Scientia Iranica C (2013) 20 (3), 549–554

Sharif University of Technology

Scientia IranicaTransactions C: Chemistry and Chemical Engineering

www.sciencedirect.com

Calcium oxide nanoparticles catalyzed one-step multicomponentsynthesis of highly substituted pyridines in aqueous ethanol media

J. Safaei-Ghomi a,∗, M.A. Ghasemzadeh a, M. Mehrabi baDepartment of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, P.O. Box 87317-51167, Islamic Republic of Iranb Institute of Nano Science and Nano Technology, University of Kashan, Kashan, P. O. Box. 87317–51167, Islamic Republic of Iran

Received 27 April 2012; revised 29 September 2012; accepted 23 December 2012

KEYWORDSMulticomponent reactions;Nanoparticles;Calcium oxide;Poly functionalizedpyridines;

Heterogeneous catalyst;One-pot.

Abstract An efficient one-pot three-component condensation of aldehydes, thiols and malononitrilehas been developed in the presence of calcium oxide nanoparticles. Highly substituted pyridines asprivileged medicinal scaffolds have been efficiently prepared via carbon–carbon and carbon–heteroatombond formation. Thismethodprovides a novel and improved approach for the synthesis of 2-amino-4-aryl-3,5-dicyano-6-sulfanylpyridines in terms of excellent yields, short reaction times, reusability and littlecatalyst loading.

© 2013 Sharif University of Technology. Production and hosting by Elsevier B.V.Open access under CC BY-NC-ND license.

1. Introduction

Multicomponent reactions (MCRs) are special types of syn-thetically useful organic reactions, in which three or morevarious substrates react to give a final product in a one-potprocedure [1]. Clearly, for multi-step synthetic pathways, anumber of reactions and purification steps are the most im-portant criteria for the efficiency and ability of the process, andshould be as low as possible [2]. MCRs are powerful devices innovel drug discovery procedures and allow the fast, automatedand high-throughput generation of organic compounds [3]. Theformation of C–N, C–O and C–S bonds by MCRs is usual in nu-merous compounds with pharmaceutical, biological and mate-rial properties [4].

Because of significant biological and physiological activ-ities, synthesis of pyridines has attracted much attention

∗ Corresponding author. Tel.: +98 361 5912385; fax: +98 361 5912397.E-mail address: safaei@kashanu.ac.ir (J. Safaei-Ghomi).

Peer review under responsibility of Sharif University of Technology.

1026-3098© 2013 Sharif University of Technology. Production and hosting by Els

http://dx.doi.org/10.1016/j.scient.2012.12.037

in recent years [5–7]. Polyfunctionalized pyridine deriva-tives, known as medicinally privileged scaffolds, can inhibitMAPK-activated PK-26 [8] and modulate androgen receptorfunctions [9]. Among them, 2-amino-3,5-dicyano-6-sulfanylpyridines, in particular serve as a ‘privileged scaffold’ due totheir potential therapeutic applications in the treatment of uri-nary incontinence [10], HBF infections [11], Creutzfeldt-Jacobdisease, Parkinson’s disease, hypoxia/ischemia, asthma, kid-ney disease, epilepsy and cancer [12–14]. Also, a 2-amino-3,5-dicyano-6-sulfanyl pyridines skeleton is often used as ananti-prion [15], anti-hepatitis B virus and anti-bacterial [16].Consequently, synthesis of highly functionalized pyridinederivatives, with the aim of developing new drug molecules,has been an active area of research. Recently, much atten-tion has been paid to the development of new methodolo-gies for the preparation of pyridines. The synthetic routes forpreparation of substituted pyridines, mainly, are the Mannichreaction of iminium salts and aldehydes [17], azaelectrocy-clization of azatrienes [18], conversion of ketene dithioacetalsto substituted pyridines [19], reaction of 3-siloxy-1-aza-1,3-butadiens and 2H-1,4-oxazinones with acetylenes [20],conversion of conjugated oximes under Vilsmeier condi-tions [21], cycloisomerization of 3-azadienynes [22], Vilsmeier-Haack reaction of α-hydroxyketenedithioacetals [23], andthe Diels-Alder cycloadditions of oximinosulfonates [24]. One

evier B.V. Open access under CC BY-NC-ND license.

550 J. Safaei-Ghomi et al. / Scientia Iranica, Transactions C: Chemistry and Chemical Engineering 20 (2013) 549–554

Scheme 1: Synthesis of highly substituted pyridine derivatives catalyzed byCaO nanoparticles.

of the most attractive ways for the synthesis of thesecompounds involves the cyclocondensation of aldehydes,malononitrile and thiols. Generally, this method has beencarried out under basic conditions using various bases, such as:Et3N, DABCO, piperidine, morpholine, thiomorpholine, pyrro-lidine, N,N-DIPEA, pyridine, 2,4,6-collidine, DMAP, aniline,N-methylaniline, N,N-dimethylaniline and N,N-diethylaniline[25,26]. The preparation of pyridines has been reported inthe presence of [bmim]OH [27], KF/alumina [28], DBU [29],TBAH [30], ZnCl2 [31], microporous molecular sieves [32] andboric acid [33]. Moreover, some heterogeneous nanocatalysts,such as silica nanoparticles [34] andmagnesiumoxide nanopar-ticles [35], have been used in the synthesis of poly functional-ized pyridine derivatives.

The last decade has witnessed enormous development inthe field of nanoscience and nanotechnology. Several reportsshow the amazing level of the performance of nanoparticlesas catalysts in terms of selectivity, reactivity and improvedyields of products. In addition, the high surface-to-volume ratioof nanoparticles provides a larger number of active sites perunit area, in comparisonwith their heterogeneous counter sites[36,37].

Among various nanoparticles, calcium oxide nanoparticleshave received considerable attention because of their unusualproperties and potential applications in diverse fields [38].Calcium oxide (CaO), in particular, being cheap, has a highbasicity, and is non-corrosive, economically benign and easyto handle compared to homogeneous base catalysts. Also, theyrequire only mild reaction conditions to produce high yields ofproducts in short reaction times, in comparisonwith traditionalcatalysts, and can also be recycled [39–41]. Recently, calciumoxide nanoparticles were used as an active catalyst in manychemical transformations such as: adsorption of Cr (VI) fromaqueous solutions [42], transesterification of sun flower oil [43],removal of toxic heavy metal ions in water [44], artificialphotosynthesis [45] and transesterification of palm oil [46].

In accordance with the above mentioned significance ofnanoparticles in catalysis, and the importance of highlysubstituted pyridines as privileged medicinal scaffolds, herein,we wish to report a novel, green and mild method for thesynthesis of 2-amino-3,5-dicyano-6-sulfanyl pyridines 4 viamulticomponent coupling of aldehydes 1, malononitrile 2 andthiols 3, using CaO nanoparticles (CaO NPs) in aqueous ethanolmedia (Scheme 1). Calcium oxide nanoparticles, as an efficient,non-explosive, eco-friendly, non-volatile, recyclable and easy tohandle catalyst, can be used in the catalysis of many organictransformations.

2. Experimental

2.1. Material and methods

Chemicals were purchased from the Sigma-Aldrich andMerck in high purity. All the materials were of commercialreagent grade and were used without further purification.Calcium oxide nanoparticles were prepared in accordance with

the procedure reported by Tang et al. [47]. All melting pointsare uncorrected and were determined in capillary tubes on aBoetiusmelting pointmicroscope. 1HNMRand 13CNMRspectrawere obtained on a Bruker 400 MHz spectrometer, with CDCl3as the solvent. Using tetramethylsilane (TMS) as an internalstandard, the chemical shift values are in δ. The FT-IR spectrumwas recorded on a Magna-IR, spectrometer, 550 Nicolet, inKBr pellets, in the range of 400–4000 cm−1. The elementalanalyses (C, H, N) were obtained from a Carlo ERBA Model EA1108 analyzer. Powder X-ray diffraction (XRD) was carried outon a Philips diffractometer of the X’pert Company with monochromatized Cu Kα radiation (λ = 1.5406 Å). The microscopicmorphology of products was visualized by SEM (LEO 1455VP).

2.2. Preparation of CaO nanoparticles

NaOH (1 g)was added to amixture of ethylene glycol (12ml)and Ca(NO3)2. 4H2O (6 g) and the solution stirred vigorouslyat room temperature for 10 min; the gel solution was keptabout 5 h at static state. Afterwards, it was washed usingwater anddried under vacuumdrying. Finally, the preparedCaOnanoparticles were calcinated at 700 °C for 3 h.

2.3. Typical procedure for the sysnthesis of 2-amino-3,5-dicyano-6-sulfanyl pyridines (4a–4o)

To a mixture of aldehyde (1 mmol), malononitrile (0.145 g,2.2 mmol), in 2.5 mL ethanol and 2.5 mL of water, was addedCaO nanoparticles (0.01 g, 0.2 mmol, 20 mmol%), and thereaction mixture was stirred for 10 min at 50 °C. Then, thedesired thiol (1mmol)was added and the solutionwas refluxed.Progress of the reaction was continuously monitored by TLC.When the reaction was complete, the mixture was cooled toroom temperature and then was centrifuged to separate thecatalyst. The solvent was evaporated under vacuum and thesolid obtained was recrystallised from EtOH to afford purepyridines.

2.4. Spectral data of the new products

2-Amino-4-(3-hydroxyphenyl)-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile (4d)

White solid; mp 265 °C; IR (KBr) v: 3445, 3366, 3211, 2213,1622, 1575, 1536, 1483, 1255, cm−1; 1HNMR (CDCl3, 400MHz)δ: 5.42 (s, 2H, NH2), 7.05 (s, 1H, Ar-H), 7.23–7.25 (m, 3H, Ar-H), 7.48–7.53 (m, 3H, Ar-H), 7.57–7.59 (m, 2H, Ar-H), 10.51 (bs,1H, OH); 13C NMR (CDCl3, 100 MHz) δ: 87.8, 94.2, 113.1, 115.3,127.2, 129.1, 129.8, 130.7, 132.1, 133.5, 134.1, 135.8, 136.6,157.1, 161.8, 164.5, 168.2.; Anal. Calcd for C19H12N4OS : C,66.26; H, 3.5; N, 16.27%. Found: C, 66.52; H, 3.42; N, 16.08%.

2-Amino-4-(4-methylphenyl)-6-(4-methylphenylsulfanyl)-3,5-pyridinedicarbonitrile (4l)

Colorless solid; mp 222°C; IR (KBr) v: 3442, 3357, 3198,2211, 1616, 1572, 1533, 1481, 1252, cm−1; 1H NMR (CDCl3,400 MHz) δ: 2.41 (s, 3H, CH3), 2.11 (s, 3H, CH3), 5.44 (s, 2H,NH2), 7.25–7.36 (m, 4H, Ar-H), 7.41–7.59 (m, 4H, Ar-H); 13CNMR (CDCl3, 100 MHz) δ: 15.7, 17.1, 86.1, 96.3, 114.2, 115.5,126.6, 129.1, 129.2, 129.7, 130.1, 131.4, 131.8, 134.6, 135.2,136.1, 156.2, 158.9, 167.6.; Anal. Calcd for C21H16N4S : C, 70.76;H, 4.52;, 15.72%. Found: C, 70.52; H, 4.65; N, 15.84%.

2-Amino-4-(4-nitrophenyl)-6-(4-methylphenylsulfanyl)-3,5-pyridinedicarbonitrile (4n)

Yellow solid; mp 301°C; IR (KBr) v: 3472, 3332, 3218, 2215,1626, 1541, 1509, 13.44, 1262, cm−1; 1HNMR (CDCl3, 400MHz)

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Figure 1: SEM images of CaO NPs.

Figure 2: The XRD patern of CaO nanoparticles.

δ: 2.40 (s, 3H, CH3), 5.50 (s, 2H, NH2), 7.26–7.28 (d, J = 7.8 Hz,2H, Ar-H), 7.43–7.45 (d, J = 8 Hz, 2H, Ar-H), 7.66–7.68 (d, J =

7.8 Hz, 2H, Ar-H), 8.39-8.41 (d, J = 8 Hz, 2H, Ar-H); 13C NMR(CDCl3, 100 MHz) δ: 18.9, 86.8, 96.2, 115.1, 116.9, 125.3, 131.3,132.9, 134.1, 134.9, 135.5, 136.2, 137.3, 156.1, 158.2, 165.1.;Anal. Calcd for C20H13N5O2S : C, 62.01; H, 3.38; N, 18.08%.Found: C, 61.85; H, 3.26; N, 18.16%.

2-Amino-4-(4-cyanophenyl)-6-(4-methylphenylsulfanyl)-3,5-pyridinedicarbonitrile (4o)

White solid; mp 272 °C; IR (KBr) v: 3479, 3352, 3215, 2218,1634, 1551, 1498, 1256, cm−1 ; 1H NMR (CDCl3, 400 MHz) δ:2.41 (s, 3H, CH3), 5.50 (s, 2H, NH2), 7.28–7.30 (d, J = 8 Hz, 2H,Ar-H), 7.37–7.51 (m, 4H, Ar-H), 7.71–7.73 (d, J = 8 Hz, 2H, Ar-H); 13C NMR (CDCl3, 100MHz) δ: 87.2, 94.5, 114.9, 115.8, 128.1,130.5, 131.5, 133.8, 134.1, 134.4, 135.7, 136.5, 155.4, 156.3,165.1.; Anal. Calcd for C21H13N5S : C, 68.65; H, 3.57; N, 19.06%.Found: C: 68.78; H, 3.44; N, 18.95%.

3. Results and discussion

Initially, in order to investigate the morphology and particlesize of prepared CaO nanoparticles, a SEM image of CaO NPs ispresented in Figure 1. These results show that spherical calciumoxide nanoparticles were obtained with particle size 30–40 nmusing the thermal-decomposition method.

The XRD pattern of CaO nanoparticles has been shown inFigure 2. All reflection peaks in Figure 2 can be readily indexedto a pure cubic phase of CaO with a Fm-3m space group (JCDPSNo. 77-2376). The crystallite size diameter (D) of the CaO NPshas been calculated by the Debye–Scherrer equation (D =

Kλ/β cos θ), where β FWHM (full-width at half-maximum orhalf-width) is in radian and θ is the position of the maximumof the diffraction peak. K is the so-called shape factor, whichusually takes a value of about 0.9, and λ is the X-raywavelength(1.5406Å for CuKα). The average crystallite size of CaOhas beenfound to be 35 nm.

Figure 3: FT-IR spectrum of CaO nanoparticles.

Scheme 2: The model reaction for the preparation of poly functionalizedpyridines.

Figure 3 shows the FT-IR spectrum of CaO nanoparticles.The broad peak at 3431 cm−1 can be attributed to the ν(OH) stretching vibration. These peaks indicate the presence ofphysisorbed water linked to nanoparticles.

In continuation of this research, the reaction conditionswereoptimized on the basis of the catalyst, solvent and reactants forcarbon–carbon and carbon–heteroatombond formation. To testthe efficiency of the catalytic activity, we chose to focus ourinitial studies on the cyclization reaction of aldehydes, thiolsand malononitrile in the presence of different nanocatalystssuch as CuO, Mn3O4, MgO, NiO, SiO2, CaO and also in thepresence of regular CaO. Therefore, we run the model reactionusing benzaldehyde, thiophenol and malononitrile, by the useof each catalyst separately (Scheme 2).

As a result of these experiments, we found that CaO NPs isthe most effective catalyst, in comparison with other catalysts,in this cyclization reaction. The increased catalytic activity ofCaO nanoparticles over the commercially available bulk CaOis attributed to the higher surface area of nanomaterials. So,we run the model reaction using calcium oxide nanoparticles(Table 1), Also, the optimum ratio of the catalyst was 20 mol%CaO NPs, and increasing this amount did not a show significantchange in the yield and time of the reaction. Several reportsdealing with the role of the CaO NPs show highly effective

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Figure 4: Recoverability of CaO nanoparticles.

Table 1: Preparation of 2-Amino-4-phenyl-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile (4a) in different catalysts.a

Entrry Catalyst Time (min) Yields(%)b

1 CuO NPs 140 602 Mn3O4NPs 150 553 MgO NPs 130 704 NiO NPs 140 655 SiO2NPs 180 406 CaO NPs 100 857 CaO bulk 260 40

a 1 mmol of benzaldehyde, 2.2 mmol of malononitrile and 1 mmol ofthiophenol under reflux conditions.

b Isolated yields.

catalytic behavior, because of surface properties, includingacidity by Ca2+ and basicity by O2−, in which, the interactionof these ions with reactants leads to accelerating the reactionconditions.

The significant results of Table 1 are related to the reactivityof catalytic nanoparticles, which is largely determined by theenergy of surface atoms, and which can be easily gauged bythe number of neighboring atoms by the bonding modes andaccompanying energies of small molecules to be transformedon the nanoparticle surface.

During the optimization of reaction conditions, we run themodel reaction using CaO nanoparticles in various solvents.The results in Table 2 show that a mixture of water/ethanolis the most effective solvent for this multicomponent reaction.This is not surprising, in view of the fact that the hydrogen

Table 2: One-pot synthesis of 2-Amino-4-phenyl-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile (4a) in various solvents.a

Entrry Solvent Time (min) Yields(%)b

1 Toluene 240 352 Acetonitrile 180 503 Ethanol 120 704 Water 140 605 Water/Ethanol 100 85

a Reflux conditions.b Isolated yields.

bonding betweenwater/ethanol and substrate can promote thenucleophilic attack of the reactants.

In order to establish the optimum ratio of reactants, themodel reaction was carried out several times in the presenceof calcium oxide nanoparticles. The best results were obtainedwhen benzaldehyde, malononitrile and thiophenol were em-ployed as substrates in a 1:2.2:1 ratio. To study the scope ofthis procedure, we next used a diversity of aldehydes and thi-ols to investigate three component reactions under the op-timized conditions. We observed that electron-withdrawinggroups, such as NO2, Cl and Br, reacted with malononitrile verysmoothly in the beginning of the reaction, which resulted toproduce 2-amino-3,5-dicarbonitrile-6-thio-pyridines in shortreaction times. In addition, the reaction of sterically hinderedaldehydes was performed slowly in comparison with unhin-dered aldehydes. The results are summarized in Table 3.

3.1. Catalyst recovery

After completion of the process, the calcium oxide nanopar-ticles were separated by centrifuge, were then washed three tofour times with water and ethyl acetate and dried in an ovenovernight at 80 °C. The separated catalyst was used severaltimes with a slightly decreased activity, as shown in Figure 4.This slight reactivity is related to the trace solubility of calciumoxide in solvent.

The characterization of the CaO NPs, before and after reusethree times, showed the same particle size by the SEM image(Figure 5). Interestingly, the shape and size of the nanoparticlesalmost remained unchanged after recovery.

4. Conclusion

In summary, an efficient, facile and economical method forthe preparation of poly functionalized pyridine derivatives has

Figure 5: SEM images of CaO NPs after three times reuse.

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Table 3: One-pot synthesis of poly functionalized pyridines catalyzed by CaO nanoparticles.

Entry Ar Ar′ Product Time (min) Yield (%) mp (°C) Lit. mp (°C)

1 Ph Ph 4a 100 85 218–220 (220–221)29

2 m-MeC6H4 Ph 4b 120 85 277–279 (278–280)29

3 p-MeC6H4 Ph 4c 140 90 208–210 (206–207)324 m-HOC6H4 Ph 4d 130 80 265–267 –5 p-HOC6H4 Ph 4e 145 85 314–316 (315–317)32

6 p-MeOC6H4 Ph 4f 150 92 240–242 (241–244)29

7 m-O2NC6H4 Ph 4g 110 78 218–220 (219–220)29

8 p-O2NC6H4 Ph 4h 85 75 288–290 (289–290)32

9 p-ClC6H4 Ph 4i 80 80 221–223 (221–222)32

10 p-BrC6H4 Ph 4j 90 80 254–256 (255–257)29

11 Ph p-MeC6H4 4k 110 82 248–250 (246–249)3512 p-MeC6H4 p-MeC6H4 4l 115 80 222–224 –13 p-MeOC6H4 p-MeC6H4 4m 130 85 229–231 (230–233)3514 p-O2NC6H4 p-MeC6H4 4n 80 70 301–303 –15 p-NCC6H4 p-MeC6H4 4o 95 78 272–274 –

been developed using CaO NPs as a catalyst in green media.The products were obtained in excellent yields and the reactiontimes were significantly low. The present protocol representsa simple and remarkable method for the three-componentreactions of aldehydes, thiols and malononitrile, in orderto synthesize some 2-amino-3,5-dicyano-6-sulfanyl pyridinederivatives in the presence of novel nano-scale materials.

Acknowledgments

The authors are grateful to the University of Kashan forsupporting this work with Grant No: 159196/X.

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Javad Safaei-Ghomi received a B.S. degree in Chemistry from the University ofKashan, Iran, in 1985, a M.S. degree in Organic Chemistry from the Universityof Mazandaran, Babolsar, Iran, in 1988, and a Ph.D. degree in Organic Chemistryfrom the University of Wollongong, Australia, in 1995. He is currently Professorin the Department of Organic Chemistry at the University of Kashan, wherehe is Head of the International Science Cooperation Office. His researchinterests lie in: asymmetric synthesis of amino acids, extraction of essential oils,antioxidant and antibacterial activity of the extracts and using nanoparticles inmulticomponent reactions.

Mohammad Ali Ghasemzadeh received B.S., M.S. and Ph.D. degrees inChemistry and Organic Chemistry from the University of Kashan, Iran, in 2005,2008 and 2012, respectively. His research interests lie in nanoscience andnanotechnology, application of nanoparticles as catalyst in multi-componentreactions and ionic liquids in organic synthesis.

Mohsen Mehrabi received a B.S. degree in Physics from the University ofYasooj, Iran, in 2007, a M.S. degree in Nanotechnology and Nanosciencefrom the University of Kashan, Iran, in 2010, and is now a Ph.D. studentin Laser Physics at Amirkabir University of Technology, Tehran, Iran. He iscurrently a Lecturer at the Institute of Nanoscience and Nanotechnologyin the University of Kashan. His research interests lie in: nanoparticles(synthesis and characterization) nanophotonic (thermo luminescence andphoto luminescence) and nanostructure solar cells.