Letters in Organic Chemistry - Volume 14, Issue 1, 2017

Background: The reaction of 7-diethylamino 3-formyl coumarin with active methylene group afforded in good yields the corresponding new 3-(substituted ethenyl)coumarins. The structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR spectral data, IR and elemental analysis. Optical properties were studied in dimethyl sulfoxide by UV/Vis absorption and fluorescence spectroscopy. Methods: In a 250 mL, three-necked flask equipped with a condenser a mixture of 3-formyl-7- diethylaminocoumarin 1 (0.02 mol, 4.902 g), IRA 900 resin (0.02 mol, 2 g), and toluene (25mL) were introduced under a nitrogen atmosphere at 85°C and stirred for 3 h. 4-nitrobenzylcyanid a (0.02 mol, 3.243 g) was added then the mixture was refluxed for 27 h. Finally, the organic phase was separated from the solid catalyst and concentrated under reduced pressure. The solid obtained was recrystallised in ethanol. Results: In this work we describe the synthesis of 3-(substituted ethenyl) coumarins via Knovenagel condensation of 3-formyl-7-diethylaminocoumarin with active methylene compounds. 3-formyl-7- diethylaminocoumarin was utilized as key starting material in the synthesis of 3-(substituted ethenyl) coumarins. 3-formyl-7-diethylaminocoumarin was reacted with various active methylene compounds in the presence of an equimolar amount of homogeneous basic catalysis (piperidine) or under heterogeneous conditions (Amberlite IRA 900) to give the corresponding 3-(substituted ethenyl) coumarins in moderate to good yields. Piperidine or Amberlite IRA 900 is highly selective, yielding products of inversion with nearly 100% selectivity. FTIR, 1H NMR, 13C NMR and Elemental analysis assigned their structures. The experimental UV/visible spectra of the 3-(substituted ethenyl) coumarins 1a-1b and 1e in DMSO were obtained and. The absorption spectra, for all compounds, showed only one intense band above 400 nm, without any fine vibronic structure. The absorption maxima of all the dyes were observed at 504 to 512 nm (coumarin 1 at 450 nm). This behaviour is associated with increasing conjugation length of the chromophoric system due to overlapping of π-orbitals of ethenyl group with π- orbitals of coumarin moiety. The fluorescence spectra 1a-1b and 1e with excitation at absorption wavelength of the conjugated backbone (504-512 nm) showed observable single bands at 646, 588 and 564 nm, respectively as show in Table 2. The Stokes' shift of the obtained compounds is larger than that of the precusseur coumarin 1 (Fig. 1). Fluorescence quantum yields () of the compounds dyes in DMSO were estimated at ambient temperature (25 ± 1C) using a comparative method (Table 2). We were a little disappointed that the quantum yield of the compounds obtained was less than that of the starting coumarin. Conclusion: We have presented the synthesis and the characterization of new heterocyclic compounds containing coumarin nuclei. In this investigation the process developed is particularly interesting for its simplicity and for the advantage of providing this family of coumarin compounds in good yield and high selectivity. The optical properties of two new coumarins dyes, differing by the substitution in the 3 position, were investigated in DMSO by UV/vis absorption and fluorescence spectroscopy.

Background: Aminoisoquinolines are an important class of heterocyclic compounds. These compounds present a wide range of pharmacological properties including antimalaric, anticonvulsant and anti-inflammatory. Although several preparation routes may be found in the literature for the preparation of these compounds, many of these methods present difficulties, including laborious isolation methods, drastic conditions and extended reaction times. Methods: The synthesis of N-substituted 1-alkyl and 1-aryl- 3-aminoisoquinolines is developed through the reaction of 2-acylphenylacetonitriles with amines under microwave irradiation conditions. The reactions were performed in ethanol as a solvent without the use of catalyst. In parallel, these reactions were performed under identical conditions of temperature using P2O5/SiO2 as a catalyst in different amounts. Results: A series of N-substituted 1-alkyl and 1-aryl- 3-aminoisoquinolines were synthesized using microwave irradiation with as high selectivity, short reaction times and without the use of catalyst. The use of P2O5/SiO2 as catalyst under microwave irradiation conditions was not effective for these reactions. Conclusion: The results show an efficient method for the synthesis of N-substituted 1-alkyl and 1-aryl- 3-aminoisoquinolines by the reaction of 2-acylphenylacetonitriles with amines using microwave irradiation. Some important advantages for this method include a strong decrease in reaction time, a good selectivity, and the absence of catalyst, with simplicity in operation and a benefit to the environment.

Background: Panax notoginseng, a traditional Chinese materia medica, is widely used in Chinese medicine to arrest internal and external hemorrhages, eliminate blood stasis, improve blood circulation, disperse bruises, and reduce swelling and pain. However, root rot hampers the sustainable development of planting for P. notoginseng. Root rot always occurs in the presence of pathogenic microbes. Endophytic microorganisms, residing in the living tissues of the host plant and forming complex relationships with the host, are found in every plant on the earth. The chemical investigation focused on Aspergillus has led to the diverse classes of active compounds. This research was a part of our ongoing search for naturally occurring anti-phytopathogen products from endophytic fungi associated with P. notoginseng. Methods: The fermentation broth and mycelia were extracted with EtOAc and MeOH to give crude residues. The extracts were subjected to column chromatography over macroporous resin, silica gel, and Sephadex LH-20 to produce 7 compounds. The structures were determined based on a combination of 1 D and 2 D NMR and mass spectral data. Results: Three acyclic isoprenoids (1-3) together with other compounds were isolated from Aspergillus sp., and their structures were determined as (R)-4,8-dimethylnon-3E-en-1,7,8-triol (1), (R)-10,11- dihydroxyfarnesol (2), canangalias A (3), ergosterol peroxide (4), microperfuranone (5), veratic acid (6), and sterigmatocystin (7). The acyclic isoprenoid was rarely found in the metabolites of Aspergillus. Compound 1 was a new compound, 2 was isolated from the natural source for the first time. Antiphytopathogenic activities of these compounds were also evaluated. Conclusion: One new isoprenoid, a first isolate, and five known constituents were found in this fungus. Some compounds showed anti-phytopathogenic activities.

Background: 1,3,5-Hexahydrotriazine derivatives show broad spectrum of biological activities such as anticancer, antitumor. Some of their derivatives are used as carcenolytics, herbicides and show antidote and growth stimulating activities. Very few methodologies are reported for the synthesis of symtriazines. Synthesis of trimer of hexahydrotriazines is pH sensitive reaction and instead of using any acidic and basic conditions, we tried to synthesize this trimer under neutral conditions. Methods: Synthesis of 1,3,5-hexahydro symtriazine derivatives has been achieved by treating parasubstituted aniline with solution of paraformaldehyde using PEG-400 as neutral medium using grindstone method. Results: Symtriazine derivatives were synthesized in good to excellent yields (95-70%) within a short time of 5-7 minutes by grindstone technique using PEG-400 as neutral solvent medium. All the synthesized compounds were characterized by 1HNMR, 13CNMR, Mass and Melting point. Conclusion: This is the first report for the synthesis of 1,3,5-hexahydro-sym-triazine trimer starting from aniline/substituted aniline and paraformaldehyde in the presence of reusable and environmental friendly solvent media PEG-400 by grindstone technique.

Background: Many synthetic and natural uracil derivatives have biological activity. Furthermore, many of these derivatives have pro- and antioxidant properties, but the mechanism of these processes is far from being understood. Methods: Oxygen-uptake kinetics and computational methods (CBS-QB3, M062X/MG3S and SMDM05/ MG3S) were combined to study the reaction of peroxyl radicals with five organic-soluble derivatives: 5-amino- and 5-hydroxy-1,3-dimethyluracil, 5-amino- and 5-hydroxy-1,3,6-trimethyluracil, and 5-hydroxy-1,3-dimethyl-6-phenyluracil in chlorobenzene. Results: The studied uracil derivatives should be classified as inhibitors of medium reactivity kin = (1-10) x 10-4 M-1 s-1. The methyl group in the 6-position of the pyrimidine ring increases the rate constant of the reaction with peroxyl radicals by 3-4 times and the stoichiometric coefficient of inhibition. The calculation of the reaction barrier heights at the SMD-M05/MG3S level of theory for the hydrogen abstraction is in good agreement with experimental data. Conclusion: 1,3-Dimethyl-5-aminouracil is transformed by the addition of a methyl group at the 6-position into a favic-like pyrimidine, while the 5-hydroxy derivative becomes a more effective antioxidant. The bound dissociation energy (O-H or N-H) and the IP for the reactivity forecasting of uracil derivatives were used, but it was found that this methodology did not lead to good correlation between experimental and theoretical results. The SMD-M05/MG3S method provided the most accurate calculations of the reaction barrier heights for hydrogen abstraction from uracil derivatives by peroxyl radical.

Background: The benzimidazole core structure is an interesting platform for drug discovery since it possess a wide spectrum of pharmacological activities such as antiviral, anti-inflammatory and anticancer. Previously the antiproliferative effect of novel substituted benzimidazole derivative was demonstrated based on the ethyl 1-(2-hydroxyethyl)-2-phenyl-1H-benzo[d]imidazole-5-carboxylate scaffold through the inhibition of sirtuin activity. This work aimed to further explore the previous work for identifying novel fluorescent benzimidazoles which possess anti proliferative activities based on the reported scaffold. Methods: Compounds were synthesized based on a multistep but facile protocol. Structure of the compounds was elucidated using NMR, FT-IR, LC-MS, elemental analysis and unambiguously confirmed through crystal X-ray diffraction. Molar extinction coefficient of the autofluorescence compounds were determined using UV spectroscopy while cancer cell growth inhibitory activity was carried out using MTS assay. Results: Four novel benzimidazole derivatives were successfully synthesized in this study. All four compounds were found to emit blue fluorescence when light-irradiated with molar extinction coefficient ranging from 21000 to 29000 (mol L-1)-1cm-1. Two of the synthesized compounds showed good anti proliferative activity against four cancer cell lines tested in this study. Conclusion: Four novel benzimidazole derivatives presented in this study were synthesized using multistep protocol starting from 4-fluoro-3-nitrobenzoic acid. Their structures have been elucidated using multiple techniques such as NMR, FT-IR, LC-MS, elemental analysis and X-ray crystallography where possible. They were found to have high autofluorescence and two of them were able to inhibit the growth of cancer cells tested in this study.

Background: Based on the previous studies, used protoapigenone as a model, we adopted chemical synthesis methods to develop the new compounds. It was specifically named as 2-(1-hydroxy- 4-oxo-2, 5-cyclohexadien-1-yl)-4H-Pyran-4-one, including a core group: 1-hydroxycyclohexa-2, 5- dien-4-one. Through our research it significantly inhibited human gynecological tumor, prostate tumor, digestive system tumors and hematological tumors, but without affecting the normal hematopoietic system and immune system. Additionally, this compound can effectively inhibit tumor growth in H22 mice with tumor, while had no effect to peripheral blood leukocytes, ratio of peripheral blood granulocyte cell and lymphocyte, thymus index and spleen index. But the synthetic methods of the compound has been plaguing us and now we invent a new synthetic process of it. The present invention in this article provides the method capable of industrially producing the target product. Methods: In this article we report on a new route to the synthesis of 2- (1-hydroxy-4-oxo-cyclohexa-2, 5-dienyl)-pyran-4-one (1). Compound 1 was prepared from 4-Methoxyacetophenone by the trimethylsilylation, trimethylsilyl enol ethers intermediate 3 was generated. Using the intermediate 3 with Oxalyl chloride, β-diketone 4 have been prepared. Under a thermal condition, Compound 4 reacted with ethyl vinyl ether to give pyran-4-ones 5. Demethylation of Compound 4 by BBr3, then through oxidization to give the target compound. Results: The target compound can be efficiently prepared by the method reported in this article. And the overall yield rises to about 25.1% much higher than the existing methods. All of the intermediates were structurally characterized, physico-chemical properties of the synthetic compounds are as follows: 1H NMR (400 MHz, DMSO) δ 8.08 (d, J = 5.8 Hz, 1H, CH), 7.07 (s, 1H, CH), 6.93 (d, J = 10.0 Hz, 2H, ArH), 6.52 (d, J = 2.5 Hz, 1H, CH), 6.32 - 6.23 (m, 3H, ArH, OH); 13C NMR (100 MHz, DMSO) δ 185.3, 178.3, 167.1, 156.9, 148.4, 129.1, 116.9, 113.5, 69.0; HRMS: calcd for C11H8O4 [M-H]- 203.0344, found 203.0347. Conclusion: The synthesis can be performed in “one pot”, and the target product is yielded. Therefore, the product can be readily separated and purified, whereby the process can be carried out in simple manner at high efficiency. And the overall yield much higher than the existing methods. Thus, the production process of the present invention can reduce production cost, and also, shorten production time.

Background: Spiro compounds are one of the most important organic molecules. Spiro rings such as spiroketals are present in numerous natural products; simple spiroketals are known insect pheromones. A small number of spiro containing drugs has been investigated during the last several decades. New attempts resulted in the incorporation of new synthetic building blocks for Spiro scaffold to facilitate more active drug molecules. Thus, we have redesigned the chemical process for the synthesis of active pharmacological Spiro derivatives in avoiding harmful organic solvent and toxic catalyst under ambient reaction conditions. Methods: Spiro[furan-2,11'-indeno[1,2-b]quinoxaline]s were prepared through domino one-pot and multicomponent condensation reactions of 2,2-dihydroxy-1,3-indanedione, 1,2-diaminobenzenes, dialkyl acetylenedicarboxylates and alkyl isocyanides in the presence of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim] BF4) at ambient temperature. The whole of the products constructions were detected by elemental analyses and IR, 1H NMR, 13C NMR, mass spectra. Results: A range of spiro[furan-2,11'-indeno[1,2-b]quinoxaline] derivatives were synthesized from a variety of substrates under the optimized reaction condition. Different types of dialkyl acetylenedicarboxylate and isocyanide derivatives were examined. All of them gave excellent yields of the desired products under the optimized reaction conditions. Also, we planned to perform the model reaction in the presence of neutral ionic liquids as reusable reaction medium. These results indicated that, in comparison with catalyst free conditions, ionic liquids resulted in a faster reaction with a higher yield. Also, hydrophilic [bmim] BF4 showed better results than hydrophobic [bmim] PF6. Conclusion: It is noteworthy to mention that a very quick, efficient and eco-compatible process for the synthesis of Spiro[furan-2,11'-indeno[1,2-b]quinoxaline]s is explained. These compounds were prepared through domino one-pot and multicomponent condensation reactions of 2,2-dihydroxy-1,3-indanedione, 1,2-diaminobenzene, dialkyl acetylenedicarboxylates and alkyl isocyanides in the presence of 1-butyl-3- methylimidazolium tetrafluoroborate ([bmim] BF4) at ambient temperature. Among the most important advantages of this method is simple work up procedure, excellent yields and high purity with short reaction times using ILs as green recoverable solvents.

Background: Although the exploitation of facile and efficient preparation for S-aryl phosphorothioates has gained considerable interest, there is still great demand for the development of a direct, convenient and especially environmentally benign protocol to access various phosphorothioates under relatively mild conditions. The paper attempts to investigate the application of molecular iodine, an environmentally friendly reagent in the construction of S-P bond between phosphonates and diaryl disulfides under metal, base and solvent-free conditions. Methods: Diaryl disulfide (0.5 mmol), H-phosphonate (2.5 mmol), I2 (0.1 mmol) and 30% H2O2 (0.5 mmol) were taken in a 25 mL two-neck flask under air. The reaction mixture was stirred at 80oC for 12 h. Water (20 mL) was added and then the mixture was extracted with EtOAc (4x10 mL). The extracts were combined and washed by brine (3x10 mL), dried over MgSO4, filtered, and evaporated, and purified by chromatography on silica gel to obtain the desired products with ethyl acetate/hexane (v/v=1:3~1:10). The products were characterized by their spectral and analytical data and compared with those of the known compounds. Results: The optimal reaction conditions were screened as follows: 1 equiv of diphenyl disulfide, 5 equiv of H-phosphonate, 10mol% of I2 and 30mol% of H2O2 in air at 80oC. Various H-phosphonates were employed for coupling with diphenyl disulfide, affording to the corresponding products in 60- 78%. On the other hand, either an electron-donating or an electron-withdrawing group such as methyl, i-propyl, methoxy, nitro or halogen substituents including fluoro, chloro and bromo was introduced into the S-aryl phosphorothioates without any problem by employing diaryl disulfides bearing such a group on the phenyl ring at para or meta position, and the corresponding products were between 48-80%. Conclusion: A molecular iodine-catalyzed cross-coupling reaction between phosphonates and diaryl disulfides with H2O2 as oxidant was successful. A series of S-aryl phosphorothioates were afforded under metal, base and solvent-free conditions.

Background: Linezolid (I) [(S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide] is a synthetic antibiotic used for the treatment of serious infections caused by grampositive bacteria that are resistant to other antibiotics. Linezolid empirical formula is C16H20FN3O4 and its molecular weight is 337.35. It is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia, although it may be used for a variety of other infections. Linezolid was discovered in the 1990s by a team at Pharmacia and Upjohn Company and first approved for use in 2000. Lohray et al., in 1999, have reported a synthetic method for Linezolid starting from D-mannitol, the chemical synthesis of Linezolid by alternate route has attracted several research groups in the past 15years. Methods: An improved and economically viable process is described to prepare Linezolid wherein methyl 3- fluoro-4- morphinolino phenyl carbamate (V) is reacted with R-epichlorohydrin in the presence of n-butyllithium in hexane to obtain (R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin- 2-one (IV) which reacts with potassium phthalimide in presence of polar solvent to give (S)-2- [3-(3-3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidine-5-yl methyl]-isoindole-1,3-dione (III), which is subsequently converted to Linezolid. Results: Linezolid was obtained via only four steps with yield 90% and high purity. This process avoids formation and use of sensitive intermediates. It is an improved process for the preparation of an intermediate (R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (formula IV). Conclusion: Linezolid was successfully synthesized from (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic ester via R-epichlorohydrin and potassium phthalimide and developed new intermediate (5R)-5-chloromethyl -3-(3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one (IV). The present method relates to a novel, cost effective and industrially viable process. Thus, the process described is less cumbersome by way of reduced reaction stages, high purity and quantity of the yield. In comparison with previously reported synthetic strategies, this novel approach is believed to be the shortest and the most efficient synthetic route to date.

Background: Over a decade, a number of papers have been published on the usage of ionic liquids (ILs) and Microwave-Assisted Organic Synthesis (MAOS), which displayed their benefits with respect to the conventional synthetic procedures, for current generation of fast, efficient and environmental friendly synthetic methodologies. The aim of the present study is the synthesis of linear and angular spirochromanone derivatives using microwave irradiation with the IL. As the microwave assisted organic synthesis (MAOS) with IL as a solvent is environmental friendly and non-volatile, therefore it allows simple separation and catalyst recycling. Methods: Though various methods for the synthesis of linear and angular spirochromone derivatives have been developed, one of the widely used methods is the Kabbe condensation synthesis. In this paper, we report an efficient synthesis of spirochromone conjugates by substituted 1-(6-hydroxy-3- methylbenzofuran-5-yl) ethan-1-one (1a) linear isomer or 1-(4-hydroxy-3-methylbenzofuran-5- yl)ethan-1-one (1b) angular isomer with various cycloalkanones catalyzed by pyrrolidine in ionic liquid [bmim]Cl.AlCl3 under microwave irradiation. Results: The comparative results of 3a-g (linear isomers) and 4a-g (angular isomers) are summarized in Table 1. A series of new spirochromone conjugates synthesized were purified by column chromatography and obtained with good yields. All new compounds were synthesized and characterized by 1H NMR, 13C NMR, IR and LCMS. Conclusion: A new series of linear/angular spirochromanone derivatives (3a-g/4a-g) have been successfully synthesized under conventional and microwave irradiation methods using ionic liquid as solvent. The microwave irradiation with the ionic liquid mediated method has proven to be highly yielding with a higher rate of acceleration and being eco-friendly.