Letters in Organic Chemistry - Volume 14, Issue 2, 2017

Background: Several GC and HPLC methods have been proposed for the separation of aldose enantiomers. Method: We developed a general HPLC method for the discrimination of (D,L)-monosaccharide components from natural products. The reaction involves the preparation of L-cysteine (3-nitrophenyl) methyl ester hydrochloride, which reacts with aldoses leading to thiazolidine derivatives. Results: Direct HPLC analysis with reversed-phase column and UV detection, discriminated enantiomeric D- and L-monosaccharides in a highly sensitive manner. Conclusion: This method was applied for the determination of the absolute configurations of monosaccharides in the natural poliumoside B, a tetraglycoside obtained from Teucrium polium.

Background: The unique physiochemical properties of nanoparticles as compared to their bulk state make them highly useful in the area of catalysis, fuel cell development, photonics, medicines, solar cell and biomedical imaging. The small size structures of nanoparticles are certainly very unstable mainly because of their high surface energies and large surface area. To produce stable nanoparticle, it is important to reduce the particle growth reaction (to avoid agglomeration). The advantage of the use of SBA-15 material as support also includes its high surface-to-volume ratio, variable framework compositions and high thermal stability. Thus SBA-15 exhibits mainly mesoporous structure and possesses a small amount of micropores. The large pore size of this mesoporous material can mitigate the diffusion barrier for the reactants and the products. In some recent technical reports, silica materials with grafted silicon hydride groups have been successfully applied for the synthesis of gold, silver and palladium nanoparticles. With respect to common normal hydrogen reduction, direct reduction of ions followed by varying concentration of metal salt and reduction time, the hydride silica surface offers the controlled shape and size selective metal nanoparticles. Methods: In the present report, we have exploited the catalytic application of mesoporous silica supported Ru metal nanoparticles for CO2 hydrogenation reaction. Silica hydride groups, possessing reducing properties, grafted to the surface of silica allowed obtaining metal nanoparticles immediately at reducer attachment position. Ru-silica (SBA-15-xRu) catalysts were characterized by different physiochemical methods and tested for CO2 hydrogenation reaction. Results: A series of SBA-15 supported Ru catalysts were prepared with 1, 2 and 3% (by weight) Ru metal loading followed by impregnation method and well-characterized by sophisticated analytical techniques. Among all the SBA-15-xRu catalysts, SBA-15-3Ru catalyst was found to be highly active for hydrogenation of CO2 to formic acid. Low catalyst loading, ligand free approach, simple reaction protocol and catalyst recycling are major merits of this proposed work. Conclusion: In summary, Ru nanoparticles synthesis on the surface of SBA-15 with different structural characteristics was studied. The SBA-15-3Ru catalyst was found to be highly efficient for hydrogenation of CO2 to formic acid. CO2 hydrogenation reaction enjoyed the catalytic system and offered the corresponding hydrogenated reaction product in good yield and selectivity. Good catalyst recycling, low catalyst loading, simple work up procedure and easy catalyst preparation step were the major outcomes of this proposed protocol.

Background: The catalytically active site of CA enzyme is Zn (II) bound hydroxide ion part which acts as a strong nucleophile (at neutral pH) on the CO2 molecule bound in a hydrophobic pocket nearby. We designed a series of thiazolidinone molecules which are able to approach the active side by way of hydrophobic part and may interact with the hydroxide and Zn (II) by ring opening of thiazolidinone. Methods: Thirteen novel aminoindane thiazolidinone derivatives, 2a-m were synthesized, characterized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and II were evaluated. hCA I and II from human erythrocytes were purified by a simple one step procedure by using Sepharose 4B-L-tyrosine-sulphanilamide affinity column. Results: In vitro results showed that all compounds were inhibited by the CA izoenzymes activity. 2d was found to be most active compound IC50=6.75 μM and 7.55 μM for hCA I and hCA II, respectively. Conclusion: New aminoindane thiazolidinone derivatives have been designed, synthesized and evaluated as Carbonic Anhydrase Inhibitors. According to the results, these compounds can be conceivable as new candidates for the treatment of the illness that CAI and CAII enzyme inhibitors are used in the treatment.

Background: Nanoparticles (NPs) for large surface area and unique physicochemical properties have a potential to perform excellent catalytic activity in comparison to bulk materials. As part of our growing program to design fundamental and potent methods for the synthesis of heterogeneous catalyst and organic compounds, We characterize preparation functionalization, and application of silica nanoparticles (silica NPs)/ nanosilica sulfuric acid (NSSA) as novel heterogeneous catalyst for one-pot combinatorial synthesis sterically congested 2-(heteroaryl)acetamide derivatives from an isocyanide, a secondary amine and heteroarylcarbaldehydes at room temperature in excellent yields under mild conditions. Methods: A general synthetic route to the synthesis of 2-(heteroaryl)acetamide derivatives has been developed using silica nanoparticles/nanosilica sulfuric acid (Silica NPs / NSSA) as a reusable catalyst under solventfree conditions. The multicomponent reactions of heteroarylcarbaldehyde, a secondary amine and isocyanide were carried out to afford some sterically congested 2-(heteroaryl)acetamide derivatives in high yields. Results: Silica nanoparticles/nano silica sulfuric acid (Silica NPs/NSSA) acts as excellent solid acid system to condensation aldehyde, amine and isocyanide in high yields. It seems that the size of silica nanoparticles enhances the catalytic activity of this solid catalyst, providing a more heterogeneous effective surface area in the reaction media. Furthermore, nano silica sulfuric acid as an H+ source, promotes the condensation step between a secondary amine and heteroarylcarbaldehydes to produce iminium ion intermediate and followed accelerated the nucleophilic addition of the alkyl isocyanide to afford products. Another advantage is that the reaction proceeds cleanly and smoothly at ambient temperature and pure product were achieved. Based on the TLC investigations, when the three-component reaction was performed in the absence of Silica NPs/NSSA, several by-products were observed. Furthermore, we investigated effect of electronic structure of aldehyde derivatives on the yield of the corresponding product. In the presence of benzaldehyde, the yield of target was very low and several by-products were achieved but when electron-poor aldehyde derivatives such as 2-pyridinecarbaldehyde, 2-thiophenecarbaldehyde and 4-pyridinecarbaldehyde were used in three-component reaction, the yield of the product was improved. Moreover, the reusability of catalyst was investigated to verify its activity in the multicomponent reaction. The silica NPs/NSSA catalyst could be easily separated from the reaction medium with centrifuge at 8000 rpm for 15 min and thoroughly washed with CH2Cl2. The activity of reused silica NPs/NSSA catalyst compared to initial activity after 5 cycles decreased gradually to about 75%. Conclusion: In conclusion, we introduce an efficient and powerful route for the one-pot synthesis of sterically congested 2-(heteroaryl)acetamide derivatives from simple and readily available alkyl isocyanides, secondary amine and heteroarylcarbaldehyde in the presence of silica nps and nssa (100/10). This procedure offers significant advantages such as ease of work-up, mild reaction conditions, high yields and cleaner reaction profiles which makes it a useful addition to modern synthetic methodologies.

Background: Isoxazole and pyrimidines are interesting heterocyclic molecules, which are present as structural motif in numerous natural products synthetic drugs. Isoxazole and thiopyrimidines exhibit antidiabetic, cytotoxic tuberculostatic, and anticonvulsant activities. Herein we report the synthesis of isoxazole and thiopyrimidine by the reaction of ring opening of 2-arylchromones with hydroxylamine hydrochloride and thiourea, using β-cyclodextrin as a reusable catalyst under supramolecular catalysis, for the first time in aqueous media Methods: The β-Cyclodextrin catalyzed synthesis of isoxazole and thiopyrimidine derivatives by the reaction of 2-arylchromones with hydroxylamine hydrochloride and thiourea respectively in ethanol-water under ultrasonication is reported. This reaction proceeded at 80oC giving good to excellent yield and the β-cyclodextrin can be recovered and reused. The newly synthesized isoxazoles and thiopyrimidines were evaluated for their antimicrobial activity. Results: In continuation of our work on β-CD and development of newer methodologies, we disclosed a newer methodology for the synthesis of, isoxazoles 2a-n and thiopyrimidines 3a-n involving reaction of 2-arylchromones with hydroxyl amine hydrochloride and thiourea in the presence of β-cyclodextrin as a recyclable catalyst in water at 80oC under ultrasonication in excellent yield. The general scheme for the synthesis of isoxazoles 2a-n and thiopyrimidines 3a-n from 2-arylchromones is depicted in Scheme 1. The structure of the products thus obtained was assigned by, 1H NMR, 13C NMR, elemental analysis and melting point data. Conclusion: In this paper, we describe β-cyclodextrin as suprlamolecular catalyst, for the synthesis of isoxazoles and thiopyrimidine derivatives. The key advantages of this method such as good to excellent yields of products, shorter reaction times; simple and clean workup of the desired product without column chromatography, easy recovery as well as reuse of the catalyst and the overall protocol is to be the approach towards green chemistry. And also the promising antibacterial and antifungal activities of some of the novel compounds have potential as novel drugs in pharmaceutical formulation.

Background: A one-pot pseudo-five-component green synthesis of new bis-Betti bases is described. The reported bis-Betti bases are obtained via the condensation of one equivalent of 2,3- dihydroxynaphthalene, two equivalents of aryl aldehydes, and two equivalents of heteroaryl amines in the presence of formic acid catalyst under solvent-free conditions. The broad substrate scope, operational simplicity, clean reaction, high yield, easy work up and shortened reaction times make this procedure a practical and environmentally friendly method for the synthesis of new bis-(1-aminomethyl-2- hydroxy)naphthalenes. Methods: As a model reaction, one equivalent of 2,3-dihydroxynaphthalene, two equivalents of benzaldehyde and two equivalents of 2-aminopyrimidine were heated at a temperature of 60-110oC in the presence of formic acid as catalyst (10% mol) without the use of solvent. We were pleased to find that the reaction proceeded smoothly and almost complete conversion of reactants was observed at 80oC to afford the corresponding product in 83% yield within 80 min. We also varied the amount of formic acid catalyst and the results revealed that 10% mol gives excellent yield of the product in a short duration. Results: After optimizing the conditions, the generality of this method was examined by the reaction of different substituted aldehydes with various heteroaryl amines and 2,3-dihydroxynaphthalene for the synthesis of new bis-Betti bases via the one-pot pseudo-five-component reaction under solvent-free conditions. It was found that various aromatic aldehydes containing electron-donating or electronwithdrawing functional groups at different positions of the benzene ring show a difference in the reaction time but the yields of products were almost the same. Identification of the structures of the products was achieved by spectral analysis. The formation of the products in the present reaction is expected to involve the initial formation of the imine intermediate from an aldehyde and amine in the presence of formic acid catalyst. Then, in the second step, two equivalents of imine reacted with one equivalent of 2,3-dihydroxynaphthalene affording the corresponding bis-(1-aminomethyl-2-hydroxy)naphthalene. Conclusion: We have demonstrated a simple and efficient method for the synthesis of new bis-Betti bases. The attractive features of this protocol are: use of inexpensive catalyst, mild and environmentally benign reaction conditions, easy isolation of the product and almost quantitative conversion into the corresponding products.

Background: A one-pot coupling reaction of aldehyde bisulfite adducts was developed for McMurry reaction using Zn-TiCl4 in 1,4-dioxane solvent medium. The treatment of sodium hydroxy( phenyl)methane sulfonate (2a) with TiCl4 in 1,4-dioxane favoured the deprotection of the bisulfite adduct 2a, and the in situ regeneration of benzaldehyde (1a) underwent reductive coupling to afford stilbene 3a in a relatively good yield, thus leading to an improved synthesis of a series of (E)-1,2- diphenylethenes 3. The present approach provides a new solution to the inherent instability of aldehydes and also provides a direct access to C-C bond formation for the synthesis of 1,2-diphenylethenes from aryl aldehyde bisulfite adducts. Methods: All reactions were performed at 70-80o and the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectrometric techniques. Results: The present approach provides a new solution to the instability of aldehydes and also provides a direct access to C-C bond formation for the synthesis of 1,2-diphenylethenes from aryl aldehyde bisulfite adducts. Conclusion: In the present work, we have reported an efficient method for the synthesis of 1,2- diphenylethene derivatives. Aldehydes are commonly used as the starting materials in the McMurry reaction, which affords the stilbene derivatives, the core skeleton of various valuable compounds. To increase the stability of the aldehydes, bisulfite adducts are usually employed, but the deprotection process causes loss of process efficiency. To address this issue, we developed a method based on the single-pot reaction of aromatic bisulfite adduct using TiCl4/Zn in 1,4-dioxane.

Background: 1,3-Aminooxygenated functional groups exhibit a variety of biological and pharmacological activities including nucleosides, antibiotics and HIV protease inhibitors. On the other hand, carbazole-containing molecules show antiviral, antimalarial and antitumor activity. However, to the best of our knowledge there are no reports available on the synthesis of amidoalkyl carbazolols. In this connection, we wish to report the synthesis of amidoalkyl carbazolol derivatives by one-pot threecomponent reaction. Methods: The synthetic one-pot three-component reaction of 4-hydroxycarbazole, different substituted aromatic aldehydes and amides was carried out under microwave-assisted heating conditions. The structures of obtained 1-amidoalkyl-2-carbazolol derivatives were confirmed by IR, NMR and mass spectra. Results: Various aromatic aldehydes such as fluoro-, nitro-, dimethoxy-, trimethoxy-derivatives reacted smoothly with 4-hydroxycarbazole and acetamide to give the corresponding amidoalkyl carbazolol derivatives in good yields (69-84%). Furthermore, the optimized reaction conditions worked well with benzamide with several benzaldehydes. Conclusion: We have developed the catalyst-free procedure for the one-pot three-component reaction of 4-hydroxycarbazole with aromatic aldehydes and acetamide/benzamide under MW conditions. Catalyst free, simple reaction conditions, good yields and environmentally benign procedure are the advantage of this protocol.

Background: Refractive index is an important optical property which can be used to identify substances such as intermediates in organic reactions. Objective: To predict this property we used molecular dynamics simulations and density functional theory. We have calculated refractive indices of intermediates in the Paal-Knorr reaction for 200nm ≤ λ ≤ 800nm. Method: The molecular dynamics simulation with the generalized Amber force field (GAFF) was used to obtain equilibrium densities of intermediates. Molecular polarizabilities were derived from quantum calculations at the B3LYP level. Results: The data obtained show that values of densities, polarizabilites and susceptibility depend on substituent groups. Also, we have found a meaningful ordering for refractive indices of studied intermediates at wavelengths of more than 400 nm. Conclusion: Our calculated refractive indices can be used for detection of intermediate molecules.

Background: A series of novel anil-like compounds was constructed via a three-component domino condensation of 2,3-dihydroxynaphthalene, triethylorthoformate and heteroaryl amines in the presence of formic acid catalyst under solvent-free conditions. Significant features of this method are: simplicity of the procedure, clean reaction, short reaction time, the ready accessibility, and cost effectiveness of the catalyst, high yields, easy work-up and purification of novel products by non-chromatographic methods. Methods: Initially, the three-component condensation reaction of 2,3-dihydroxynaphthalene, 2- aminopyrimidine, and triethylorthoformate as a model reaction was performed at a temperature of 80- 150oC in the presence of formic acid as catalyst (10 mol%) without the use of solvent. We were pleased to find that the reaction proceeded smoothly and almost complete conversion of reactants was observed at 110oC to afford the desired product in 87% yield after running the reaction for 20 min. We also varied the amount of formic acid for this condensation. To our delight, the reaction worked very well in the formic acid as catalyst (10 mol%) at 110oC under solvent-free conditions. Results: After optimizing the conditions, we turned to explore the scope of the reaction using different heteroaryl amines, 2,3-dihydroxynaphthalene and triethylorthoformate under the optimized reaction conditions for the synthesis of novel anil-like compounds. It was found that, various heteroaryl amines containing electron-donating or electron-withdrawing functional groups at different positions showed almost the same yields. It is very important to mention here that according to the 1H NMR and 13C NMR spectra, these Schiff bases favor the keto-enamine form over the enol-imine form which is also in agreement with strong intramolecular hydrogen bond (O…H-N). Conclusion: We described a convenient, efficient, and environmentally greener methodology for the synthesis of novel anile-like compounds (Schiff bases) in the presence of formic acid catalyst under solvent- free conditions. The present method has advantages, such as omitting organic solvent, simplicity, generality, cleanliness, shorter reaction time, easy work-up and purification of novel products by nonchromatographic methods.

Background: Spiro(pyrazolo[4,3-e][1,2,4]triazin-3′-yl) derivatives are key building blocks of many pharmaceuticals, agrochemicals and biologically active compounds. Fluorinated compounds have a remarkable record in medicinal chemistry and provide lead compounds for therapeutic applications, the influence of fluorination on acidity, hydrogen-bonding and lipophilicity that affect compound absorption and distribution. Methods: Novel fluorinated steroidal spiro(pyrazolo[4,3-e](1,2,4)-triazin-3′-yl) derivatives have been synthesized and evaluated as effective enzymatic agents for cellobiase activity against some fungi. The synthesis achieved by a cyclocondensation of 3-(antipyrin-4-imino)steroids with hydrazine hydrate followed by fluorinated acylation and aroylation. Results: The synthesized compounds with different fluorine substituents were obtained in moderate to good yields (56-83%). Most of the compounds (5a, 6a, 5b, 6b) were found to be more active over control and other tested compounds and have also showed significant antibacterial and antifungal activity. Conclusion: A series of novel compounds with high activity are synthesized, showed excellent enzymatic effects on the tested fungi C. Thermophilum and T. Lanuginosus due to the presence of fluorine atoms or group on the ring. The synthesized compounds bearing trifluoro acetyl substituents were more effective than their p-fluorobenzoyl substituents for the same fungi. Thus, the synthesized compounds shall prove as future enzymatic effects drugs with further research.

Background: A rapid and efficient synthesis of amides via Beckmann rearrangement of ketoximes with good to excellent yields has been carried out using Mukaiyama reagent/Et3N system. The procedure is mild and suitable for both aromatic and cycloaliphatic substrates affording the products in good to quantitative yields with short reaction times. Methods: A suspension of acetophenone oxime (0.135 g, 1 mmol), Mukaiyama reagent (0.383 g, 1.5 mmol), and Et3N (0.21 mL, 1.5 mmol) in CH3CN (3 mL) was magnetically stirred at room temperature. After completion of the reaction (monitored by TLC) and evaporation of CH3CN, aqueous HCl (5%, 10 mL) was added and the organic layer extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification of the crude product by short column chromatography on silica gel (n-hexane/EtOAc, 5/2) provided N-phenylacetamide (0.120 g, 89%) as a white solid: mp 112oC (lit. 113-115oC); 1H NMR (CDCl3, 250 MHz) 8.03 (brs, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.28 (t, J=7.8 Hz, 2H), 7.09 (t, J=7.4 Hz, 1H), 2.15 (s, 3H). Results: In a continuation of our studies on the use of the Mukaiyama reagent in organic transformations, we became interested in evaluating it as a reagent in the presence of triethylamine as a base for the conversion of ketoximes into corresponding N-substituted amides under mild conditions. To optimize the reaction conditions and find the best base and solvent using benzophenone oxime as a model substrate, a few experiments were carried out with Mukaiyama reagent and various bases and solvents at room temperature. The optimum conditions of reaction involved benzophenone oxime (1 mmol), Mukaiyama reagent (1.5 mmol), triethylamine (1.5 mmol), CH3CN (3 mL) at room temperature. Under the optimized conditions, a series of N-substituted amides were studied to establish the scope and limitations of this method. A wide range of substituted ketoximes derived from various aromatic, cycloaliphatic, and heterocyclic ketoximes gave desired products in good to excellent yields. Conclusion: We have disclosed a mild procedure for obtaining amides from the corresponding ketoximes via Beckmann rearrangement using Mukaiyama reagent. Among the attractive features of this protocol are its use of inexpensive and commercially available reagent, mild reaction conditions, simplicity, general applicability, relatively short reaction time, high yield and good selectivity.