Letters in Organic Chemistry - Volume 14, Issue 8, 2017

Background: Ketenium ions are rarely used in chemical synthesis, despite a strong potential and their high reactivity, which can be mostly attributed to their difficult generation. There is therefore an important need for efficient methods enabling their in situ generation from stable and readily available starting materials in order to fully exploit the unique reactivity of ketenium ions. Method: We report in this manuscript a simple and efficient process for the generation of these highly reactive intermediates by simple protonation of the corresponding stable and readily available aryl ynol ethers with bistriflimide. By simply mixing these two reagents in dichloromethane at -50°C for 30 minutes, a transient ketenium ion is formed and is further, quite unexpectedly, trapped by the poorly nucleophilic bistriflimidate. Results: The scope of the reaction was delineated by using various aryl ynol ethers which were shown to be excellent precursors of ketenium ions. Their trapping with bistriflimidate further highlights the exceptional electrophilicity of these unique intermediates. Conclusion: We have demonstrated that ketenium ions can be conveniently prepared by simple protonation of the corresponding aryl ynol ethers, bench-stable and readily available starting materials. The unique electrophilicity of these cationic heterocumulenes was showcased by their trapping with poor nucleophiles such as bistriflimidate and in an intramolecular Friedel-Crafts reaction.

Background: A useful and simple strategy for the synthesis of sulfonyl-spiro-pyrimidines derivatives via a five-component reaction between sodium arylsulfinates, trichloroacetonitrile, primary amines, isatin and malononitrile in the DMF at room temperature is described in this study. Methods: Initially, we performed the five-component reaction of trichloroacetonitrile, benzylamine, sodium arylsulfinate, isatin and malononitrile as a simple model, and then we optimized the reaction conditions by changing the solvent. DMF proved to be the most optimal solvent with highest yield for this reaction compared to MeOH, EtOH, MeCN, CH2Cl2, acetone, and tetrahydrofuran (THF). Therefore, the reaction was carried out in DMF at room temperature for 7 h, by using 1 mmol of benzylamine, 1 mmol of sodium arylsulfinate, 1 mmol of trichloroacetonitrile, 1.5 mmol of isatin, and 1.5 mmol of malononitrile. Under these conditions, functionalized sulfonyl-spiro-pyrimidines was indeed obtained with 89% yield. Results: Using the optimized conditions described above, various sulfonyl-spiro-pyrimidines derivatives were synthesized from sodium arylsulfinates, malononitrile, isatin, trichloroacetonitrile, and various benzylamines with various electron-withdrawing or electron-donating substituents on the aromatic rings in DMF at room temperature. Conclusion: In summary, the one-pot tandem reaction of benzylamine, sodium arylsulfinate, trichloroacetonitrile, isatin and malononitrile in DMF at room temperature led to the formation of functionalized sulfonyl-spiro-pyrimidines in good yields. The procedure described here has the advantage that the reaction is mild and fairly general, thus providing a useful path for the synthesis of functionalized spiro systems containing various sulfonyl groups.

Background: An efficient and green synthesis of various diethyl-1,4-dihydro-2,6-dimethyl- 4-(3-aryl-1-phenyl-1H-pyrazol-4-yl)pyridine-3,5-dicarboxylate derivatives was achieved by the multicomponent condensation of 3-aryl-1-phenyl-1H-pyrazole-4-carboxaldehydes, ethyl acetoacetate, and NH4OAc in the presence of 1-methyl-2-pyrrolidonium hydrogen sulphate [HNMP][HSO4] as a catalyst in ethanol. A series of 1, 4-dihydropyridine (DHP) derivatives have been synthesized by simply stirring at room temperature in a sealed tube for suitable time. This protocol has the number of benefits including simple work-up procedure, excellent yields and environmentally benign condition. Methods: A 25 mL sealed tube was filled with a mixture of 3-aryl-1-phenyl-1H-pyrazole-4- carboxaldehydes 1 (1 mmol), ethyl acetoacetate 2 (0.130 g, 2 mmol), NH4OAc 3 (0.085 g, 1.2 mmol) and 100 mg of ionic liquid [HNMP][HSO4] in 10 mL of ethanol. Then the sealed tube was capped and the reaction mixture was stirred at room temperature using a magnetic stirrer for appropriate time. The progress of the reaction was monitored by TLC. Once the reaction was completed, the content was poured over crushed ice, and solid DHP derivative thus obtained was separated by filtration. The product was dried and in some cases, the impure product was recrystallized from DMF-H2O. Results: We synthesized diethyl 1,4-dihydro-2,6-dimethyl-4-(3-aryl-1-phenyl-1H-pyrazol-4- yl)pyridine- 3,5-dicarboxylate 4a-j by one pot multi-component reaction of 3-aryl-1-phenyl-1H- pyrazole-4- carboxaldehydes 1, ethyl acetoacetate 2, and NH4OAc 3 in the presence of 100mg of ionic liquid [HNMP][HSO4] as illustrated in Table 2. The reactions worked smoothly with different 3-aryl-1- phenyl-1H-pyrazole-4-carboxaldehydes bearing both electron releasing and withdrawing groups to give the DHPs derivatives in excellent yields. The experimental and work-up method is very straightforward, suitable, and has the capability to tolerate a diversity of other functional groups. Conclusion: In summary, we developed a new protocol for the synthesis of various diethyl 1,4- dihydro-2,6-dimethyl-4-(3-aryl-1-phenyl-1H-pyrazol-4-yl)pyridine-3,5-dicarboxylate derivatives using acidic ionic liquid [HNMP] [HSO4] as a highly efficient catalyst. The DHPs 4a-j were obtained by simply stirring at room temperature for appropriate time. A significant benefit of this protocol is lacking of formation of side product since the reaction was carried out at room temperature. Also, this fascinating protocol offers several advantages such as cleaner reaction, simple work-up procedure, and use of non-corrosive catalysts, excellent yield with eco-friendly approach and a significant contribution, moving towards green chemistry.

Background: 1,2,3-Triazoles represent an important structural motif frequently found in organic chemistry, biological science, medicinal chemistry, and material science. Thus, the synthesis of novel 1,2,3-triazoles derivatives by an efficient method has attracted considerable attention. Methods: In this paper, we developed a simple and efficient azidation system of biphenyl tosylhydrazones with sodium azide. A series of new 4-(1-azidoethyl)-1,1'-biphenyl derivatives were prepared by the metalfree reductive reaction and further reacted with aryl acetylenes to afford novel 1,4-substituted 1,2,3-triazoles by water-soluble (salicyladimine)2Cu complex catalyzed azide-alkyne cycloaddition in water. Results: The desired 1,4-substituted 1,2,3-triazoles were obtained in 27-94% yields in pure water without any organic solvent or phase transfer agents. Conclusion: The catalytic system presented here enables the use of easily accessible starting materials and good functional group tolerance.

Background: Compounds having N-heterocyclic moieties are of huge importance in the field of agrochemical, pharmaceutical, biological, fragrances, etc. Due to a lot of applications associated with pyrazine moieties, their synthesis has always been important for organic chemists. Method: Surfeit synthetic methodologies are documented in literature. Most of the methodologies used expensive solvents, harmful metal catalyst and all suffer from rigorous work-up procedures. An efficient, environmentally benign methodology, needs to be developed. We mixed ethylenediamine (2mmol) with 1,2-diketone(1mmol), later, α-hydroxy ketone and α-bromo ketone on magnetic stirrer at room temperature under neat reaction condition for 5 to 10 hrs. Results: After purification by column chromatography using silica gel(60-120 mesh) and pet-ether, ethylacetate mixture as eluent, we achieved pyrazine derivatives from moderate to high yield. Conclusion: Efficient and clean procedure for one-pot preparation of pyrazines from ethylenediamine and 1,2-diketones or with α-hydroxy ketone or with α-bromo ketone has been carried out under neat reaction condition at room temperature. Environmentally benign process furnishing moderate to excellent yields of the product and simple work-up giving pure products are special features of this reaction.

Background: Although economically very important in view of the significance of the oxidized products for the manufacture of adipic acid and caprolactam (precursors to polyamides widely used in several industries), the current cyclohexane oxidation industrial process leads to very low conversions (ca. 4%) to assure a reasonable selectivity (ca. 85%). Therefore, there is an urgent need to develop sustainable selective cyclohexane oxidation chemistry, which is the main objective of this work. Methods: The partial oxidation of cyclohexane by aqueous tert-butyl hydroperoxide (TBHP, 70% aq. sol.) in phosphonium ionic liquid medium [P6.6.6.14][DCA] and in the presence of catalytic amounts of ferrocene was investigated. The reaction proceeded during 2 h at room temperature. Results: It was found that TBHP, under the above conditions, oxidizeD cyclohexane with high selectivity (> 98%), yielding mainly cyclohexanone (up to 16%, based on the substrate) with total TOFs up to 1 x 10⁴ h^-1. Conclusion: The combination of a commercial iron-complex catalyst (ferrocene) and well-adjusted unconventional reaction conditions led to a highly selective, fast and reusable catalytic system for the mild oxidation of cyclohexane. Moreover, the found [Fe(C5H5)2]/[PP6.6.6.14][DCA] catalytic system can be of significance to produce polyamide 6.

Background: Synthesis of lipophilic mitochondria-targeted antioxidants is a topical problem of modern biochemistry. The so-called "radical sponges" effect is a very high ability of fullerene C60 and its derivatives to catch free radicals. The experiments showed that the fullerene derivatives increase resistance of animals towards oxidative stress and prevent passing of neurodegenerative processes. Objective: Synthesis of lipophilic fullerene C60 conjugates based on maleopimaric acid derived from resin.. Methods: Synthesis of new diterpene containing fullerene C60 conjugates based on the bromo- and chloromethylketones by primary functionalization of the fullerene core by the Bingel cyclopropanation reaction was shown. Bromo- and chloromethylketones were obtained from methyl maleopimarateproteinogenic amino acids condensation products by the Arndt-Eistert reaction. Results: Diazoketones and chloromethylketones were received from carboxylic acids and corresponding chlorides under Arndt-Eistert reaction conditions. Chloromethylketones formed due to a Nierenstein side reaction. The IR spectra of diazo compounds 2a-e contained a strong absorption band for the diazo group at 2103-2115 cm128;“1. The reaction of diazoketones with HBr produced bromomethylketones in excellent yield. Bromo- and chloromethylketones were reacted with fullerene C60 in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) in toluene to give diterpene containing fullerene conjugates. Fullerene conjugates formed 6% oil solutions in different sunflower oils. The structures of all compounds obtained were proved using 2D NMR HSQC, HMBC, COSY, NOESY experiments. Conclusion: Rosin-based methanofullerenes were synthesized for the first time under Bingel conditions by [2+1]-cyclopropanation of the chloro- and bromomethylketones to fullerene C60 in the presence of DBU. In our case chloromethylketones gave better yields in the Bingel reaction than bromomethylketones. The obtained diterpene containing fullerene conjugates have the ability to dissolve in sunflower oils.

Background: Aminolysis of alkynyl epoxides was accomplished with excellent regioselectivity and good yields using microwave reactor. The reactions occurred exclusively at carbon atom next to the triple bond. Interestingly, aminolysis of alkynyl epoxide containing an ester group at γ-C (to the oxirane ring) led to a mixture of products. The first step of this reaction involved the attacks of amine to oxirane ring and ester group to form a lactone and an amide epoxide, respectively. Then intramolecular and intermolecular amine attacks of the former and intramolecular aminolysis of the latter formed a mixture of four products. Method: Aminolysis of alkynyl epoxide was carried out in a microwave reactor 110°C, 200 W for 1.5 h with catalyst lithium triflate. All reactions were monitored by thin-layer chromatography (TLC) using silica gel (Merck, 60-120 mesh). Column chromatography for isolation of products was performed using Merck silica gel (40-63 μm) packed by the slurry method, under a positive pressure of air. 1H and 13C NMR spectra were recorded on a Varian Inova NMR Spectrometer (1H NMR running at 500 MHz and 13C NMR running at 125 MHz) instrument. CDCl3 was used as the NMR solvent. Low-resolution mass spectra were obtained on a Shimadu GC spectrometer (EI) or Water LCZ single quadropole (ESI). High resolution spectra were obtained on a VG Autospec mass spectrometer (EI) or Waters QTOF (ESI). Infrared spectra were obtained as neat samples on a Smart Omni-Sampler Avator ESP Nicolet-Brand. The melting points were recorded on a Gallenhamp MF-370 carpillary tube, melting point apparatus and are uncorrected. The values are expressed in degree Celcius (°C). Uncertanties in the quoted values are ±2°C. Result: Aminolysis of alkynyl epoxide 3,4 occurred exclusively at the α carbon in good yield (72-76%), while with amine 8, the reaction produced a mixture of four products. Structure of all products was elucidated using IR, NMR, low-resolution MS, high-resolution MS. Conclusion: We examined the ring opening reaction of some alkynyl epoxides by amines catalysed by lithium triflate using microwave reactor. These reactions were accomplished with excellent regioselectivity and good yields. Because of time constraint, only three alkynyl epoxides were studied. In future, more alkynyl epoxides will need to be prepared and examined for the aminolysis reaction. Other amines will be also examined for the aminolysis of alkynyl epoxides.

Background: The aim of the current research was to synthesize novel symmetrical N,N'-diacylhydrazines through oxidation of acid carbohydrazide using ethyl 2-cyano-3-methoxyacrylate or 2-(methoxymethylene)malononitrile as organo-catalyst. Also, novel 2-(1,2,3-triazol-4-yl)-1,3,4-oxadiazoles from the reaction of acid carbohydrazides with various carboxylic acids in boiling phosphoryl chloride were synthesized. Methods: Facile synthetic methods were used for the synthesis of target compounds using commercially available chemicals. Also, the structures of the products obtained were elucidated with the use of analytical and spectroscopic data along with the single x-ray crystal structures. Results: A series of novel symmetrical N, N'-diacylhydrazines, 2-(1,2,3-triazol-4-yl)-1,3,4-oxadiazoles and aldehyde N-acylhydrazones, were synthesized in good yields using convenient and simple procedures. Conclusion: New one-step synthetic procedures were introduced for the production of several symmetrical N, N'-diacylhydrazines and 2-(1,2,3-triazol-4-yl)-1,3,4-oxadiazoles in good yields from the corresponding acid hydrazides.

Background: 2-Azetidinones (β-lactams) has occupied an important role in organic chemistry and drugs. β-Lactam antibiotics are extensively applied to fight against microorganisms as antibiotic drugs. The Staudinger's ketene-imine cycloaddition is one of the most common approaches in the synthesis of 2-azetidinones. The aim of this paper to describe a methodology based on the use of 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT) for the synthesis of 2-azetidinones under mild reaction conditions at room temperature. Methods: The present methodology deals with one pot [2+2] ketene-imine cycloaddition reaction of imine and substituted ketene to synthesis of 2-azetidinones in mild condition at room temperature. In addition, detailed experimental procedures are provided. Results: A series of 2-azetidinones were synthesized in good to excellent yield via one pot [2+2] ketene-imine cycloaddition reactions. The obtained products were purified in good yield by simple crystallization. All the synthesized compounds were well characterized by spectral and physical data. Conclusion: A simple method for one-pot transformation of various carboxylic acids and imines to 2-azetidinones using 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT) has been developed. The yield of [2+2] ketene-imine cycloaddition was good to excellent, and starting materials were readily available. An aqueous work up and simple crystallisation was sufficient to obtain pure products because DEPBT produces water-soluble by-products.

Background: Direct N-alkylation of murrayafoline A (1) by epichlorohydrin, followed by the opening of 3-(1-methoxy-3-methyl-N-carbazolyl)-1,2-epoxypropane (2) with aliphatic and heterocyclic amines catalyzed by Zn(HClO4)2.6H2O in mild condition led to the formation of thirteen β-amino alcohols (6a-n) in moderate yields. In vitro anticancer activity of these β-amino alcohols (6a-n) was evaluated against four human cancer cell lines including Hep-G2, LU-1, P 338 and SW 480 in comparison with murrayafoline A. The results showed that the synthesized β-amino alcohols (6a-n) (excluding 6e, 6n.1) inhibited proliferation of cancer cell lines and compound 6c was found to have the best activity against Hep-G2 and LU-1 with IC50 values of 3.99 and 4.06 μg/mL, respectively. Methods: All chemicals and reaction solvents were purchased from Merck and Aldrich. Melting points were determined in open capillaries on a Shimazu Electrothermal IA 9200 apparatus and are uncorrected. IR spectra were recorded on a FT-IR IMPACT-410 using KBr discs. 1D- and 2D-NMR Spectra were recorded on a Brucker AVANCE 500 MHz spectrometer in CDCl3 and DMSO-d6. Chemical shifts (δ) are in ppm relative to TMS, multiplicities are shown as follows: s (singlet), d (doublet), t(triplet), m (multiplet) and coupling constants (J) are expressed in hertz (Hz). HRMS was recorded by using a FTICR MS and ESI-TOF-MS Agilent 6230 TOF-MS spectrophotometer (Varian). Progress of the reaction was monitored by thin-layer chromatography (TLC) using precoated TLC sheets with ultraviolet (UV) fluorescent silica gel (Merck 60F254) and spots were visualized by UV lamp at 254 nm. Column chromatography was carried out using silica gel (40-230 mesh). Results: β-Amino alcohols of murrayafoline A (6a-n) were synthesized in 45-67% yields as outlined in Scheme 1 and 3 starting from N-alkylation reaction of murrayafoline A (1) with epichlorohydrin, followed by the opening reaction with different amines using Zinc perchlorate as an effective catalyst. Structure of target compounds was confirmed by NMR and HRMS spectra. The in vitro cytotoxic evaluation was undertaken according to the described protocol. In the present study, murrayafoline A (1) was also evaluated for cytotoxicity against Hep-G2, LU-1, P338 and SW 480 cell lines along with β-amino alcohols (6a-n), and ellipticine was used as positive control for SAR evaluation (Table 1). Although no β-amino alcohols can be compared to the parent compound (murrayafoline A) and ellipticine in terms of IC50 values, some compounds exhibit potential cytotoxic effects against tested cancer cell lines and could be used as important scaffolds in drug development design against human cancer cell lines: Hep-G2, LU-1, P 338 and SW 480 with IC50 values ranging from 3.99-39.89 μg/mL. Conclusion: It is for the first time that thirteen novel β-amino alcohols were synthesized in a simple two-step procedure from murrayafoline A, a carbazole alkaloid isolated from glycosmis stenocarpa in Vietnam. Structures of intermediate and target compounds were elucidated by 1D-, 2D-NMR and HRMS. Evaluation of their cytotoxicity showed that most synthesized β-amino alcohols exhibited activity against four human cancer cell lines: Hep-G2, LU-1, P 338 and SW 480 with IC50 values ranging from 3.99-39.89 μg/mL.

Background: A new convenient and practical green synthetic method for nanosilica molybdic acid (nano-SMA) catalyzed chemoselective synthesis of some new 4-dihydropyrano[2,3-c]pyrazoles through a one-pot reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one, ethyl cyanoacetate and aryl aldehydes is described in this study. Results: Nanosilica molybdic acid was synthesized and then characterized by X-ray fluorescence (XRF), powdered X-ray diffraction (XRD), IR spectroscopy and transmission electron microscopy (TEM). Due to the importance of novel catalyst applications, after preparation and characterization of the catalyst, we decided to use nano-SMA for the synthesis of 4-dihydropyrano[2,3-c]pyrazoles. After optimizing conditions, we found that this reaction was performed with 1 mol% of nano-SMA in refluxing EtOH. Then, the generality of the procedure was evaluated by examining various aryl aldehydes under optimized reaction conditions. The data obtained from elemental analysis, 1H and 13C NMR spectra confirmed the proposed products. Conclusion: Overall, we reported a green protocol for the chemoselective synthesis of 4-dihydropyrano [2,3-c]pyrazole derivatives. The advantages of this method are high yield of pure products, reusability of catalyst, short reaction times and a simple workup procedure, that make it an attractive and economical method for the synthesis of these useful heterocycles.