Zinc oxide nanoparticle promoted highly efficient one ...

Arabian Journal of Chemistry (2013) xxx, xxx–xxx

King Saud University

Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Zinc oxide nanoparticle promoted highly efficient one pot three-component synthesis of 2,3-disubstituted benzofurans Javad Safaei-Ghomi *, Mohammad Ali Ghasemzadeh

*

Department of Chemistry, Qom Branch, Islamic Azad University, Qom, Islamic Republic of Iran Received 29 March 2012; accepted 27 June 2013

KEYWORDS ZnO nanoparticles; Multi-component reactions; Heterogeneous catalyst; Benzofurans; One-pot

Abstract A convenient one-pot synthesis of 2,3-disubstituted benzo[b]furan derivatives has been developed using zinc oxide nanoparticles. The present approach provides a novel, effective and improved procedure for the three-component coupling of aldehydes, secondary amines and alkyne with several advantages such as short reaction times, high yields and little catalyst loading. ZnO nanoparticles are cheap, stable and can be easily recovered for several circles with consistent activity. Characterization and structural elucidation of the products have been done on the basis of chemical, analytical and spectral analyses. ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University.

1. Introduction In recent years, significant attention has been paid to the synthesis of benzofurans because of their highly noticeable biological and physiological activities. Benzo[b]furans and their derivatives are of interest, because of their frequent occurrence in nature and their broad range of biological and potential therapeutic applications (Simpson and Thomson, 1985), which not only act as key structural subunits in naturally occurring * Corresponding authors. Tel.: +98 361 5912385; fax: +98 361 5912397. E-mail addresses: [email protected] (J. Safaei-Ghomi), [email protected] (M.A. Ghasemzadeh). Peer review under responsibility of King Saud University.

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compounds that exhibit remarkable medicinal properties but also represent useful building blocks in the synthesis of natural products (Lipshuts, 1986). Derivatives of these compounds are known to possess important pharmaceutical (Buu-Hoi et al., 1957), antifungal (Gundogdu-Karaburun et al., 2006), antitumor (Baraldi et al., 2000) and other bioorganic properties (Li et al., 2005). In addition, benzofurans are used in cosmetic formulations (Leung and Foster, 1996) and have the application as synthetic precursors of optical brighteners (Elvers et al., 1999). Therefore, many considerations have been given to the development of new methodologies for the preparation of benzofurans. The synthetic pathways for the preparation of benzofurans mainly are dehydrative annulations of phenols bearing appropriate ortho vinyllic substituent (Thielges et al., 2004), intramolecular cyclization of substituted allyl–aryl ethers (Hennings and Iwasa, 1997), [3,3]-sigmatropic rearrangement of various arenes (Takeda et al., 2007), dehydrative cyclization of a-(phenoxy)-alkyl ketones (Wright, 1960), cyclization reaction of 2-hydroxybenzaldehydes, amines and

1878-5352 ª 2013 Production and hosting by Elsevier B.V. on behalf of King Saud University. http://dx.doi.org/10.1016/j.arabjc.2013.06.030

Please cite this article in press as: Safaei-Ghomi, J., Ghasemzadeh, M.A. Zinc oxide nanoparticle promoted highly efficient one pot threecomponent synthesis of 2,3-disubstituted benzofurans. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.030

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J. Safaei-Ghomi, M.A. Ghasemzadeh

alkynes using copper catalysts (Zhang et al., 2011; Hongfeng et al., 2009; Sakai et al., 2008), Sonogashira cross-coupling reaction of 2-iodonitrophenol acetates (Dai and Lai, 2002) and coupling of o-iodophenols and aryl acetylenes (Jaseer et al., 2010). Consequently, synthesis of benzofuran derivatives with the aim to develop new drug molecules has been an active area of research. Multi-component reactions (MCRs) are particular types of synthetically valuable organic reactions in which three or more different starting materials react to afford a final product in a one-pot process (Weber, 2002). The formation of carbon–carbon and carbon–heteroatom bonds by MCRs is known in multitudinous compounds that are of pharmaceutical, biological and material interest (Negwar, 1994). Recent advances in nanoscience and nanotechnology have led to a new research interest in using nanometer-sized particles as an alternative matrix for catalytic reactions (MorenoManas and Pleixats, 2003). Several reports showed a surprising level of the performance of nanoparticles as catalyst in terms of reactivity, selectivity and improved yields of products (Min et al., 2008). Recently ZnO nanoparticles (ZnO NPs) have been used as an efficient heterogeneous catalyst for several organic transformations (Altavilla and Ciliberto, 2011; Lockwood, 2007). Nanocrystalline zinc oxide has gained significant attention as a photocatalyst for the refine of organic pollutants in water and air due to its benefits in non-toxic nature, inexpensive and high reactivity (Driessen, 1998). In addition ZnO nanoparticles are one of the extensively used surface materials for different chemical transformations in chemistry such as gas sensors (Zhang et al., 2005), photocatalyst (Amapoorani et al., 1997), solar cells (Matsubara et al., 2003), luminescent material (Zang et al., 2002) and antibacterial material (Sanches et al., 1996). In the last decade zinc oxide NPs were used as an active catalyst in many reactions such as the Mannich reaction (MaGee et al., 2011), synthesis of coumarins (Kumar et al., 2011), synthesis of b-phosphono malonates (Sarvari and Etemad, 2008), Knoevenagel condensation (Sarvari et al., 2008), synthesis of benzimidazole (Alinezhad et al., 2012), synthesis of b-acetamido ketones/esters (Mirjafary et al., 2008), synthesis of 4-amino-5-pyrimidinecarbonitriles (Hekmatshoar et al., 2010), synthesis of polyhydroquinoline (Kassaee et al., 2010) and synthesis of 2,3-disubstituted quinalolin-4(1H)-ones (Yavari and Beheshti, 2011). In accordance with the significance of carbon–carbon and carbon–heteroatom bond formation, different synthetic methods have been developed for the construction of fused heterocycles. Herein we have researched for three-component coupling of aldehydes, amines and alkyne in the presence of ZnO nanoparticles to the synthesis of benzo[b]furan derivatives (Scheme 1). In the view of recent interest in the use of heterogeneous catalysis we have developed ZnO NPs as a

recyclable, easy to handle, inexpensive, non-volatile, nonexplosive and eco-friendly catalyst which can be used in the catalysis of many organic transformations. 2. Experimental 2.1. Material and methods Chemicals were purchased from Sigma–Aldrich and Merck in high purity. Zinc oxide nanoparticles were prepared according to the procedures reported by Shen et al., 2006. Flash-column chromatography was performed by using Merck silica gel 60 with freshly distilled solvents. All melting points are uncorrected and were determined in a capillary tube on Boetius melting point microscope. 1H, 13C NMR spectra were obtained on Bruker 400 MHz spectrometer with CDCl3 as solvent using tetramethylsilane (TMS) as an internal standard, the chemical shift values are in d ppm. FT-IR spectrum was recorded on Magna-IR, spectrometer 550 Nicolet in KBr (disks) in the range of 400–4000 cm 1. The elemental analyses (C, H and N) were obtained from a Carlo ERBA Model EA 1108 analyzer. Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer of X’pert company with mono chromatized Cu Ka radiation (k = 1.5406 A˚). Microscopic morphology of products was visualized by scanning electron microscopy (SEM) (LEO 1455VP). 2.2. Preparation of zinc oxide nanoparticles In a typical procedure, zinc acetate (9.10 g, 0.05 mol) and oxalic acid (5.4 g, 0.06 mol) were combined by grinding in an agate mortar for 1 h at room temperature. Afterward, the formed ZnC2O4.2H2O nanoparticles were calcinated at 450 C for 30 min to produce ZnO nanoparticles under thermal decomposition conditions. The prepared ZnO NPs have been structurally characterized by SEM and XRD analyses. In order to study the morphology and particle size of ZnO nanoparticles, SEM image of ZnO nanoparticles is presented in Fig. 1. This result shows that spherical ZnO NPs were gained from Zn(CH3COO)2 and H2C2O4.2H2O with a particle size of 20–30 nm under solution-free mechanochemical conditions. The XRD pattern of ZnO nanoparticles is shown in Fig. 2. All reflection peaks in Fig. 2 can be easily indexed to pure hexagonal phase of ZnO with the P63mc group (JCDPS No. 36– 1451). The crystallite size diameter (D) of the ZnO nanoparticles has been calculated by the Debye–Scherrer equation (D = Kk/bcosh), where b FWHM (full-width at half-maximum or half-width) is in radians and h is the position of the maximum of diffraction peak, K is the so-called shape factor, which usually takes a value of about 0.9, and k is the X-ray

R1

CHO OH +

X 1 a- l

Scheme 1

R1

N H

2 a-c

R2

N R2

X

Ph

ZnO nanoparticles

+

Reflux 3

O 4 a- l

One-pot synthesis of benzo[b]furans catalyzed by ZnO nanoparticles.

Please cite this article in press as: Safaei-Ghomi, J., Ghasemzadeh, M.A. Zinc oxide nanoparticle promoted highly efficient one pot threecomponent synthesis of 2,3-disubstituted benzofurans. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.030

Zinc oxide nanoparticle promoted highly efficient one pot three-component synthesis of 2,3-disubstituted benzofurans

Figure 1

Figure 2

3

SEM images of ZnO nanoparticles.

The XRD pattern of ZnO nanoparticles.

wavelength (1.5406 A˚ for Cu Ka). Crystallite size of ZnO has been found to be 24 nm.

2.4. Spectral data of products 2.4.1. 4-(2-Benzylbenzofuran-3-yl)morpholine (4a)

2.3. General procedure for the synthesis of 2,3-disubstituted benzo[b]furan (4a-l) To a stirred solution of the salicylaldehyde derivatives (2.0 mmol), secondaryamines (1.0 mmol) and phenylacetylene (1.5 mmol) in water (5.0 mL) and ethanol (5.0 mL), were added ZnO NPs (0.015 g, 0.2 mmol, 20% mol), K2CO3 (0.13 g, 1.0 mmol) and Cu(OTf)2 (0.36 g, 1.0 mmol) at room temperature. Then the resulting mixture was refluxed for about 1–2 h. The reaction was continuously monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and then was centrifuged to separate the catalyst. The nanoparticles were first washed with water to remove some of the K2CO3 and Cu(OTf)2, then several times with chloroform and dried in an oven overnight at 150 C. Afterward the solution was extracted by using ethyl acetate (2 · 10 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated in vacuum to give the crude product. After removal of the solvent, the residue was purified by column chromatography on silica gel using hexane–ethyl acetate (15:1) as eluent to afford pure corresponding benzo[b]furan derivatives. All the products were identified with mp, 1H NMR, 13C NMR and FT-IR spectroscopy techniques.

Yellow solid. mp = 106–108 C; 1H NMR (CDCl3, 400 MHz) d: 3.19 (t, J = 4.5 Hz, 4H, 2 CH2-N), 3.87 (t, J = 4.5 Hz, 4H, 2 CH2-O), 4.20 (s, 2H, CH2), 7.19–7.34 (m, 7H, ArH), 7.40– 7.42 (d, J = 8 Hz, 1H, ArH),7.69–7.71 (d, J = 8 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 31.4, 51.7, 67.0, 112.7, 114.7, 121.5, 125.6, 126.3, 127.6, 127.8, 128.0, 128.2, 137.1, 150.8, 152.1; IR (KBr) v: 3033, 2921, 2853, 1603, 1445, 1262 cm 1. 2.4.2. 4-(2-Benzylbenzofuran-3-yl)piperidine (4b) Yellow solid. mp = 73–75 C; 1H NMR (CDCl3, 400 MHz) d: 1.60–1.63 (m, 2H, CH2) 1.70 (m, J = 4.8 Hz, 4H, 2 CH2), 3.14 (t, J = 4.8 Hz, 4H, 2 CH2-N), 4.18 (s, 2H, CH2), 7.14–7.33 (m, 7H, ArH), 7.35–7.37 (d, J = 8 Hz, 1H, ArH), 7.66–7.68 (d, J = 8 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 23.6, 25.7, 30.7, 52.1, 115.9, 118.9, 126.0, 126.6, 127.4, 128.1, 128.9, 130.1, 131.3, 137.1, 142.5, 151.2; IR (KBr) v: 3031, 2922, 2850, 1603, 1461 cm 1. 2.4.3. N,N-dibenzyl-(2-benzylbenzofuran-3-yl)amine (4c) Yellow oil. 1H NMR (CDCl3, 400 MHz) d: 3.78 (s, 2H, CH2), 4.34 (s, 4H, 2 CH2), 6.90–7.77 (m, 19H, ArH); 13C NMR (CDCl3, 100 MHz) d: 31.1, 58.0, 109.6, 111.0, 111.9, 115.6, 118.4, 125.9, 126.1, 127.0, 127.8, 128.1, 128.5, 128.8, 135.5 m 137.2, 142.5, 156.1; IR (KBr) v: 3038, 2924, 2851, 1606, 1442 cm 1.

Please cite this article in press as: Safaei-Ghomi, J., Ghasemzadeh, M.A. Zinc oxide nanoparticle promoted highly efficient one pot threecomponent synthesis of 2,3-disubstituted benzofurans. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.030

4

J. Safaei-Ghomi, M.A. Ghasemzadeh O CHO

+ 1a

N H

Ph

ZnO NPs

+

O

Reflux, 1.5 h 4a

3

2a

Scheme 2 Table 1

N

O

OH

Model reaction for the preparation of benzo[b]furans.

Optimization for the synthesis of benzo[b]furan 4a by various catalysts.

Entry

Catalyst

Time (h)

Yieldsa

1 2 3 4 5 6

None MgO CuO Fe3O4 ZnO ZnO NPs

8 5 4.5 3 2.5 1.5

None 25 40 60 70 92

a

Isolated yields.

2.4.4. 4-(2-Benzyl-5-bromobenzofuran-3-yl)morpholine (4d) 1

Yellow solid. mp = 110–111 C; H NMR (CDCl3, 400 MHz) d: 3.14 (t, J = 5 Hz, 4H, 2 CH2-N), 3.85 (t, J = 5 Hz, 4H, 2 CH2-O), 4.16 (s, 2H, CH2), 7.21–7.53 (m, 8H, ArH), 7.79 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 32.3, 52.4, 67.6, 113.1, 115.2, 122.4, 126.3, 126.6, 128.0, 128.2, 128.5, 128.6, 137.3, 151.7, 152.2; IR (KBr) v: 3033, 2923, 2852, 1601, 1448, 1260 cm 1. 2.4.5. 4-(2-Benzyl-5-bromobenzofuran-3-yl)piperidine (4e) Yellow solid. mp = 86–87 C; 1H NMR (CDCl3, 400 MHz) d: 1.43–1.47(m, 2H, CH2) 1.61 (m, J = 4.8 Hz, 4H, 2 CH2), 3.10 (t, J = 4.8 Hz, 4H, 2 CH2-N), 4.15 (s, 2H, CH2), 7.22–7.72 (m, 7H, ArH), 7.77 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 23.7, 27.0, 31.9, 52.3, 115.9, 118.9, 126.0, 126.6, 127.4, 128.1, 128.9, 130.1, 131.3, 137.1, 142.5, 151.2; IR (KBr) v: 3028, 2918, 2848, 1606, 1459 cm 1. 2.4.6. N,N-Dibenzyl-(2-benzyl-5-bromobenzofuran-3-yl)amine (4f) Yellow oil. 1H NMR (CDCl3, 400 MHz) d: 3.68 (s, 2H, CH2), 4.24 (s, 4H, 2 CH2), 6.82 (s. 2H, ArH), 6.84–7.25 (m, 14H, ArH), 7.76 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) d: 31.0, 58.1, 111.0, 111.9, 112.1, 115.7, 119.2, 125.9, 126.2, 126.9, 128.1, 128.4, 128.6, 130.1, 135.0, 137.1, 143.5, 157.1; IR (KBr) v: 3038, 2924, 2851, 1606, 1442 cm 1. 2.4.7. 4-(2-Benzyl-5-chlorobenzofuran-3-yl)morpholine (4g) Yellow solid. mp = 110–111 C; 1H NMR (CDCl3, 400 MHz) d: 3.12 (t, J = 4.5 Hz, 4H, 2 CH2-N), 3.78 (t, J = 4.5 Hz, 4H, 2 CH2-O), 4.18 (s, 2H, CH2), 7.21–7.53 (m, 8H, ArH), 7.89 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 32.0, 51.1, 66.7, 112.8, 115.5, 124.1, 126.1, 126.6, 127.8, 128.3, 129.0, 129.2, 137.5, 151.1, 152.3; IR (KBr) v: 3033, 2920, 2855, 1604, 1446, 1258 cm 1.

3.14–3.16 (t, J = 5 Hz, 4H, 2 CH2-N), 4.19 (s, 2H, CH2), 7.17– 8.14 (m, 7H, ArH), 8.54 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 21.9, 26.7, 31.0, 51.3, 111.8, 117.5, 119.1, 124.1, 127.0, 128.0, 129.5, 129.9, 132.1, 139.2, 141.9, 153.2; IR (KBr) v: 3028, 2918, 2848, 1606, 1459 cm 1. 2.4.9. N,N-Dibenzyl-(2-benzyl-5-chlorobenzofuran-3-yl)amine (4i) Yellow oil. 1H NMR (CDCl3, 400 MHz) d: 3.97 (s, 2H, CH2), 4.35 (s, 4H, 2 CH2), 6.92–8.00 (m, 18H, ArH); 13C NMR (CDCl3, 100 MHz) d: 30.3, 57.7, 111.1, 112.1, 112.19, 114.2, 118.5, 126.0, 126.6, 126.9, 127.6, 128.4, 129.1, 130.8, 133.9, 136.8, 144.1, 156.9; IR (KBr) v: 3035, 2921, 2847, 1601, 1446 cm 1. 2.4.10. 4-(2-Benzyl-5-nitrobenzofuran-3-yl)morpholine (4j) Yellow solid. mp = 118–120 C; 1H NMR (CDCl3, 400 MHz) d: 3.19 (t, J = 4.8 Hz, 4H, 2 CH2-N), 3.87 (t, J = 4.8 Hz, 4H, 2 CH2-O), 4.21 (s, 2H, CH2), 7.27–7.35 (m, 5H, ArH), 7.43– 7.45 (d, J = 10 Hz, 1H, ArH), 8.14–8.17 (d, J = 10 Hz, 1H, ArH), 8.57 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 32.5, 53.1, 68.5, 113.1, 114.6, 122.7, 125.1, 126.5, 127.1, 127.3, 128.1, 128.3, 138.8, 150.7, 151.1; IR (KBr) v: 3025, 2935, 2848, 1626, 1522, 1447, 1337 cm 1. 2.4.11. 4-(2-Benzyl-5-nitrobenzofuran-3-yl)piperidine (4k) Yellow solid. mp = 106–108 C; 1H NMR (CDCl3, 400 MHz) d: 1.53–1.64 (m, 2H, CH2) 1.74–1.77 (m, J = 5 Hz, 4H, 2 CH2), 3.13–3.16 (t, J = 5 Hz, 4H, 2 CH2-N), 4.19 (s, 2H, CH2), 7.23–7.55 (m, 6H, ArH), 8.11–8.13 (d, 1H, ArH), 8.54 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d: 24.1, 26.7, 32.6, 53.7, 111.7, 116.5, 119.3, 126.7, 128.4, 128.5, 129.2, 132.5, 137.5, 143.3, 152.3, 156.3; IR (KBr) v: 3028, 2958, 2851, 1588, 1524, 1341, 1268 cm 1.

2.4.8. 4-(2-Benzyl-5-chlorobenzofuran-3-yl)piperidine (4h)

2.4.12. N,N-Dibenzyl-(2-benzyl-5-nitrobenzofuran-3-yl)amine (4l)

Yellow solid. mp = 75–78 C; 1H NMR (CDCl3, 400 MHz) d: 1.41–1.63 (m, 2H, CH2) 1.64–1.75 (m, J = 5 Hz, 4H, 2 CH2),

Yellow oil. 1H NMR (CDCl3, 400 MHz) d: 3.68 (s, 2H, CH2), 4.24 (s, 4H, 2 CH2), 6.82 (s. 2H, ArH), 6.84–7.25 (m, 14H,

Please cite this article in press as: Safaei-Ghomi, J., Ghasemzadeh, M.A. Zinc oxide nanoparticle promoted highly efficient one pot threecomponent synthesis of 2,3-disubstituted benzofurans. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.030

Zinc oxide nanoparticle promoted highly efficient one pot three-component synthesis of 2,3-disubstituted benzofurans Table 2

Optimization for the synthesis of benzo[b]furan 4a in various solventsa.

Entry

Solvent

Time (h)

Yieldsb (%)

1 2 3 4 5 6

DMF CH3CN Water THF EtOH Water/EtOH

5.5 4 2.5 4 2 1.5

30 45 70 55 80 92

a b

All the reactions were carried out under reflux conditions using ZnO NPs as catalyst. Isolated yields.

Table 3

ZnO nanoparticle catalyzed synthesis of 2,3-disubstituted benzofuransa.

Entry

Aldehyde (x)

R1R2NH

Product

Time (min)

Yields (%)

mp, C

Refs.

1 2 3 4 5 6 7 8 9 10 11 12

H H H Br Br Br Cl Cl Cl NO2 NO2 NO2

Morpholine Piperidine Dibenzyl Morpholine Piperidine Dibenzyl Morpholine Piperidine Dibenzyl Morpholine Piperidine Dibenzyl

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l

90 90 110 70 75 90 60 65 80 55 55 65

92 90 80 94 94 85 92 94 85 96 94 88

105–108 74–75 Oilb 109–111 87–88 Oilb 110–111 75–77 Oilb 119–120 106–108 Oilb

Hongfeng et al. (2009) Hongfeng et al. (2009) Hongfeng et al. (2009) Hongfeng et al. (2009) Sakai et al. (2008) Zhang et al. (2011) Zhang et al. (2011) Zhang et al. (2011) Zhang et al. (2011) Hongfeng et al. (2009) Sakai et al. (2008) –

a b

5

All reactions were carried out in the presence of phenylacetylene as alkyne substrate. The product was obtained in viscose form.

ArH), 7.76 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) d: 31.0, 58.1, 111.0, 111.9, 112.1, 115.7, 119.2, 125.9, 126.2, 126.9, 128.1, 128.4, 128.6, 130.1, 135.0, 137.1, 143.5, 157.1; IR (KBr) v: 3038, 2924, 2851, 1606, 1442 cm 1; Anal. Calcd. for C29H24N2O3: C, 77.66; H, 5.39; N, 6.25. Found C, 77.85; H, 5.24; N, 6.14. 3. Results and discussion To optimize the reaction conditions, the reaction of salicylaldehyde (1a), morpholine (2a) and phenylacetylene (3) was carried out as model reaction (Scheme 2). This reaction was optimized on the basis of the catalyst, solvent and reactants under reflux conditions for carbon–carbon and carbon–heteroatom bond formations. To examine the influence of the catalytic activity, we choose to focus our primary studies on the coupling reaction of mentioned substrates in the presence of diverse catalysts such as CuO, MgO, Fe3O4 and ZnO in this cyclization reaction. As a result of these experiments we found that ZnO is the most effective catalyst for this condensation reaction. When the reaction was conducted in the absence of catalyst no product was formed. Therefore, in continuation of this work we run the model reaction by use of zinc oxide nanoparticles. Result of Table 1 shows ZnO NPs produce excellent yields in shorter reaction times compared to bulk ZnO. The effective activity of zinc oxide nanoparticles is related to high surface area of nanomaterials over the bulk zinc oxide. During optimization of reaction conditions, we run the model reaction using ZnO nanoparticle in different solvents.

As shown in Table 2, a mixture of water/ethanol is the most effective solvent for this multi-component reaction. This is not amazing in view of the fact that the hydrogen bonding between water/ethanol and substrate can prompt the nucleophilic attack of the reactants. In order to fix the optimum ratio of reactants, the model reaction was performed several times in the presence of various amounts of substrates. The best result was obtained when salicylaldehydes, amines and phenylacetylene were employed as reactants in 2:1:1.5 ratios. To research the scope of this process, we used a variety of salicylaldehydes and amines to study this three-component reaction under the optimal conditions (Scheme 1 and Table 3). We found that, the electron-withdrawing groups in salicylaldehyde derivatives, such as NO2 and Cl reacted very smoothly and shorter time reaction with high yields was obtained. In this research aliphatic alkynes such as 1-octyne and 1-heptyne could not produce the corresponding benzo[b]furans even after 8 h. In addition, different types of secondary amines were examined. Either aliphatic amines (morpholine and piperidine) or aromatic ones such as dibenzylamine were capable of creating 2,3-disubstituted benzofurans. During the experiment we considered those primary amines such as PhNH2 that could not produce the desired benzo[b]furans. 3.1. Proposed mechanism A possible mechanism for the synthesis of benzo[b]furan derivatives on the basis of our experimental results together with some literatures is shown in Scheme 3. We suppose ZnO

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6

J. Safaei-Ghomi, M.A. Ghasemzadeh

Scheme 3

Proposed reaction pathway for the ZnO nanoparticle catalysis.

NPs generate a zinc acetylide intermediate from alkyne, which this intermediate is able to attach to iminium ion that is prepared in situ by the reaction between salicylaldehyde and amine. Cu(OTf)2 has a dual role: (i) it behaves as a Lewis acid and (ii) activation of triple bond to promote cyclization reaction via nucleophilic attack by the hydroxy group. Ultimately compound 4 was obtained and the ZnO nanoparticles being released for more reactions. 3.2. Catalyst recovery After completion of the process, the zinc oxide nanoparticles were separated by centrifuge and then ZnO NPs were washed three to four times with chloroform and methanol and dried at

100 C for 5 h. The separated catalyst was used several times with a slightly decreased activity as shown in Fig. 3. 4. Conclusion In conclusion an efficient and mild method for the synthesis of poly functionalized benzo[b]furan derivatives has been developed using ZnO nanoparticles as a catalyst. The products were obtained in excellent yields and the reaction times were significant low. The present approach demonstrates a simple and appropriate method for the three-component coupling of aldehydes, amines and alkyne in order to synthesize some 2,3disubstituted benzofurans in the presence of zinc oxide nanoparticles.

100

Acknowledgements

Yield(%)

80

The authors gratefully acknowledge the financial support of this work by the Research Affairs Office of the Islamic Azad University, Qom Branch, Qom, I. R. Iran.

60 40

References

20 0 1

2

3

4

5

6

Run

Figure 3

Recoverability of ZnO nanoparticles.

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Please cite this article in press as: Safaei-Ghomi, J., Ghasemzadeh, M.A. Zinc oxide nanoparticle promoted highly efficient one pot threecomponent synthesis of 2,3-disubstituted benzofurans. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2013.06.030