furthermore, these compounds can be emerged as pH-sensitive fluorescent materials for visualization of biomolecules, in laser technologies and as dyes. There are several reports in the literature for the synthesis of xanthenes such as alkylations of heteroatoms, cyclodehydrations, cyclocondensations between 2-hydroxyaromatic aldehydes and 2- tetralone, trapping of benzynes by phenols and intramolecular phenyl-carbonyl coupling reactions of benzaldehydes and acetophenones bearing tethered carbonyl chains in the presence of hexamethylphosphoramide and SmI2. Other methods for the synthesis of xanthenes include the reaction of formamide with β-naphthol, carbon monoxide, and 1- hydroxymethyl-naphthalen-2-ol. Methods: procedure a: A mixture of substituted benzaldehyde, 2-naphtol and Fe+3-montmorillonite K10 was mixed. After completion of the reaction, the product was solved in CHCl3 (3x10 mL) and insoluble catalyst was removed by filtration. The organic phase including the product and chloroform was evaporated under vacuum. The resulting crude material was purified by recrystallization from EtOH to afford pure products. procedure b: A mixture of substituted benzaldehyde, phenylhydrazine and Fe+3-montmorillonite K10 were added to a mortar and the mixture was pulverized with a pestle. After completion of the reaction, 2-naphtol was added to the consulting mixture and pulverized with a pestle. The organic phase including the product and chloroform was evaporated under vacuum. The resulting crude material was purified by recrystallization from EtOH to afford pure products. Results: As part of our going interest for the development of efficient and environmentally friendly procedures for the synthesis of heterocyclic and pharmaceutical compounds, we wish to report the first grind mediated synthesis of some derivatives of xanthenes using catalytic amount of Fe+3-montmotillonite. Conclusion: In conclusion, we have investigated the Fe+3-montmorillonite K10 under grinding as a mild and efficient catalyst for the synthesis of substituted 14-aryl-14H-dibenzo [a,j]xanthenes. The remarkable advantages offered by this method are: catalyst is inexpensive, non-toxic, easy handling and reusability, simple work-up procedure, short reaction time, high yields of product with better purity and green aspect by avoiding toxic catalyst and hazardous solvent.

Background: Mannich reaction is one of the most important carbon-carbon bond formation reactions in organic synthesis. Traditional methods require a large amount of ungreen catalysts or much longer reaction time, which limits the scope of their application. So, a recyclable catalyst with high activity and selectivity is highly appreciated, and the highly shortened reaction time is also very appealing. Methods: An efficient and facile process to prepare a series of β-amino carbonyl compounds was found via Mannich reactions catalyzed by caprolactam-based Brønsted acidic ionic liquids under ultrasonic irradiation. Results: [Capl][BF4] was the most effective catalyst in the Mannich reaction, and good yields was gained within 2-6 h. The activity and stability of the catalyst was maintained very well even after five times, and ultrasound can effectively shorten the reaction time and enhance the yield at ambient condition. Conclusion: A convenient procedure for Mannich reaction using acidic ILs catalyst under ultrasonic irradiation has been designed with many superiorities, such as simple manipulation, less reaction time and high yields. The Mannich reaction takes place in no presence of organic solvents such as toluene or ethanol, etc. The new synthetic method reported in this paper would make appreciable contribution to the subject of environmental friendly chemistry and it is available for industrial applications.

Background: Thiazolidinone and pyrazoles are promising heterocyclic systems enormously contributing to medicinal chemistry and when pyrazole nucleus was incorporated in other biodynamic heterocycles, the resulting molecules have displayed an increased spectrum of biological activities. There are several synthetic routes for the synthesis of thiazolidinone molecules but are having certain lacunas like, need of catalysts and desiccants, higher reaction temperature, longer reaction time, organic solvents and tedious work up procedure. Methods: Here an ultrasound promoted one pot multicomponent protocol is developed for 2-[(1-phenyl-3-(substituted phenyl) -pyrazol-4-yl)] methylene hydrazolyl-4-thiazolidinones (6a-g). Here freshly prepared substrates, 3-(4-substituted phenyl)-1-phenyl-1H-pyrazole-4-carbaldehydes (5a-g), have been condensed with thiosemicarbazide (2) and ethylbromo acetate (3) in aqueous emulsion of surfactant, CTAB under ultrasonication. Results: In our study the titled compounds 2-[(1-phenyl-3-(substituted phenyl) -pyrazol-4-yl)] methylene hydrazolyl-4- thiazolidinones obtained with good to excellent yields using 20 mol% aqueous emulsion of CTAB under ultrasound irradiation at 60°C. Conclusion: First time we have provided an environmentally friendly ultrasound promoted synthetic route to 2- hydrazolyl-4-thiazolidinones (4a-g) and biologically significant 2-[(1-phenyl-3-(substituted phenyl) -pyrazol-4-yl)] methylene hydrazolyl-4-thiazolidinones (6a-g) using aqueous emulsion of CTAB as reaction medium. The method offered several advantages such as operational simplicity, easy work-up procedure, shorter reaction times and high yields. The protocol is safe, economic and convenient for obtaining library of 2-hydrazolyl/imino-4-thiazolidinones rapidly.

Background: This paper investigates the thermal behavior of some synthesized bentshaped compounds with liquid crystalline properties. The newly synthesized resorcinol-based compounds contain five benzene-rings connected by azo bond type and ester linkage. Methods: The thermal stability studies were performed under dynamic conditions of temperature, by applying thermogravimetry, derivative thermogravimetry and differential thermal analysis, the same operational parameters being used in order to obtain comparable results. Results: Compounds with shorter chain length presented liquid crystalline properties, as they were evidenced by polarizing optical microscopy (POM) and differential scanning calorimetry (DSC). Conclusion: The length of terminal flexible chains was related to various temperatures of thermal degradation and was shown to influence favorably the thermal stability of bent core resorcinol derivatives.