Preparation and characterization of ZrO2-supported Fe3O4-MNPs as an effective and reusable superparamagnetic catalyst for the Friedländer synthesis of quinoline derivatives J. Serb. Chem. Soc. 80 (8) 971–982 (2015) UDC 546.831–31+546.723’+22+547.831: JSCS–4773 542.9+544.47:544.344 Original scientific paper 971 Preparation and characterization of ZrO2-supported Fe3O4-MNPs as an effective and reusable superparamagnetic catalyst for the Friedländer synthesis of quinoline derivatives SEYYEDEH ZOHA HEJAZI, ABDOLLAH FALLAH SHOJAEI*, KHALIL TABATABAEIAN and FARHAD SHIRINI Department of Chemistry, Faculty of Sciences, University of Guilan, P. O. Box 41335-1914, Rasht, Iran (Received 23 October 2014, revised 4 March, accepted 27 March 2015) Abstract: In this study, a convenient, appropriate and eco-friendly method for the synthesis of quinoline derivatives via a Friedländer reaction was developed using ZrO2/Fe3O4-MNPs as an effective and reusable heterogeneous catalyst. The morphology of ZrO2/Fe3O4-MNPs was studied by the XRD, FT-IR, SEM, TEM and VSM techniques. Green reactions, straight and easy work-up, high yields of the products and good reaction times are the benefits of this pro- cedure. Further, the catalyst could be recovered using an external magnetic field and reused at least three times without a considerable decrease in its cat- alytic activity. Keywords: quinoline derivatives; Friedländer reaction; ZrO2/Fe3O4-MNPs; heterogeneous catalyst; green procedure. INTRODUCTION Quinoline and its derivatives are very important intermediates in organic and medicinal chemistry that show various physiological and pharmacological acti- vities, such as antimalarial, anti-inflammatory, anti-asthmatic, antibacterial, anti- hypertensive, and are tyrosine kinase inhibiting agents.1–3 These heterocycles are valuable compounds for the preparation of nano- and meso-structures with enhanced electronic and photonic properties.4,5 Furthermore, quinoline deriva- tives have been employed in the study of bio-organic and bio-organometallic pro- cesses.6,7 Due to the importance of the use of quinolines in the fields of medi- cinal, bioorganic, industrial and synthetic organic chemistry, there is immense interest in the development of effective procedures for their synthesis. Thus, several methods, such as the Skraup, Doebner–von Miller, Friedländer and * Corresponding author. E-mail: a.f.shojaie@guilan.ac.ir doi: 10.2298/JSC141023031H _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 972 HEJAZI et al. Combes, have been mentioned in the literature for the creation of quinoline derivatives.8–11 Among various methodologies suggested for the preparation of quinolines, the Friedländer annulation12,13 is one of the most frequently used pathways for the synthesis of polysubstituted quinolines. This method involves an acid- or base-catalyzed or thermal condensation between an aromatic 2-aminoaldehyde or ketone with a carbonyl compounds containing a reactive α-methylene group fol- lowed by a cyclodehydration.14,15 In general, Friedländer reactions are carried out either by refluxing an aque- ous or alcoholic solution of reactants in the presence of a base or by heating a mixture of the reactants at high temperatures ranging from 150 to 220 °C in the absence of a catalyst.16 However, under thermal or basic catalysis conditions, 2-aminobenzophenone does not react with simple ketones, such as cyclohex- anone and β-keto esters.17 Subsequent work showed better yields of quinolines were achieved under acid catalysis.17 Several acid catalysts, such as Brønsted acids including hydrochloric acid in water,18 sulfamic acid,19 sulfuric acid,20 sil- ica sulfuric acid,21 dodecylphosphonic acid,22 PEG-supported sulfonic acid,23 arylidene pyruvic acids (APAs),24 oxalic acid,25 Lewis acids containing Zr(NO3)4 or Zr(HSO4)4,26 zirconium tetrakis(dodecyl sulfate) Zr(DS)4,27 GdCl3·6H2O,28 BiCl3,29 SnCl2,30 FeCl3,31 Y(OTf)332, NiCl233, Ag3PW12O4034 and ZnCl235 have been reported for this conversion. However, most of the previously reported procedures suffer from different drawbacks, such as low yields of the products, poor selectivity, long reaction times, harsh conditions, high temperatures, usage of hazardous, corrosive and rel- atively expensive catalysts, tedious work-up procedures and using toxic/polar solvent leading to complex isolation and recovery procedures. Moreover, the main disadvantage of a number of previous methods is that the catalyst cannot be recovered. Therefore, the development of a simple, efficient and environmentally friendly method for the synthesis of quinoline derivatives is still a challenging task. Recently, the applications of heterogeneous nanocatalysts have attracted remarkable attention as inexpensive, non-toxic and eco-friendly catalysts for var- ious organic transformations under mild and convenient conditions. The catalysts have advantages over conventional homogeneous catalysts, including simple recovery from the reaction mixture by easy filtration, higher surface activity and reusability.36–38 Among heterogeneous catalysts, inorganic oxides especially zirconia have different physical and chemical properties and have gained much consideration by researchers. Good chemical and dimensional stability, high electrical resist- ivity, high refractive index, mechanical strength and toughness, biocompatibility and low cost are the origin of the interest in using the zirconia as a catalyst.39,40 _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ FRIEDLÄNDER SYNTHESIS USING ZrO2/Fe3O4-MNPs CATALYST 973 However, the specific surface area and thermal stability of pure ZrO2 is low41 and it shows weak catalytic activity in a number of chemical transformations.42 In order to enhance the catalytic performance of zirconia-based catalysts, many endeavors have been inducted by introducing various metal oxides where- upon zirconia acts as a support for the preparation of the solid catalysts.43–48 Although the doping of appropriate cations with specific concentration into zir- conia improves thermal stability, surface area and acidity of solid acids, the separation and recovery of mixed oxide catalysts from the reaction products are still difficult and require a large amount of separation energy and cost. For this reason, a material immobilized onto the solid support plays a fundamental role in the efficiency of the resulting supported reagent catalyst. Among the different modified zirconia materials, Fe3O4 magnetic nanoparticles (MNPs) are widely used due to easy handling, a simple work-up procedure, nontoxicity, enhanced catalytic activity and chemical selectivity in various organic synthesis.49,50 In addition, ZrO2-supported Fe3O4-MNPs can be easily separated from the reaction media by applying an external magnetic field. In continuation of ongoing studies on metal oxides as catalysts,51 herein, a simple and eco-friendly procedure is demonstrated for the synthesis of quinoline derivatives using the Friedländer heteroannulation method in the presence of ZrO2/Fe3O4-MNPs as catalyst. EXPERIMENTAL Chemicals and apparatus All materials and solvents were purchased from Merck and Fluka, and used without further purification. Yields refer to isolated products. Products were characterized by their physical constants, comparison with authentic samples, and IR and NMR spectroscopy. The IR spectra were obtained in KBr discs on a Perkin–Elmer model Spectrum One FT-IR spec- trometer. The structures of the synthesized catalysts were characterized by X-ray diffraction analysis (XRD Equinox 3000, INEL, France). The XRD patterns were obtained using CuKα radiation (wavelength 1.54056 Ǻ) at a current of 200 mA and a voltage of 40 kV in the 2θ range of 10–100 at a scanning rate of 8° min-1. The surface microscopic morphologies of the ZrO2-supported Fe3O4-MNPs were visualized by scanning electron microscopy (SEM MIRAII TESCAN). The size of Fe3O4-MNPs was investigated by transmission electron microscopy (TEM Philips MC 10) with an acceleration voltage of 80 kV. A magnetic study was performed using a vibrating sample magnetometer at room temperature (VSM JDM-13). Reaction progress was checked by thin-layer chromatography (TLC) with detection by UV light. The 1H-NMR spectra were obtained on a Bruker DRX-400 Avance spectrometer, while the 13C-NMR spectra were obtained on a Bruker DRX-100 Avance spectrometer. Samples were analyzed in CDCl3 and chemical shift values are reported in ppm relative to tetramethylsilane (TMS) as the internal reference. Melting points were measured on an elec- trothermal apparatus and are uncorrected. Elemental analyses were realized using a Carlo Erba EA1110 CHNS-O analyzer and the values agreed with the calculated ones. _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 974 HEJAZI et al. Preparation of the catalyst (ZrO2/Fe3O4-MNPs) Firstly, 96 mg of ZrO2 nano particles were well dispersed in 30 mL of distilled water in a two-necked round bottom flask (100 mL) by ultrasonic irradiation for 30 min. After adding 81 mg of FeCl3·6H2O, the solution was stirred vigorously for 30 min. Subsequently, 120 mg FeCl2·4H2O was slowly added into the mixture under stirring for 30 min. The whole process was performed under an argon atmosphere. Then, 8 mL of a concentrated aqueous solution of NH3 was added into the solution dropwise over 1 h. Thereafter, the mixture was stirred at 60 °C for 2 h. After cooling the solution to room temperature, the black magnetic ZrO2/Fe3O4- -MNPs were recovered by centrifugation at 6000 rpm, rinsed several times with deionized water and dried at 60 °C for 24 h. It was expected that the positive ferrous and ferric ions would be in proximity with the oxygen atoms of ZrO2 and that they would be converted to Fe3O4-MNPs after the dropwise addition of the concentrated aqueous solution of NH3 into the solution. General procedure for the synthesis of quinolines catalyzed by ZrO2/Fe3O4-MNPs A mixture of 2-amino-5-chlorobenzophenone (1 mmol), a ketone or β-diketone (1.5 mmol) and ZrO2/Fe3O4-MNPs (20 mg) in ethanol (5 mL) was stirred magnetically and heated at 70 °C. After completion of the reaction, confirmed by TLC, the catalyst was collected by magnetic separation using an external magnet and washed repeatedly with warm ethanol. The aqueous phase was filtrated and cooled to room temperature. Then the solid product was col- lected and washed with cold water to afford the pure product. In some cases, further puri- fication was achieved by recrystallization in ethanol to give the pure product. RESULT AND DISCUSSION Catalyst characterization X-Ray diffraction studies. To confirm the synthesis of the catalyst, first, the XRD patterns of the pure ZrO2 nanoparticles and ZrO2/ Fe3O4 magnetic nano- particles were studied. All the diffraction peaks in the XRD patterns of the pure ZrO2 imply the monoclinic phase of pure ZrO2 nanoparticles (m-ZrO2, JCPDS NO 24-1165). The additional diffraction peaks at 2θ 30.6, 36.5, 43.7, 53.9, 57.6, and 62.8° appearing in the XRD patterns of the ZrO2/Fe3O4-MNPs correspond to the standard XRD data for the cubic Fe3O4 phase of inverse spinel crystal struc- ture (JCPDS file No. 19-0629).52 No peaks corresponding to impurities were pre- sent. The average diameter of the crystallites (D) of the synthesized catalyst was calculated using the Scherrer formula and found to be 21 nm, as confirmed by TEM analysis. Fourier transform infrared spectroscopy. The FT-IR spectrum of pure zir- conia was compared with the synthesized ZrO2/Fe3O4-MNPs. The pure zirconia spectrum exhibited bands at 734, 581 and 508 cm–1, which could be attributed to the Zr–O stretching vibration of ZrO2. These bands were not distinctly found in the spectrum of ZrO2/Fe3O4-MNPs. They are related to the broad band at around 579 cm–1, which was assigned to the Fe–O stretching vibration of Fe3O4-MNPs that may overlap with the Zr–O peaks. Moreover, the absorption bands in the _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ FRIEDLÄNDER SYNTHESIS USING ZrO2/Fe3O4-MNPs CATALYST 975 region 3435 and 1630 cm–1 may be related to the stretching and bending vib- rations of the O–H bond due to physically adsorbed water molecules. SEM and TEM analysis. The morphology and size of the synthesized ZrO2/ /Fe3O4-MNPs were examined by scanning electron microscopy (SEM) and trans- mission electron microscopy (TEM). From the SEM image (Fig. 1a), it can be seen that the loaded Fe3O4-MNPs were uniform in shape and size distribution and had a porous structure. The particles sizes derived from TEM analysis (Fig. 1b) were in the range 5–25 nm, which is comparable with the crystallite size calculated from the X-ray spectrum. (a) (b) Fig. 1. a) SEM and b) TEM image of ZrO2/Fe3O4-MNPs. Vibrating sample magnetometer (VSM) analysis The magnetic properties of ZrO2/Fe3O4 magnetic nanoparticles were inves- tigated by the most common method of examining the magnetic properties of a material, using a vibrating sample magnetometer (VSM). The results showed that the synthesized nanoparticles exhibit superparamagnetic behavior at room tem- perature and the hysteresis loops of the samples exhibited no coercivity and ret- entivity. The saturation magnetization (Ms) values of the synthesized catalysts were 33 emu g–1, which is mainly attributed to a high weight ratio of Fe3O4 mag- netic nanoparticles that were loaded onto the ZrO2. Catalyst synthesis optimization At the beginning of the investigations on the usage of ZrO2/Fe3O4-MNPs as a green and efficient heterogeneous nanocatalyst, the reaction of 2-amino-5-chlo- robenzophenone and ethyl acetoacetate (EAA) was selected as a model for deter- mining the optimal conditions. For this reason, several reactions were performed using diverse amounts of catalyst at various temperatures in different solvents to achieve a good yield of the desired products. The results are summarized in Table I. _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 976 HEJAZI et al. TABLE I. Optimization of the conditions for the synthesis of ethyl 2-methyl-4-phenylqui- noline-3-carboxylate; reaction conditions: 2-amino-5-chlorobenzophenone (1 mmol), EAA (1.5 mmol) in different solvents at different temperatures with different amount of cat- alyst Entry Catalyst [amount, mg] Solvent t / °C τ / min Yielda, % 1 – Ethanol Reflux 300 Trace 2 ZrO2-NPs [300] Ethanol Reflux 240 18 3 ZrO2/Fe3O4-MNPs [10] Ethanol Reflux 60 88 4 ZrO2/Fe3O4-MNPs [20] Ethanol Reflux 24 91 5 ZrO2/Fe3O4-MNPs [30] Ethanol Reflux 25 90 6 ZrO2/Fe3O4-MNPs [20] Ethanol 25 320 Trace 7 ZrO2/Fe3O4-MNPs [20] Ethanol 50 300 51 8 ZrO2/Fe3O4-MNPs [20] Ethanol 70 25 92 9 ZrO2/Fe3O4-MNPs [20] Methanol Reflux 30 86 10 ZrO2/Fe3O4-MNPs [20] Acetonitrile 70 120 22 11 ZrO2/Fe3O4-MNPs [20] n-Hexane Reflux 120 Trace aIsolated yield As can be seen in Table I, the best result was obtained when the reaction was performed at 70 °C, with a relative ratio of the substrate: EAA:ZrO2/Fe3O4-MNPs of 1 mmol:1.5 mmol:20 mg, respectively (Table I, entry 8). In this procedure, any further increase in temperature and amount of catalyst did not lead to consider- able improvement in the reaction times and yields. Moreover, when the same procedure was run at room temperature, the yield of the product was poor after 320 min (Table I, entry 6). It is noteworthy that without any catalyst at reflux, the product was isolated in low yield after a long reaction time (Table I, entry 1). Moreover, it can be seen that the pure m-zirconia as the catalyst led to a lower yield of the product (Table I, entry 2). In order to examine the effect of the sol- vent, the reaction was explored in different solvents, i.e., ethanol, methanol, ace- tonitrile and n-hexane (Table I, entries 8–11) and ethanol was selected as the best solvent. Under the optimized conditions, the model reaction gave 92 % yield of the corresponding product after 25 min (Table I, entry 8 and Scheme 1). O Ph NH2 OEt OO N Ph OEt O + Cl Cl ZrO2/Fe3O4-MNPs (20 mg) Ethanol, 70oC Scheme 1. ZrO2/Fe3O4-MNPs catalyzed synthesis of ethyl 2-methyl-4-phenylquinoline-3-carboxylate. Subsequently, in order to evaluate the generality of this methodology, a series of ortho-aminoaryl ketones were reacted with different 1,3-dicarbonyl compounds under the optimum conditions and the results are reported in Table II. _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ FRIEDLÄNDER SYNTHESIS USING ZrO2/Fe3O4-MNPs CATALYST 977 TABLE II. Synthesis of various quinolines using ZrO2/Fe3O4-MNPs as the catalyst; reaction condition: 2-aminoaryl ketone (1 mmol), ketone or β-diketone (1.5 mmol) and ZrO2/Fe3O4- MNPs (20 mg) at 70 °C in ethanol (5 mL) Entry Substrate Ketone or β-diketone Quinoline τ min Yielda % M.p., °C Measured Reported 1 O Ph NH2 OO N Ph O 40 89 109–111 111–11225 2 O Ph NH2 OEt OO N Ph OEt O 30 91 98–100 100–10125 3 O Ph NH2 OMe OO N Ph OMe O 35 90 99–100 98–10053 4 O Ph NH2 O O N Ph O 60 86 191–194 190–19234 5 O Ph NH2 O O N Ph O 45 90 154–156 155–15634 6 O Ph NH2 O N Ph 50 89 129–131 130–13234 7 O Ph NH2 O N Ph 60 87 153–156 156–15734 8 O Ph NH2 Cl OO N Ph O Cl 45 90 151–153 150–15134 9 O Ph NH2 Cl OEt OO N Ph OEt O Cl 25 92 101–103 102–10422 10 O Ph NH2 Cl OMe OO N Ph OMe O Cl 30 90 134–136 133–13525 11 O Ph NH2 Cl O O N Ph O Cl 45 89 207–209 208–20934 12 O Ph NH2 Cl O O N Ph O Cl 35 92 184-186 185–18634 13 O Ph NH2 Cl O N Ph Cl 45 90 107-108 106–10725 _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 978 HEJAZI et al. TABLE II. Continued Entry Substrate Ketone or β-diketone Quinoline τ min Yielda % m.p., °C Measured Reported 14 O Ph NH2 Cl O N Ph Cl 60 89 165–167 164–16534 15 O Ph NH2 Cl O O N Ph O Cl 65 87 239–241 240–24354 aIsolated yield According to Table II, both cyclic and acyclic diketones such as 5,5-dime- thylcyclohexanedione and acetylacetone, cyclic ketones including cyclohexanone and cyclopentanone and β-ketoesters such as EAA reacted with 2-amino-5-chlo- robenzophenone and 2-aminobenzophenone to afford the corresponding quino- lines. It can easily be seen that in all cases, the Friedländer annulation proceeded smoothly and gave good to high yields ranging from 86 to 92 %. The reactions were remarkably clean and no chromatographic separation was necessary to obtain spectra-pure compounds. Furthermore, the work-up of present method was easy and the process is beneficial in avoiding the application of strong acids, high temperatures and volatile and/or toxic reactants. All of the synthesized products are known compounds and were characterized by comparing their melting points, IR, 1H- and 13C-NMR spectra with those of authentic samples. The possibility of reusing the catalyst is one of the most significant benefits of heterogeneous catalysts over homogeneous systems. Thus, the recovery and reusability of ZrO2/Fe3O4-MNPs was investigated in the model reaction under the optimized condition. After completion of the reaction, the catalyst was easily separated from the reaction mixture by an external magnetic field and reused in subsequent runs. The results of continuous runs showed that the recovered cat- alyst could be reused three times without any appreciable decrease in its activity (Table III). The strength of catalyst is emphasized via measurement of Fe ions leaching by atomic absorption spectroscopy and trace metal ions were detected in the filtrate of this reaction. TABLE III. Reusability of the ZrO2/Fe3O4-MNPs in the model reaction (Table II, entry 8) Run No. τ / min Yield, % 1 25 92 2 25 92 3 27 90 4 30 88 Moreover, in order to demonstrate the excellent catalytic activity of ZrO2/ /Fe3O4-MNPs and the performance of this method, some of the results obtained _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ FRIEDLÄNDER SYNTHESIS USING ZrO2/Fe3O4-MNPs CATALYST 979 by the presented procedure were compared with other previously reported hetero- geneous catalytic systems in the literature. As shown in Table IV, the obtained results show the advantage of the present protocol in terms of catalyst amount, yields or reaction times. TABLE IV. Comparison of the result obtained for the synthesis of model reaction (Table II, entry 8) using ZrO2/Fe3O4-MNPs with other catalysts reported in the literature Entry Catalyst amount Solvent t / °C τ / min Yielda, % Reference 1 (BSPY)HSO4/MCM-41 (70 mg) – 100 80 94 55 2 NH2SO3H (5 mol %) – 70 45 89 56 3 SiO2/I2 (100 mg/50 mg) – 60 120 80 57 4 Amberlyst-15 (10 % w/w) C2H5OH Reflux 150 87 58 5 Nano-Flake ZnO (10 mol %) – 100 120 92 59 6 ZrO2/Fe3O4-MNPs (20 mg) C2H5OH 70 25 92 This Work aIsolated yield Two possible mechanisms exist for the Friedländer synthesis of quinolines that are shown in Scheme 2. Based on these mechanisms and in the first step, the carbonyl group is activated by ZrO2/Fe3O4-MNPs. Then, 2-amino-5-chloro sub- stituted carbonyl compound 1 and carbonyl compound 2 react in a rate-limiting step to the aldol adduct 3. This intermediate loses water in an elimination reac- tion to the unsaturated carbonyl compound 4 and then loses water again in imine formation to quinoline 5. In the second mechanism, the first step is Schiff base formation to 6 followed by an aldol reaction to 7 and elimination to 8. Scheme 2. Proposed mechanism for the synthesis of quinoline derivatives in the presence of ZrO2/Fe3O4-MNPs. _________________________________________________________________________________________________________________________ (CC) 2015 SCS. All rights reserved. Available on line at www.shd.org.rs/JSCS/ 980 HEJAZI et al. CONCLUSIONS In conclusion, a green, one-pot, effective and environmentally friendly approach has been explained for the synthesis of quinoline derivatives via Fried- länder annulation using ZrO2/Fe3O4-MNPs as a convenient, mild and reusable catalyst. The remarkable benefit of the described method include good substrate generality, mild reaction conditions, high yields, good reaction times, simple experimental procedure, the use of a low cost catalyst, easy work-up, clean reac- tion profiles and green conditions by avoiding the usage of toxic organic sol- vents. Furthermore, the catalyst was successfully recovered and reused at least for four runs without significant loss in its activity, which make the presented procedure an interesting alternative to previously reported methods. Acknowledgement. The authors are thankful to the Guilan University Research Council for the partial support of this work. И З В О Д ДОБИЈАЊЕ И КАРАКТЕРИЗАЦИЈА ZrO2/Fe3O4 МАГНЕТНИХ НАНОЧЕСТИЦА (MNPs) КАО ЕФИКАСНОГ СУПЕРПАРАМАГНЕТНОГ КАТАЛИЗАТОРА ЗА ФРИДЛEНДЕРОВУ СИНТЕЗУ ДЕРИВАТА ХИНОЛИНА SEYYEDEH ZOHA HEJAZI, ABDOLLAH FALLAH SHOJAEI, KHALIL TABATABAEIAN и FARHAD SHIRINI Department of Chemistry, Faculty of Sciences, University of Guilan, P. O. Box 41335-1914, Rasht, Iran Током истраживања развијен је приступачан и еколошки прихватљив поступак син- тезе деривата хинолина Фридлендеровом реакцијом, употребом ZrO2/Fe3O4-MNPs као ефикасног хетерогеног катализатора. Морфологија ZrO2/Fe3O4-MNPs је испитана XRD, FT-IR, SEM, TEM и VSM аналитичким техникама. Предности овог поступка су лака обрада реакционе смеше, висок принос производа и кратко реакционо време. Употреб- љен катализатор се уклања спољашњим магнетним пољем и може се поново употребити најмање три пута без значајнијег смањивања каталитичке активности. Током синтезе и обраде реакционе смеше избегава се употреба органских растварача што целокупан процес чини еколошки прихватљивим. (Примљено 23. октобра 2014, ревидирано 4. марта, прихваћено 27. марта 2015) REFERENCES 1. Y. L. Chen, K. C. Fang, J. Y. Sheu, S. L. Hsu, C. C. Tzeng, J. Med. Chem. 44 (2001) 2374 2. G. Roma, M. D. Braccio, G. Grossi, M. Chia, Eur. J. Med. Chem. 35 (2000) 1021 3. O. Billker, V. Lindo, M. 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