Letters in Organic Chemistry - Volume 13, Issue 3, 2016

Background: In this research, pyridinium hydrogen sulfate ionic liquid (PHSIL) was employed as a green, efficient and reusable catalyst for the synthesis of 1,8-dioxo-decahydroacridines. Different primary amines and aromatic aldehydes were subjected to the reaction with 5,5-dimethyl- 1,3-cyclohexanedione (dimedone) in the presence of this catalyst and the corresponding products were achieved in excellent yields and short reaction times. Two important advantages of the study were easily separation of ionic liquid from the reaction mixture by water extraction and a high recycling capability of up to six times. Methods: Different primary amines and aromatic aldehydes were subjected to the reaction with 5,5-dimethyl-1,3- cyclohexanedione (dimedone) in the presence of, pyridinium hydrogen sulfate ionic liquid (PHSIL) catalyst and the corresponding 1,8-dioxo-decahydroacridines derivatives were achieved in excellent yields and short reaction times. Results: Having established optimum conditions as follows: aldehyde (1 mmol), amine (1 mmol), PHSIL (0.65 mmol), CH3CN (3 mL) at 80°C, a series of 1,8-dioxo-decahydroacridines were synthesized via the one-pot three component reaction between various aromatic aldehydes and amines with dimedone. The aromatic aldehydes containing electrondonating and electron-withdrawing groups afforded 1,8-dioxo-9-aryl-10-aryl-decahydroacridines with high yields within short reaction times in comparison with other conventional procedures. The presence of substituent on the amine has the same effect. All compounds were identified by melting point (in some cases), IR spectra, 1H- and 13C-NMR and elemental analysis. Conclusion: In summary, pyridinium hydrogen sulfate ionic liquid was used as a green catalyst for the synthesize of 1,8- dioxo-decahydroacridines. Various derivatives of acridinediones were synthesized in high yield. Short-time reaction, high yield, stability, reusability up to six times, relatively non-toxicity of the catalyst, economically viable and one-pot synthesis of acridinedione derivatives are the important advantages of the reported method.

Background: In our previous publications we have described the synthesis of aminosubstituded diaryl adamantanes and their pharmacological evaluation in vitro and in vivo against many cancer cell lines. More recently, we have reported the synthesis of mono C2-aryl substituted aminoadamantane derivatives that have moderate antiproliferative activity at low micromolar IC50 against a panel of four tumor cell lines. Methods: The synthesis and the pharmacological evaluation of 4-(1-adamantyl) phenylalkylamines 1-4 is described in this work. The new derivatives present an aryl substitution at C-1 adamantane position and diverge from the methylene spacer between the phenyl ring and the amine heterocycle moiety. Results: Piperazines 1a (R:N-H) and 1b (R:N-Me) are more active than piperidine 1c. This difference indicates the importance of the presence of this nitrogen atom in 1a and 1b, which is at a distance of 3 atoms (two carbons and the piperazine nitrogen included) from the benzene ring. Adducts 2a,b are less active than the rest of the products, because neither the R:N-H nitrogen atom (compound 2a) nor the R:N-Me nitrogen (compound 2b) are in an optimum distance from the benzene ring. Derivatives 3a-c are almost as potent as the piperazines 1a and 1b, which means that also in this case, the distance of 2 atoms (PhβCH2αCH2N) is sufficient for antiproliferative activity. Products 4a-c have also significant activity, possibly due to the fact that the benzene moiety is attached to the nitrogen atom via a three methylene linker. Piperidine 4c is the most potent compound, showing that the nitrogen atom of these cyclic amines, which is near to benzene ring, is important for the pharmacological action. Conclusion: The comparison of the pharmacological results of the present work in relation to our previous publication shows that C-1 substitution in adamantane skeleton with aminoaryl or aminoalkyl groups enhances the antiproliferative activity towards to C-2 substitution. Our approach shows that the optimization of the antiproliferative activity is the incorporation of the p-aminoalkylphenyl side chain at C-1 adamantane position.

Background: A new method for the removal of Cbz protective group was established. It is accomplished by using methanol, ethanol or t-butanol as a deprotective reagent, and the scope and limitations of this method were also preliminarily investigated. These results broaden utility of N-Cbz protective group in synthetic chemistry, especially in synthesis or use of imidazole, benzimidazole, pyrazole or their derivatives. Methods: Using N-Cbz-imidazole as a model compound, the feasibility of the deprotection method was investigated. We studied various reaction conditions including solvent, reaction temperature and catalyst on the influence of the deprotection reaction. Typical experimental procedure, N-Cbz-imidazole (0.40 g, 2.0 mmol) was added to a solution of methanol (30 mL), and the reaction mixture was stirred at room temperature. Hourly tracking and detection by HPLC analysis. Results: These results indicate that the deprotection method effectiveness is closely related with the substrate structure. In the explored scope, it is valid for some heterocyclic compounds, such as N-Cbz-protected imidazole, pyrazole compound, benzimidazole and benzimidazole derivatives, but possibly not for other amino chemicals. Further application of the method to other types of heterocyclic amine compounds is in progress in our labs. The novel deprotection approach can widen use of N-Cbz protective group in synthetic chemistry. There currently are many active pharmaceutical ingredients containing azole structures, for example: omeprazole, esomeprazole, lansoprazole, dexlansoprazole and pantoprazole etc. It has potential to be utilized in pharmaceutical industries and fine chemicals. Conclusion: In summary, this new method of removal of Cbz protective group using low-carbon alcohols of methanol, ethanol or tert-butanol as deprotective reagents is feasible and effective in the kind of heterocyclic amino compounds of imidazoles, pyrazoles and their derivatives. This new approach is simple and mild. Furthermore, removal of Cbz protective group does not affect other functional groups on the molecule, i.e., the structure remains unchanged.

In this study, a series of substituted secondary amide compounds were synthesized starting from 2,3-dimethoxybenzoic acid and aniline derivatives. The structures of these synthesized compounds were determined using IR, 1H NMR and 13C NMR spectroscopy, X-ray diffraction and elemental analysis techniques. Background: Amides are important groups in organic compounds. Amides moieties are found in many natural products. We now report a complementary study of the amide derivatives and the structures of these synthesized compounds were determined using IR, 1H NMR and 13C NMR spectroscopy, X-ray diffraction and elemental analysis techniques. Methods: Substituted secondary amides were prepared from the corresponding 2,3-dimethoxybenzoic acid. This involved reaction of 2,3-dimethoxybenzoyl chloride with the appropriate aniline derivatives in the presence of THF to give substituted secondary amides. Results: A summary of crystallographic data, experimental details, and refinement results for compounds are given. Conclusion: In this study a simple, yet effective method was used for the synthesis of some benzamides from acyl chlorides with aniline and its derivatives in the presence of triethylamine. All the products were obtained with moderate-good yields.

Background: The ionic liquid triethylammonium acetate (TEAA) was found to be an efficient solvent in the acetylation of alcohols, amines, oximes and thiols to their corresponding acetyl compounds using only a 10% excess of acetic anhydride under mild conditions. Moreover TEAA is not only an inexpensive and recyclable solvent but also an anomeric selective catalyst in the per-Oacetylation of sugar moieties. Methods: Simple and effective organic synthesis protocols were provided for the selective acetylation of several substrates. The products were fully characterized by 1H and 13C NMR spectroscopy and the anomeric ratios were obtained from the 1H spectra. Results: Structurally diverse alcohols, phenols, thiols, amines, carbohydrates and oximes underwent acylation under mild conditions by this procedure to provide the corresponding acetates in excellent yields. TEAA ionic liquid is unique in its capability to act as both, solvent and high selective catalyst. As expected, the reaction proceeds with high b anomeric selectivity for sugars derivatives. Moreover, the ionic liquid was regenerated, recycled and reused for three times without apparent loss of reactivity and selectivity in all cases. Conclusions: The present procedure provides a powerful and versatile acylation method for alcohols, phenols, thiols, amines, oximes and carbohydrates. This protocol is endowed with several unique merits: selectivity, cost-efficiency, atom-economy and mild reaction conditions tolerable to acid sensitive functionalities. With these features, this method may be considered as a better alternative for the acetylation of a wide range of substrates.

Background: Sulfoxides are useful intermediates in organic synthesis. Furthermore, many biologically active compounds and drugs have sulfoxide moieties in their structures. The most popular approach for the preparation of sulfoxides involve selective oxidation of the corresponding sulfides. Although a wide variety of reagent systems have been traditionally used to accomplish this transform. However, many of these procedures utilize environmentally unfavorable reagents, solvents, and catalysts that highlight the matter of eco-efficiency in our environmentally conscious times. The use of ‘green oxidants’ such as molecular oxygen and hydrogen peroxide is attractive, since they are readily available, inexpensive, and environmentally benign, with formation of water as the only by-product. CaF2 is commercially available, environmentally compatible, cheap, easy to handle, and stable. It was recently shown to be a good substitute for conventional acidic catalytic materials. Methods: The sulfides (1 mmol) were oxidized to the corresponding sulfoxides using 30% H2O2 (3.6 mequiv.) in the presence of catalytic amount of CaF2 (0.25 mmol) under solvent-free conditions at room temperature. The purification was performed using short column chromatography with EtOAc/n-hexane (1/10). All the products are known and were characterized by IR and 1H-NMR and by melting point comparison with those of authentic samples. Results: The structurally diverse sulfides (including aryl, benzylic, heterocyclic, allylic and linear) were subjected to oxidation. The reactions proceeded well to produce the corresponding sulfoxides in good to high yields ranging from 80 to 97 % in short times. thiantrene and diphenyl sulfide, which are relatively unreactive substrates, were also converted to the corresponding sulfoxides to high yields, oxidation of them require higher temperature. Interestingly, the sulfur atom was chemoselectively oxidized in the sulfides compounds that containing oxidation-prone and acid-sensitive functional groups. Conclusion: This procedure offers several major advantages: (1) the use of a commercially available, cheap, and chemically stabile catalyst and oxidant; (2) highly efficient for the selective oxidation of structurally diverse sulfides in good to high yields; (3) excellent chemoselectivity; and (4) the method conforms to several of the guiding principles of green chemistry. We believe the present method to be an improvement with respect to other procedures.

Background: Multicomponent Reactions are being widely used in the synthesis of heterocyclic compounds. Spiroheterocyclic compounds also have various physiological activities such as anti-tumor and antifungal, and they are important in drug discovery. In order to find novel spiroheterocyclic compounds having potential antifungal activity, we found a fast and efficient approach to the synthesis of novel 4'-phenyldispiro[indoline-3,2'-pyrrolidine-3',3''-thiochromane]-2,4''-dione, and the antifungal activity of the novel spiroheterocyclic compounds were tested. Methods: A variety of different substituents of 3-arylidene-thiochroman-4-one (1mmol) with isatin (1mmol) and different substituted amino acids (sarcosine, proline, leucine, glycine, phenylglycine, alanine, phenylalanine, glutamic acid or arginine, 1mmol) were mixed in [Bmim]Cl (2mL) and then gave microwave irradiation. After the reaction have finished, the reaction system was added in 10mL water, and a lot of white precipitation was obtained and filtrated. The pure objects were recrystallization by mixture of ethanol and water. The antifungal activity was determined by consecutive double dilution method. Results: Microwave irradiation dramatically decreases reaction time from hours to minutes for this multicomponent reaction, and the yields were also slightly increased. Neutral and acidic amino acids can successfully occur 1, 3-dipolar cycloaddition reactions but basic amino acids such as arginine can not. The solvent—[Bmim]Cl can be recycled to reuse after treatment. Compounds 6c and 6d have good inhibition than fluconazole for the two invasive fungi (C.n. and M.r.) and some compounds show moderate inhibition activities for tested fungi. Conclusion: A microwave-enhanced, fast, and efficient three-component reaction in [Bmim]Cl for generation of series novel 4'-phenyldispiro[indoline-3,2'-pyrrolidine-3',3''-thiochromane]-2,4''-dione compounds has been developed. Among these compounds, several show better anti-invasive fungal activity than fluconazole and some show moderate inhibiton activity.

Background: The cyclopropanation reaction was inspected by addition of carbene generated from ethyl diazoacetate in the presence of a greener Cu-exchanged bentonite catalyst to olefin under solvent free condition. The cyclopropanes were obtained with good yields. Our own contribution in this area was to introduce a modified Algerian bentonite as a catalyst and microwave activation as a mode of heating. Methods: A catalytic material developed from natural type montmorillonite clays, from deposits of Maghnia (Western Algeria), by cation exchange (Cu2+) was characterized by different spectral methods. The catalytic properties of the new material were explored in cyclopropanation reaction of olefins under microwave irradiation. A comparative study with Cu-exchanged bentonite as catalyst between microwave activation and classical heating was conducted. Results: Cu2+ exchanged clay is an efficient catalyst in the generation of carbenes from diazocompounds, under microwave irradiation. The formation of carboxylate cyclopropane was performed in solvent free condition with moderate diastereoselectivity. The yields were good, and the catalyst can be reused at least three times without noticeable loss of catalytic activity. Conclusion: This work shows that the coupling "modified clay/microwave activation" is a clean and simple access to functionalized cyclopropanes. This reusable Cu exchanged clay material is shown to be as a good substitute for many sophisticated and hardly accessible catalysts.

1, 2, 3-Triazoles were synthesized using a one-pot procedure via a threecomponent reaction between an organic halide, sodium azide and alkyne in the presence of an ionic liquid choline chloride-CuCl catalyst. The catalyst can increase the rate of the nucleophilic substitution reaction and showed a high catalytic activity for the [3+2] Huisgen cycloaddition in water. This method is applicable for a wide range of alkynes including aromatic and heterocyclic substrates.

Background: For the synthesis of tri and tetra-substituted alkenes, Knoevenagel condensations have previously been performed in solvents like dichloromethane, DMF, toluene, acetonitrile, DMSO etc. These conditions suffer from certain limitations like long reaction times are required in DMSO or harsh heating conditions are necessary using DMF as a solvent decreasing the yields to below 50%. Tedious work up is required after long reaction times or/and high temperatures, if the reaction is performed in toluene. Methods: In a typical reaction, 1 mmol of aromatic aldehyde with 1.1 mmol of malanonitrile in the presence of bismuth nitrate (3 mmol%) was refluxed in water (10 ml) for 25-30 min. After completion of the reaction (TLC analysis), excess bismuth nitrate was filtered for next use and the filtrate was kept at room temperature over night for crystallization. Crystals were filtered, washed with water and dried. In a separate reaction the catalyst was re-used for the one of the same reactions and found satisfactory results. Results: In order to generalize our newly developed methodology, we selected a variety of aldehydes to synthesize different trisubstituted alkenes and found that this method can also be applied on aromatic aldehydes. For comparison purposes, the reaction was carried out in ethanol in parallel to water and found that water is the best solvent for this reaction. Conclusion: In summary, we have discovered a facile and rapid method for Knoevenagel condensations using bismuth nitrate as Lewis acid. The advantages of bismuth nitrate as a catalyst are: easy to remove from the reaction mixture by simple filtration, recyclable, requires water as solvent, is eco-friendly and afforded high yields (90-97%).