Letters in Organic Chemistry - Volume 14, Issue 5, 2017

Background: The domino Knoevenagel/intramolecular hetero Diel-Alder (IMHDA) reaction is the most powerful tool in organic synthesis, especially in the area of heterocycles and natural products. The most widely used heterodienes are usually those where the olefinic bond is flanked between symmetrical 1,3-dicarbonyl compounds. However, the study on the mode of cycloaddition of a heterodiene wherein the olefinic segment is flanked between a keto C=O and a lactone C=O group is of interest. Methods: We carried out a domino Knoevenagel/hetero-Diels-Alder reaction of 2-(4-methyl-3-pentenyl) benzaldehyde 1 with cyclic 1,3-dicarbonyl compounds 2 using 10 mol% L-proline or D,L-proline in acetonitrile to afford the novel chromenone derivatives. This is the first example of the highly diastereoselective preparation of tetracyclic naphtho chromenone and isochromeno chromenone derivatives in a one-pot process. Results: To test the scope of the IMHDA reaction, aldehyde 1 was also reacted with dimedone (2b) and N'N-dimethylbarbituric acid (2c). These two reactions smoothly afforded the respective products 3b-c as cis isomers exclusively. Similar results were observed with the unsymmetrical 1,3-dione, such as 4,4-dimethyl-1,3-cyclohexanedione 2d produced the corresponding product 3d. However, the reaction of an unsymmetrical 1,3-dione, 4-hydroxycoumarin (2e), with 2-(4-methyl-3-pentenyl) benzaldehyde 1 in the presence of a catalytic amount of L-proline in refluxing acetonitrile proceeded in 6 h, wherein both the keto C=O and the lactone C=O groups were involved in the cycloaddition to give a 2.6:1 mixture of the corresponding angular tetrahydrobenzo isochromeno chromenone 4a and the linear isomer tetrahydrobenzo isochromeno chromenone 4b. Conclusion: We have elaborated a simple and efficient route to novel polycyclic derivatives by intramolecular domino Knoevenagel/hetero Diels-Alder reaction of symmetrical as well as unsymmetrical cyclic 1,3-diones with aromatic aldehyde 1. Importantly, the reaction is diastereoselective to produce exclusively cis-products. Further exploration towards the synthetic utility of 2-(4-methyl-3-pentenyl) benzaldehyde is underway in our laboratory.

Background: Marine molluscs, the most diverse species in ocean, have been recognized as a good source of bioactive compounds. Monodonta labio is a species of top snail belonging to the family Trochidae (class Gastropoda, phylum Mollusca). This is one of the least investigated species with few alkaloids and aminoalkylphosphonyl cerebrosides isolated and identified to date. Methods: We used various chromatographic methods to isolate compounds from the acetone extract of sea snail Monodonta labio. Spectroscopic experiments were used to elucidate the structures of isolated compounds. The cytotoxic activity against three human cancer cell lines as carcinoma (A-549), hepatocellular carcinoma (Hep3B), and cervical adenocarcinoma (Hela) was evaluated by an MTT assay. Results: Two new tetrahydropyran derivative diastereoisomers; namely monodontins A (1) and B (2), together with twelve known compounds as rivularin A (3), 2-hydroxy-1-(4-hydroxyphenyl)-1,4-pentanedione (4), L-thymidine (5), thymine (6), 5β,6-epoxy-cholestan-3β-ol (7), melithasterol A (8), 5α,6α-epoxy-3β,7α-dihydroxycholest-8(14)-ene (9), cholesta-3β,5α,6β-triol (10), cholest-7-ene-3β,5α,6β-triol (11), cholest-5-ene-3β,7β-diol (12), cholest-5-ene-3β,7α-diol (13), and 3β-hydroxycholesta-5,8-dien-7-one (14), were isolated from the acetone extract of sea snail Monodonta labio. Among the isolated compounds, compound 3 exhibited the most potent cytotoxic activity on A-549 cell line with an IC50 value of 0.04±0.01 μM and strong effect on Hep3B cell line with an IC50 value of 0.82±0.13 μM. Compounds 4 and 8 showed selective and strong activity against only A-549 cell line (IC50 = 1.92±0.79 and 2.14± 0.16 μM). Conclusion: The obtained results suggested that the constituents from Monodonta labio contained potent cytotoxic compounds and might be potential candidates for further molecular mechanism-of-action studies.

Background: Recently, pyrimidine and chromene derivatives have concerned increasing attention because of the wide range of biological activities. Considering the prominence of pyrimidine and chromene derivatives, several procedures have been reported for the synthesis of these compounds. Herein, new magnetic nanoparticles supported ionic liquid has been evaluated for the synthesis of pyrimidine and chromene derivatives. Methods: In this method, pyrimidine and chromene compounds were synthesized by the multicomponent reaction of aromatic aldehydes, malononitrile, and active methylene compounds in the presence of the new magnetic nanoparticles supported ionic liquid. The new nanocatalyst was characterized by using TEM, VSM, XRD and IR spectrum. Results: The remarkable advantages of this new procedure involve high yields, short experimental time, low cast and easy preparation of the catalyst and no need of any workup and purification. Magnetic properties of the catalyst led to the easy separation from the reaction mixture by using an external magnet. The catalyst can be reused several times in the desired reaction without significant decrease of its activity. Conclusion: An efficient and green method for the synthesis of chromene and pyrimidine compounds in the presence of magnetic nanoparticles supported ionic liquid have been developed. Thermal stability, low cost and easy synthesis of the catalyst, high yields, easy separation and purification of the product, short experimental time and using a green solvent such as water provided a useful and alternative method for such reactions.

Background: Simple and efficient method has been developed for the Knoevenagel condensation of novel 3-chloro-3-(4-oxo-4H-pyrido[1,2-a]pyrimidin-3yl)acrylaldehyde (5) with active methylene compounds such as malononitrile (6), 3-methyl-1-phenyl-pyrazole-5(4H)-one (7), 3-methyl-1Hpyrazole- 5(4H)-one (8), Meldrum's acid (9), Barbituric acid (10) and 4-hydroxycoumarin (11) by stirring in ethanol at room temperature for 2 h in the presence of L-proline as a catalyst yielding the products 12a, b to 17a, b respectively. Methods: In this article, we reported a new synthesis of 3-chloro-3-(4-oxo-4H-pyrido[1,2-a]pyrimidin- 3yl)acrylaldehyde (5) which was prepared from the 2-aminopyridine 1 condensed with ethyl ethoxymethyleneacetoacetate (2) in ethanol under refluxing conditions for 4 h giving a product which has been characterized as ethyl 3-oxo-2-((pyridin-2-ylamino)methylene)butanoate 3 on the basis of its spectral data. On thermal cyclization, in diphenyl ether for 30 min at 255oC, 3a gave a product 4. Vilsmeier-Haack formylation of 4 at RT for 4 h gave a product 5. Condensation of 5 with malononitrile, 3-methyl-1-phenyl-pyrazole-5(4H)-one, 3-methyl-1H-pyrazole-5(4H)-one, Meldrum's acid, Barbituric acid and 4-hydroxycoumarin (11) by stirring in ethanol at room temperature for 2 h in the presence of L-proline as a catalyst yielding the products 12a, b to 17a, b respectively. Result: A novel preparation of 3-chloro-3-(4-oxo-4H-pyrido[1,2-a]pyrimidin-3yl)acrylaldehyde (5) method is reported in this article, along with the condensation of 5 with various active methylene compounds by stirring in ethanol at room temperature for 2 h in the presence of L-proline as a catalyst yielding the products 12a, b to 17a, b respectively. The structures of the synthesized compounds were confirmed by 1H-NMR, 13C-NMR, GC-MS and IR spectral data. All of the intermediates were structurally characterized IR (KBr): 1747 and 1697 cm-1 (strong, sharp of absorptions due to the -CHO and -N-CO-). 1H-NMR (DMSO-d6/TMS): δ 7.4-7.8 (t, 3H, Ar-H), 8.7 (s, 1H, α-H to the enamine nitrogen), 9.2 (q, pyridine ring proton), 10.2 (s, 1H, -CHO). LC-MS (HR-MS): m/z 235.0271, [(C12H14N2O3) +H]+. Conclusion: In conclusion, L-proline has been employed as an efficient catalyst for the preparation of a simple, efficient method for the synthesis of condensed compounds and a novel synthetic route to 3- chloro-3-(4-oxo-4H-pyrido[1, 2-a]pyrimidin-3yl)acrylaldehyde(5), whose condensation with active methylene compounds (6-11) reactions at RT, led to products 12-17.

Background: 3,4-Dihydropyrimidin-2(1H)-one derivatives are an important class of nitrogen heterocycles. These compounds present a wide range of biological activities viz antibacterial, antifungal, and antidiabetic. Although many synthetic methods are available in the literature for the synthesis of these molecules, many of these methods have their own limitations such as use of excess of expensive catalyst and poor yields. Methods: The synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives is developed through the reaction of 1,2-diols, ethyl acetoacetate and urea in the presence of lead tetraacetate in dry ethanol under reflux conditions. Results: A series of 3,4-dihydropyrimidin-2(1H)-one derivatives were synthesized in good yields (82-95%) under reflux for 2-3.5 hours in ethanol solvent. The structural assignments of these compounds were made on the basis of elemental analysis and spectroscopic data. Conclusion: This protocol is an alternative to existing procedure for the synthesis of Biginelli compounds. The present methodology reduces the number of steps in total synthesis.

Background: β-Lactams are still a subject of interest of organic chemists. The main reason for this interest is due to their application as a chemotherapeutic. β-Lactam antibiotics are still the most commonly used drugs in bacterial infections. Method: Methods using 4-exo-trig radical cyclization leading to β-lactams are an alternative to classical Staudinger`s β-Lactams formation. We prepared N-alkenyl-N-(2-hydroxyethyl)amides to check the action of internal nucleophile. In the next step, with use of Mn(OAc)3 promoted radical cyclization 3- carbamoyl, 3-tiocarbamoyl and 3-phosphoryl β-lactams containing intramolecular nucleophile were prepared. These intermediates were able to induce the second ring closing through a carbocation trapping. Results: Iso-oxacepham derivatives were synthesized by the 4-exo-trig radical cyclization as innovative one-pot approach. Subsequent cyclization process of N-alkenyl-(2-hydroxyethyl)amides to 7- substituted iso-oxacephams was described. Influence of carbamoyl, thiocarbamoyl and phosphoryl moieties located on C-7 position of iso-oxacephamic scaffold on β-lactamase inhibitory activity was confirmed on bacterial β-lactamases from group C. Conclusion: In this paper, we describe alternative approach for the synthesis of 7-substituted isooxacepham. The hypothetic reaction mechanism for the second ring closing was confirmed. The β-lactamase inhibition was observed in case of four synthesized compounds.

Background: Benzothiazole is a heterocyclic compound, weak base and having various biological activities. This compound and its derivatives are widely found in bioorganic and medicinal chemistry with application in drug discovery. Spiro[indole-benzothiazoles] are one of analogs of the benzothiazole and isatin, having biological properties, such as anticancer and antioxidant. (15). The aim of this manuscript is to develop a green reaction for the synthesis of a new series of benzothiazole compounds using Michael addition reaction 3'H-spiro[indole-3,2'-[1,3]]benzothiazole-2(1H)-one to α,β-unsaturated esters under solvent-free conditions. Methods: 3'H-Spiro[indole-3,2'-[1,3]]benzothiazole-2(1H)-one and different acrylic and fumaric esters have been used to synthesize new derivatives of 3'H-Spiro[indole-3,2'-[1,3]]benzothiazole-2(1H)-one via aza-Michael addition amide nitrogen of 3'H-Spiro[indole-3,2'-[1,3]]benzothiazole-2(1H)-one to β-carbon atom of this α,β-unsaturated esters. These reactions were performed using K2CO3 (for single aza-Michael addition) and K2CO3 and tetrabutylammonium bromide (for double aza-Michael addition) at room temperature under solvent-free conditions. The structural assignments of the synthesized compounds were made on the basis of elemental analysis and spectroscopic data (IR, 1H NMR, 13C NMR and Mass). Results: The mono and bis-Michael adduct were synthesized using reaction between 3'H-Spiro[indole- 3,2'-[1,3]]benzothiazole-2(1H)-one and different acrylic esters in good to excellent yields (75%-95%). This reaction was performed in the presence of inorganic base K2CO3 and tetrabutylammonium bromide (for bis-Michael adduct) at room temperature under solvent-free conditions. Fumaric esters were unable to react with 3'H-Spiro[indole-3,2'-[1,3]]benzothiazole-2(1H)-one and produced no products. Conclusion: We developed a regioselective Michael addition reaction for the exclusive synthesis mono-Michael adduct in the presence of base K2CO3 under solvent-free conditions at room temperature. We have found that this selectivity disappears in the presence of TBAB under the same conditions. The present procedure has notable advantages, for example, simple operation procedure, environmentally benign reaction conditions, inexpensive and availability of the employed base catalyst.

Background: Oxygen heterocycles exhibit diverse biological and pharmacological activities. In particular, benzofurans are available in a wide number of natural products and have drawn considerable attention over the last few years due to their profound physiological and biological properties. The aim of this paper describes a green methodology to synthesize this potent molecule with high selectivity by using ionic resin in PEG at room temperature. Methods: The methodology is very simple and easily accessible at room temperature. It uses low catalyst loadings and is recycled subsequently. In addition, detailed experimental procedure for the selected compounds including the spectral data are provided. Results: Among the various ionic resins attempted, Amberlyst-15® in PEG-400 was the choice of selection for the synthesis of 3-benzoyl-5-hydroxy benzofuran and naphtho[1,2-b]furan derivatives at room temperature in an environmentally friendly method. This catalyst system resulted in excellent yields in short reaction times and high selectivity. Conclusion: We have developed a green highly efficient and environmentally friendly protocol for the facile synthesis of 3-benzoyl-5-hydroxy benzofuran and naphtho[1,2-b]furan derivatives at room temperature in high yields (>90-95%) using nontoxic and inexpensive ion exchange resin Amberlyst-15®. The notable advantages of the catalyst approach enables the reactions with high selectivity, short reactions time and excellent yields without generating any waste and was reused.

Background: The recent development of using heterogeneous catalysts in organic synthesis has increased the need for fine metal oxide nanoparticles. Nanosized titanium dioxide nanoparticles (TiO2 NPs) can be used in several organic and inorganic transformations because of their superior properties such as high catalytic activity, non-toxicity, easily availability, moisture stability and reusability. Pyrimidinones are privileged heterocycles in the field of drugs and pharmaceutical industry. Method: The current methodology deals with the direct assembly of Meldrum's acid, aromatic aldehydes, and guanidine nitrate in the presence of a catalytic amount of the synthesized TiO2-CNTs nanocomposite could be utilized to afford 2-amino-6-aryl-5,6-dihydro-4(3H)-pyrimidinones under solventfree conditions within 2-3 h. Results: A series of 2-amino-6-aryl-5,6-dihydro-4(3H)-pyrimidinones were synthesized in high yields (90-98%) via a simple one-pot three-component coupling reaction using the synthesized TiO2-CNTs nanocomposite with the weight ratio of 50:50 as an efficient and recyclable catalyst. All synthesized compounds were well characterized by their satisfactory elemental analyses, IR, 1H and 13C NMR spectroscopy. The synthesized catalyst was fully characterized by XRD, SEM, and elemental analysis. Conclusion: We have developed a general and highly efficient TiO2-CNTs nanocomposite catalyzed procedure for the synthesis of 2-amino-6-aryl-5,6-dihydro-4(3H)-pyrimidinones from a one-pot threecomponent coupling reaction of Meldrum's acid, aromatic aldehydes, and guanidine nitrate with high yields under solvent-free conditions. This new protocol has revealed several advantages such as recyclability of catalyst, short reaction times, high to excellent yields of products and solvent-free conditions.

Background: The seeds of Brucea javanica are known to be an abundant source of quassinoids, which have a structurally diverse and wide spectrum of biological effects, such as potential antiinflammatory, antitumor, antimalarial, antiamebic, and cytotoxic activities. However, only several dehydro-quassinoids were isolated and identified in this plant. Methods: The EtOAc extract of the seeds of B. javanica was submitted to silica gel CC, ODS, Sephadex LH-20, and RP-HPLC to get four compounds. Their chemical structures were elucidated by spectroscopic methods including UV, IR, 1D-NMR, 2D-NMR, and HR-MS. The inhibitory effects of 1-4 on nitric oxide (NO) production in lipopolysaccharide-activated macrophages were also evaluated. Results: A new dehydro-quassinoid namely, dehydrobruceine C (1), along with bruceine B (2), bruceine C (3), and bruceantinol (4) were separated from the EtOAc extract of the seeds of B. javanica. Compounds 1-4 displayed different intensity inhibitory effects on NO production, and their IC50 values were 33.11, 26.83, 9.08 and 8.25 μM, respectively, compared to indomethacin. Conclusion: B. javanica has been proven to contain structurally diverse and biologically active quassinoids. This is the first report on the isolation and chemical structure identification of dehydrobruceine C (1), this new quassinoid compound exhibited moderate anti-inflammatory activities in vitro.

Background: Among the nitrogen heterocycles, quinolones and their derivatives represent the most important class of organic scaffolds that attract the interest of both medicinal and synthetic chemists. And these molecules possess a large number of biological and pharmacological properties. Here, we have synthesized 3-(1-(1H-indol-3-yl)-3-oxo-3-phenylpropyl)-4-hydroxy-1-methylquinolin-2(1H)-ones 5 in presence of L-proline through the intermediacy of 4-hydroxy-1-methyl-3-(3-oxo-3-phenylprop-1-en-1-yl)quinolin-2(1H)-one 3. Methods: All the compounds 5(aa-ce) have been synthesized in step-wise, one-pot with sequential addition and one-pot process with all substrates present from the outset methods under green conditions. The structure of the product was established based on its spectral properties IR, 1H- NMR, 13C-NMR and Mass. Results: In this work we describe the synthesis of 3-(1-(1H-indol-3-yl)-3-oxo-3-phenylpropyl)-4-hydroxy-1-methylquinolin-2(1H)-ones 5(aa-ce) by condensation of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 1, with acetophenone 2(a-c) and indole 4(a-e) in the presence of L-proline and water. Conclusion: We have synthesized new series of indole substituted N-heterocyclic chalcones via Friedel-Crafts alkylation under green condition. The syntheses are water mediated and eco-friendly involving easy workup: moreover they gave high yields without the need of costly catalyst and column chromatography.