Letters in Organic Chemistry - Volume 15, Issue 2, 2018

Preparation and catalytic performance of nanosized copper particles supported on expanded corn starch (ECS) was investigated. The catalyst was characterized by inductively coupled plasma optical emission spectrometry (ICP-OES), X-ray powder diffraction (XRD), N2-sorption analysis, thermogravimetric analysis (TGA), energy dispersive X-ray spectroscopy (EDS), and transmission electron microscopy (TEM). The copper nanoparticles supported on expanded corn starch (CuNPs@ECS) were found to be a very efficient and durable catalyst for the preparation of propargylamines by three component reaction of secondary amines, aldehydes and alkynes. The catalyst can be successfully recycled and reused without significant loss of efficiency in 4 reaction runs. The procedure described here offers an easy and practical method accompanied by higher yields, and environmentally benign system.

Background: HIV-1 protease is a prime target for drug therapy due to its integral role in HIV viral replication. Several protease inhibitors such as lopinavir and tipranavir were shown to possess potent inhibitory activities against the HIV virus. Due to the high mutation rate of HIV, resistance remains a major problem in the treatment of this virus and design and synthesis of new protease inhibitors is an area of continued interest in new drug discovery research. Methods: Utilizing the key fragments of structures of both peptide-based and non-peptide-based protease inhibitors lopinavir and tipranavir, we explored designing some new compounds. Results: Six new protease inhibitors were designed and synthesized based on the key structural fragments in lopinavir and tipranavir. The designed new compounds contain heterocyclic groups such as thiophene, isoxazole, and imidazole groups, and the best compound exhibited 0.6 nm of the protease inhibitory activity. Conclusion: We have prepared some novel heterocyclic sulfonamides utilizing a key fragment based approach by recombining structural fragments of the potent protease inhibitors lopinavir and tipranavir. Some of these newly designed compounds showed good to excellent HIV-1 protease inhibitory activity, which indicated that this method would be useful for the discovery of new drug lead compounds that target HIV.

Background: Triazolothiadiazoles are molecules of great synthetic and pharmacological significance. They are associated with significant antimicrobial, antifungal, antibacterial, antihelmintic and anti-inflammatory activities. Method: The condensation of 5-alkyl-4-amino-3-mercapto-4H-1,2,4-triazoles with 3-aryl-1- phenylpyrazole-4-carboxylic acids was carried out in the presence of phosphoryl chloride and the resulting products were tested in vitro for their antibacterial potential against Bacillus subtilis (gram positive), Staphylococcus aureus (gram positive), Escherichia coli (gram negative) and Pseudomonas aeruginosa (gram negative) and further antifungal properties against Candida albicans, and Saccharomyces cervisiae. Results: A new series of 3-alkyl-6-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles has been synthesized by the reaction mentioned above. One specific compound, 6-(3-(4- fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole displayed an excellent antifungal activity against Candida albicans with a MIC value of 8 μg/ml, which is actually even better than the standard drug Amphoptericin B (MIC 10 μg/ml). Conclusion: An expeditious synthesis of several new 3-alkyl-6-(3-aryl-1-phenyl-1H-pyrazol-4-yl)- [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles in 77-89 % yield could be performed from readily accessible starting materials, 5-alkyl-4-amino-3-mercapto-4H-1,2,4-triazoles and 3-aryl-1-phenylpyrazole-4- carboxylic acids. Most of the resulting compounds showed moderate to good in vitro activity against Gram-positive bacteria. The title compounds seem to be more active against fungi than bacteria.

Chalcone oximes are important molecules in organic chemistry. Extant literature contains several methods for conversion of chalcones to their oxime forms but rapid and efficient new methods need to be developed. In this study; we have investigated a new, microwave assisted synthetic method for conversion of chalcones to their oxime forms. For this purpose, a series of known chalcones were synthesized and converted to their oxime forms employing the method being examined. The results show that the proposed method is efficient, providing time and energy savings. In the second part of our study, DFT calculations with B3LYP method have been performed on the synthesized molecules and computational results have been compared with the experimentally obtained data. All DFT calculations were performed at the B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311+G(2d,p) levels of theory. NMR calculations were carried out using GIAO and CSGT methods. Additionally, MEP maps, FMOs, some global reactivity descriptors and Mulliken atomic charges for the synthesized compounds were computationally determined with the same basis sets.

Background: Sulfonamide derivatives belong to the most important structural classes of drug molecules. This functional group constitutes the largest class of antibacterial agents. Antibacterial agents with a sulfonamide structure, e.g. sulfadiazine have been therapeutically used for many decades. Approved drugs with a sulfonamide structure have found widespread utility in a number of pharmacology and medicine applications. Literature on sulfonamides highlights the employment of molecular hybridization through conjugation with other pharmacologically interesting scaffolds for the enhancement of medicinal properties. Methods: The synthesis started by the preparation of N-(4-methoxy phenyl) acetamide by the acetylation of p-anisidine with acetic anhydride under solvent-free conditions. Then the product was sulfonated with chlorosulfonic acid. The synthesized sulfonylchloride was reacted with different amines under solvent-free conditions and sulfonamide-amides (3a-j) were obtained in high yield. The products were hydrolysed to the corresponding sulfonamide-amines (4a-j) in acidic conditions. Finally, the amine group was converted to the imine group in ethanol in the presence of acetic acid. The synthesized sulfonamide-amines (4a-j) have been evaluated for their in vitro antibacterial activities against two spp. of Gram positive pathogenic bacteria and 3 spp. of Gram negative bacteria. Results: A series of novel sulfonamide-imines were synthesized starting from p-anisidine with high yields under mild conditions and were screened for in vitro antimicrobial activity against two Grampositive spp. and three Gram-negative spp. The methicillin resistant Staphylococcus aureus (MRSA) showed significant sensitivity against the compounds ((5-((2-chlorobenzylidene)amino)-2-methoxy-N- (2-methoxyphenyl)benzene sulfonamide (5b), N-(4-bromophenyl)-5-((2-chlorobenzylidene)amino)-2- methoxybenzene sulfonamide (5d), 5-((2-chlorobenzylidene)amino)-N-(2-chlorophenyl)-2-methoxybenzene sulfonamide (5g), 5-((2-chlorobenzylidene)amino)-2-methoxy-N-phenethylbenzene sulfonamide (5i) and 5-((2-chlorobenzylidene)amino)-N-cyclohexyl-2-methoxybenzene sulfonamide (5j). Conclusion: In conclusion, we have described a facile, efficient and eco-friendly approach for the preparation of several structurally varied novel sulfonamide-imines in five steps. The reactions are characterized by simple reaction procedures, ease of separation, high yields and purity. Furthermore, the antibacterial activity of the synthesized sulfonamide-imines was evaluated against some Grampositive and Gram-negative microorganism. The methicillin resistant Staphylococcus aureus (MRSA) showed significant sensitivity against some of the synthesized compounds.

Background: Functional organic dyes with donor-π-conjugation-acceptor (D-π-A) molecular structure and electron transfer in the excited state have attracted much attention because of their potential applications in optical, electronics, magnets materials, dye sensitized solar cells (DSSCs), organic light emitting diodes (OLED), sensors, solid state lasers and photovoltaic cells and thin film transistors. Methods: An efficient and convenient method for synthesis of 2,6-bis-[2-(4-dialkylaminophenyl) vinyl]- 4H-Pyran-4-one starting from reaction of 4-fluorobenzaldehyde with 2,6-dimethyl-4H-pyran-4- one in the presence of MeONa as base was described. In continuation, secondary amines were reacted with 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one and 2,6-bis-[2-(4-dialkylaminophenyl)vinyl]-4HPyran- 4-one was obtained as the final product. 1H and 13C NMR, FT-IR spectroscopy supported the predicted structure of the products. The UV-Vis absorption spectra of synthesis compound were measured in diluted dichloromethane solution. Results: Knoevenagel reaction of 4-fluorobenzaldehyde and 2,6-dimethyl-4H-pyran-4-one to afford 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one was performed in room temperature.To optimize the reaction conditions, a variety of solvents (EtOH, MeOH, t-BuOH) and bases (KOH, NaOH, EtONa, Me- ONa, t-BuONa) were tested; MeOH/MeONa system was selected as the best condition for this step. The best operative system for nucleophilic aromatic substitution of secondary amines with 2,6-bis((E)- 4-fluorostyryl)-4H-pyran-4-one was obtained when DMF was used as a solvent and K2CO3 was employed as the base and HDTMAB as ligands. In addition, malononitrile was reacted with 2,6-bis((E)-4- fluorostyryl)-4H-pyran-4-one and obtained compound was employed in SNAr reaction. The UV-Vis spectroscopy studies were carried out in diluted dichloromethane solution (50-5 M) on the synthesized bis-condensed DCM derivatives. Conclusion: In summary, this study focused on preparation of novel compounds with bis-DCM-type skeleton for application in organic light-emitting diodes, for this purpose, 2,6-bis-[2-(4-dialkylaminophenyl) vinyl]- 4H-Pyran-4-one derivatives were prepared from reaction of 4-fluorobenzaldehyde with 2,6-dimethyl- 4H-pyran-4-one in the presence of MeONa as base. In continuation, secondary amines were reacted with 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one and 2,6-bis-[2-(4-dialkylaminophenyl) vinyl]-4HPyran- 4-one was obtained as the final product. Additionally, reaction of malononitrile as an active methylene group with 2,6-bis((E)-4-fluorostyryl)-4H-pyran-4-one before N-arylation reaction resulted in 2-(2,6-bis(4-(dialkylamino)styryl)-4H-pyran-4ylidene)malononitrile derivatives.

Background: Cancer is a major health problem worldwide and the major cause of human mortality in the world. The identification of novel structures for effective treatment of cancer is still a major challenge to medicinal chemists. Over the time, important milestones have been achieved in the development of various cancer static drugs for antitumor chemotherapy. Chemotherapy is still highly inadequate, and this necessitates to find novel compounds with potent anticancer activity and minimal or no side effects. Methods: 5-Amino-3-methyisoxazole 1 was treated with different salicylaldehydes 2a-d refluxing in methanol to get the desired products 2-(3-methylisoxazol)-5-ylimino)methyl)phenols 3a-d. The reduction of these imine intermediates with NaBH4 at room temperature produced the amino phenols 4a-d, which underwent smooth ring closure in the presence of formaldehyde, to give isoxazolyl-1,3- benzoxazine derivatives 5a-d. Compound 5d under Suzuki coupling conditions with different aryl and hetero aryl boronic acids furnished the products 7a-d. Results: We synthesized the 3,4-dihydro-8-methoxy-3-(3-methylisoxazol-5-yl)-2H-benzo[e][1,3]oxazine derivatives 5a-5d and 7a-7d from readily accessible starting materials in excellent yields. The newly synthesized compounds 5a-5d and 7a-7d were evaluated for in vitro and potent compounds 5b and 7b were screened for in vivo anticancer activity. Compound 5b has shown potential anticancer activity both in vitro and in vivo. Molecular docking studies were also carried out to balance the experimental results. Conclusion: The structure of all newly synthesized compounds 3-5a-d and 7a-d was confirmed on the basis of IR, 1H NMR, 13C NMR and mass spectral data. Molecular docking studies of compounds 5b and 7b revealed their efficient binding in the hydrophobic pocket in the ATP binding site of EGFR which is consistent with the biological data. Further studies are needed to identify the specific compounds in the series and to develop them as potential anticancer agents.

The Knoevenagel reaction is one of the most useful methods for the synthesis of α,β- unsaturated nitriles. We disclose an efficient protocol for the Knoevenagel reaction of aldehydes with malononitrile catalyzed by 1-alkyl-1,2,4-triazolium salts to afford the corresponding products in excellent yields. The important feature of this reaction is the catalyst; 1-alkyl-1,2,4-triazolium salts are recycled and reused. Furthermore, the reaction conditions are environment friendly and do not produce any hazardous waste.

Background: Technical mixture of styrenated phenols including mono-, di-, and tristyrenated phenol, has been commonly applied for industrial materials such as rubber or plastic stabilizer, antioxidant, and nonionic surfactant, etc. Among these styrenated phenols, di-styrenated phenol should be most effective as rubber and plastic stabilizers. Although a number of catalysts for the synthesis of styrenated phenols have been explored, researches on the synthesis of styrenated phenol generally have been focused on selective preparation of mono-styrenated phenol MSP, rather than distyrenated phenol DSP. In this paper, we have investigated the hydroarylation reaction of styrene with phenol to find the optimal catalyst, including single catalysts and mixed catalysts, to get high selectivity to DSP under mild reaction conditions. Method: Hydroarylation reactions of styrene with phenol using various single catalysts, such as inorganic acids, organic acids, Lewis acids, and metal salt catalysts, have been conducted. To optimize the reaction conditions, hydroarylation reactions of styrene with phenol employing InCl3 catalyst were carried out with a variety of styrene amount, catalyst amount, reaction time, and reaction temperature. Halogenpromoted hydroarylation reactions of styrene with phenol were investigated in the presence of NBS or I2 as a halogen source and a variety of metal halides as a Lewis acid catalyst. Br-promoted hydroarylation reactions of styrene with phenol were accomplished using InCl3 along with NBS under a variety of NBS amount and reaction temperature. To explore the scope of Br-promoted hydroarylation, the reactions of various styrene derivatives with phenol were carried out using NBS and InCl3. Results: Hydroarylation reactions of styrene with phenol using various single catalysts, such as inorganic acids, organic acids, Lewis acids, and metal salt catalysts, have been conducted. Among 19 catalysts used, best results in both high conversion of phenol and high DSP selectivity are obtained with InCl3 catalyst. Using InCl3, total yield of styrenated phenols is 98% and product selectivity MSP/DSP/ TSP is 20/65/13. When InCl3 as an optimal catalyst was applied for the hydroarylation reactions of styrene with phenol under various reaction conditions, the optimal reaction conditions for obtaining a high yield, high DSP, and low MSP are as follows: styrene/phenol = 2 molar ratio, catalyst/phenol = 0.1 molar ratio, reaction time 6 hours, reaction temperature 120 °C. In the halogen-promoted hydroarylation reactions of styrene with phenol in the presence of NBS or I2 as a halogen source and various metal halides as a Lewis acid catalyst, best yield (99%) and DSP selectivity (MSP/DSP/ TSP=13/42/41) were obtained using NBS and InCl3. The optimal reaction condition for Br-promoted hydroarylation reaction was found to be phenol 1 eq., styrene 2 eq., InCl3 0.04 eq., NBS 1 eq., 4 hours reaction time, room temperature. For the reactions of various styrene derivatives with phenol using NBS and InCl3, the best DSP selectivity was observed for the CH3-substituted styrene derivative. Conclusion: We have developed hydroarylation reaction of styrene with phenol for obtaining a high yield and a high DSP selectivity even at room temperature. Using NBS as a Br source and InCl3 as a catalyst at room temperature, Br-promoted hydroarylation reaction of styrene with phenol yields good results with respect to both yield and DSP selectivity.

Background: Carbohydrate fatty acid esters are found in important biological molecules such as bile acid 1-O-acyl galacto and bacterial glycolipids. The synthesis of glycomimetics of those biomolecules is required to study their structure-activity relationship. Method: In this work a series of carbohydrate fatty acid esters were regioselectively prepared mainly via protection and deprotection and tin-mediated strategies of partially benzyl-protected sugars, followed by hydrogenolysis of the benzyl groups. Results: We report here the regioselective synthesis of galactose palmitoyl esters along with other fatty acyl galactose glycomimetics namely fucose and lactose fatty esters. 1-O-palmitoyl-, 1,6-di-Opalmitoyl- D-galactose and 1-O-palmitoyl-L-fucose derivatives were prepared via a low-temperature esterification of the partially benzyl-protected galactose and fucose derivatives, respectively, followed by hydrogenolysis of the benzyl groups. The regioselective synthesis of 3'-O-acyl-D-lactosides of palmitic and nitrobenzoic acids was accomplished using a dibutyltin oxide activation strategy of partially protected lactoside derivatives. Conclusion: The regioselective synthesis of galactose, fucose and lactose fatty acid esters as glycomimetics of biological molecules containing the 1-O-fatty acyl-D-galactose moiety is reported in this work.

As a part of our continuous efforts in synthesizing potent anti-cancer natural product cephalostatin 1 and its analogues using a symmetrical bits-steroidal diketone, progress in the chemoselective distinction of the two parts is reported. The first strategy involves the highly chemoselective reductive opening of the spiroketal moiety (ring-F) of nonsymmetrical diol precursor. Thus, the protected 12β,12´α-diol underwent a chemoselective ketal opening using the catechol-borane complex yielding mono-opened spiroketal product with high chemoselctivity. Additionally, 11α-methoxy diketone derivative led to the corresponding mono-opened spiroketal product when treated with 4-methylcatecholborane, a modified reducing complex. The same derivative underwent a chemo- and regioselective hydration of the D-ring double bond using diaminobenzonitrile-borane complex. These key developments pave the way to prepare cephalostatin 1 and analogues.