9230 Chem. Commun., 2011, 47, 9230–9232 This journal is c The Royal Society of Chemistry 2011

Cite this: Chem. Commun., 2011, 47, 9230–9232

Hantzsch reaction on free nano-Fe2O3 catalyst: excellent reactivity

combined with facile catalyst recovery and recyclabilityw

Nadiya Koukabi,aEskandar Kolvari,*

bArdeshir Khazaei,*

aMohammad Ali Zolfigol,*

a

Behzad Shirmardi-Shaghasemicand Hamid Reza Khavasi

d

Received 7th May 2011, Accepted 27th June 2011

DOI: 10.1039/c1cc12693h

A magnetic nanoparticle catalyst was readily prepared from

inexpensive starting materials which catalyzed the Hantzsch

reaction. High catalytic activity and ease of recovery from the

reaction mixture using an external magnet, and several reuse

times without significant losses in performance are additional

eco-friendly attributes of this catalytic system.

Transition-metal catalyzed organic reactions are often con-

sidered to follow the principles of ‘‘Green Chemistry’’;

i.e. these catalyzed reactions consume a minimum of energy

and reagents or auxiliaries and minimize waste. Nanocatalysts

are considered to be a bridge between homogeneous and hetero-

geneous catalysis.1 With the development of nanochemistry it

has been possible to prepare ‘‘soluble’’ analogous of hetero-

geneous catalysts, materials that might have properties inter-

mediate between those of bulk and single particles due to high

surface areas and high densities of active sites.2 Unfortunately,

unsupported nanoparticles are usually unstable and the

coagulation of the nanoparticles during reaction is frequently

unavoidable.3 Thus, till now, the investigation of ‘‘free’’

nanoparticles as catalysts has been rare, although it is

an important tool to gain a fundamental understanding of

catalysis.4,5 Clearly, the development of ‘‘free’’ nanoparticles

with tunable catalytic activity is of great significance for both

academia and industry. However, the recycle problem must be

addressed before nanocatalytic processes can be scaled-up, due

to the fact that nanoparticles, which include nano-scaled metal

catalysts and supports, are difficult to separate from the

reaction mixture, which can lead to the blocking of filters

and valves by the nanoparticle catalyst. Currently, a method used

to address this problem is the use of magnetic nanoparticles,

a route that has attracted wide research interest for its unique

physical properties.6 They possess advantage of being

magnetically recoverable, thereby eliminating the requirement

for either solvent swelling before or catalyst filtration after

the reaction.7–9 In comparison with other transition metals

extensively used, iron-based catalysts are cheap, non-toxic,

environmentally friendly and abundant. In the past decades,

various iron salts have been applied as Lewis acids (Fe3+) in

homogeneous catalysis and different catalytically active iron

complexes were also reported.10 In heterogeneous catalysis,

iron oxides have been frequently used as catalysts and

supports in bulk industrial processes, usually at high temperature

(4300 1C) and pressure.11,12 At the onset of this study, no

example of the iron oxide nanoparticle had been reported for

the multicomponent reaction. Multicomponent reactions13

allow the creation of several bonds in a single operation and

are attracting increasing attention as one of the most powerful

emerging synthetic tools for the creation of molecular diversity

and complexity.14 In recent years, much attention has been

focused on the synthesis of 1,4-dihydropyridine compounds,

due to their significant biological activity.15–18 We were, thus,

intrigued by the possibility of applying nanotechnology to the

design of a novel, active, recyclable, and magnetically recoverable

‘‘free’’ nano-iron oxide as a Lewis-acid catalyst for the synthesis

of 1,4-dihydropyridine compounds under mild reaction conditions

for the first time.

For initial optimization of the reaction conditions and the

identification of the best iron source, temperature, and amount

of the catalyst, benzaldehyde 1, ethyl acetoacetate 2a and

ammonium acetate 3 were chosen as model substrates (Scheme 1).

By screening a wide range of iron sources, we found that the

product 4a could be obtained in yields ranging from 51 to 95% in

any oxidation state of iron salt (0, II, III; Table 1). As expected,

bulk Fe2O3 displayed only low activity (Table 1, entry 2). Next, we

Scheme 1 Synthesis of Hantzsch 1,4-dihydropyridines catalyzed by

‘‘free’’ nano-g-Fe2O3.

a Faculty of Chemistry, Bu-Ali Sina University,Hamedan 6517838683, Iran. E-mail: zolfi@basu.ac.ir,Khzaei_1326@yahoo.com; Fax: +988118257407

bDepartment of Chemistry, Faculty of Science Semnan University,Semnan, Iran. E-mail: kolvari@semnan.ac.ir; Fax: +982313354082

cDepartment of Chemistry, Payam Noor University, Hamedan, IrandDepartment of Chemistry, Shahid Beheshti University, Tehran, Iranw Electronic supplementary information (ESI) available: Generalexperimental details for starting materials and instruments, catalysismeasurement: XRD pattern, and XPS spectra and also elementalanalysis, spectral data of all compounds and literature references forknown compounds. CCDC 823102. For ESI and crystallographic datain CIF or other electronic format see DOI: 10.1039/c1cc12693h

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This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 9230–9232 9231

studied nanoparticle-sized Fe2O319 because of its super-

paramagnetic property,20 hence recovery and recycling of the

catalyst could be easily achieved. In the presence of nano-

Fe2O3, in which the majority of the particles is 14 nm in size

(Fig. 1a) the conversion reached 95% (Table 1, entry 5). The

corresponding catalytic activity is higher than the corresponding

bulk Fe2O3.

The crystal structure of the iron oxide g-Fe2O3 is reported as an

inverse spinel structure (Scheme 2),19,21,22 in which all the iron

cations are in the trivalent state, and the charge neutrality of the

cell is guaranteed by the presence of cation vacancies. The unit cell

of maghemite can be represented as (Fe3+)8[Fe3+

5/6&1/6]16O32,

where the brackets (), [] and & designate tetrahedral, octahedral

and vacant sites, respectively.23

X-Ray diffraction (XRD) powder patterns confirm that

bulk and nano-Fe2O3 have the same crystal strucure.24 From

the binding energies derived from X-ray photoelectron spectro-

scopy (XPS), it is clear that the surface iron ions are trivalent in

both samples.25

The reason for the improved activity of nano-iron oxide

most probably originates from the nanometre size of the bulk

iron oxide. In general, nanoscale heterogeneous catalysts

should offer higher surface areas, low-coordinated sites, and

surface vacancies, which are responsible for the higher catalytic

activity.26 Theoretically, it can be assumed that with a decrease

of the particle size down to a ‘‘molecular’’ level, the nanocatalyst

behaves as a homogeneous system in which the catalytic

activity is not controlled by the surface area of the catalyst

but rather governed by the concentration.27 The most important

significance of these results is that ‘‘free’’ nano-Fe2O3, but not

immobilized nano-Fe2O3, is highly active, selective, and stable

by merely controlling the particle size. Variation of the

amount of catalyst (0.15 mmol) and temperature (90 1C)

revealed an increased conversion of reactants and a product

yield of 98%. In summary, the optimal conditions for the

‘‘free’’ nano-Fe2O3 catalyzed Hantzsch reaction involved a

combination of nano-Fe2O3 (0.15 mmol), benzaldehyde 1a

(1 mmol), ethyl acetoacetate 2a (2 mmol), ammonium acetate

3 (1.5 mmol) at 90 1C under solvent-free conditions. In view

of these results, we then selected the optimized reaction

conditions to determine the scope of this ‘‘free’’ nano-Fe2O3

catalyzed reaction. A wide range of aromatic, aliphatic and

heteroaromatic aldehydes were subjected to react with 2a, 2b

in the presence of ammonium acetate 3 and 0.15 mmol of

nano-Fe2O3 to generate 4, 528 (Scheme 1) and the results are

summarized in Table 2. The aryl group substituted with

different groups and same groups located at different positions

of the aromatic ring does not show much effect on the

formation of the final product and afford the expected

products 4, 5 in good to high yields. The products were

characterized by IR, 1H NMR and 13CNMR spectroscopy,

and also by comparison with authentic samples. Product 4g

was structurally determined by X-ray single crystal diffraction

(see ESIw). This superparamagnetic property of nano-Fe2O3

made the isolation and reuse of this catalyst very easy. After

completion of the reaction, the mixture was triturated

with ethyl acetate. In the presence of a magnetic stirrer bar,

nano-Fe2O3 moved onto the stirrer bar steadily and the

reaction mixture turned clear within 10 s. The catalyst can

be isolated by simple decantation (see ESIw). After being

washed with acetone and dried in air, the nano-Fe2O3 can be

directly reused without any deactivation even after five rounds

of synthesis of product 4a (Table 3).

The characterization of the nano-Fe2O3 before and after

reuse five times showed the same particle size by transmission

electron microscopy (TEM; Fig. 1b) and the same crystal

structure by XRD. The only difference is visible from XPS,

which showed lower peak intensity after the fifth use (see

ESIw). This is due to the increased carbon content of

the surface. The C/Fe ratio rose from 1.51 atom% in fresh

nano-Fe2O3 to 2.10 atom% after the fifth use in the synthesis

Table 1 Screening of iron sources for the Hantzsch synthesis of1,4-dihydropyridinea

Entry Catalyst (0.15 mmol) t/min Yieldb (%)

1 Fe 25 512 Bulk-Fe2O3 40 703 FeCl2�4H2O 60 634 FeCl3�6H2O 35 805 Nano-g-Fe2O3 25 95

a Benzaldehyde–ethyl acetoacetate–NH4OAc= 1 : 2 : 1.5, solvent-free,

80 1C. b Yields refer to isolated products.

Fig. 1 TEM images of nano-g-Fe2O3 before use (a) and after reuse

five times (b).

Scheme 2 Proposed mechanism for ‘‘free’’ nano-g-Fe2O3 catalyzed

Hantzsch synthesis.

9232 Chem. Commun., 2011, 47, 9230–9232 This journal is c The Royal Society of Chemistry 2011

of product 4a. We believe that this is also the possible reason

for the high stability of the nano-Fe2O3 presented herein. A

thin layer of carbon is formed during the reaction which prevents

significant coagulation of the nano-Fe2O3. Obviously, carbon-

containing deposits cover the iron oxide particles partly during

reaction which, however, seems not to be detrimental to the

activity. The proposed mechanism for the synthesis of

1,4-dihydropyridines involves Lewis-acid catalyzed cyclo-

condensation of intermediates A and B, generated respectively

by Knoevenagel condensation of one equivalent of ethyl

acetoacetate with aldehyde and reaction of a second equivalent

of ethyl acetate with ammonia generated from ammonium

acetate (Scheme 2).

In conclusion, unsupported ‘‘free’’ nano-Fe2O3 has been

shown to be a stable yet highly active catalyst for preparing a

variety of 4-substituted-1,4-dihydropyridines from the one-pot

three-component condensation reaction. The catalytic research on

novel approaches toward nanomaterials should be improved

to enhance organic synthesis. For that purpose, magnetic

catalyst provides a new way for continuous processes, because

of its simple recyclability. From a scientific point, our results

expand the application of ‘‘free’’ nanoparticles. They should

be helpful to understand the advantageous combination of the

properties of homogeneous and heterogeneous catalysis and

the development of new catalytic systems.

Notes and references

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2 L. N. Lewis, Chem. Rev., 1993, 93, 2693–2730.3 C. N. R. Rao, A. A. Muller and K. Cheetham, The Chemistry ofNanomaterials: Synthesis and Applications, Wiley-VCH,Weinheim, 2004, vol. 1, pp. 555–562.

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5 B. P. S. Chauhan, J. S. Rathore and N. Glloxhani, Appl. Organomet.Chem., 2005, 19, 542–550.

6 M. Faraji, Y. Yamini and M. Rezaee, J. Iran. Chem. Soc., 2010, 7,1–37.

7 B. Brandt, W. Ludwig, J.-H. Fischer, J. Libuda, F. Zaera andS. Schauermann, J. Catal., 2009, 265, 191–198.

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10 E. B. Bauer, Curr. Org. Chem., 2008, 12, 1341–1369.11 B. Moens, H. DeWinne, S. Corthals, H. Poelman, R. De Gryse,

V. Meynen, P. Cool, B. F. Sels and P. A. Jacobs, J. Catal., 2007,247, 86–100.

12 T. Riedel, H. Schulz, G. Schaub, J. Jun and K. Lee, Top. Catal.,2003, 26, 41–51.

13 B. Jiang, T. Rajale, W. Wever, S. J. Tu and G. Li, Chem.–Asian J.,2010, 5, 2318–2335.

14 Some reviews on diversity-oriented organic synthesis:(a) S. L. Schreiber, Science, 2000, 287, 1964–1969; (b) M. D. Burkeand S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43, 46–58.

15 P. P. Mager, R. A. Coburn, A. J. Solo, D. J. Triggle and H. Rothe,Drug Design Disc., 1992, 8, 273–289.

16 R. Miri, K. Javidnia, H. Sarkarzadeh and B. Hemmateenejad,Bioorg. Med. Chem., 2006, 14, 4842–4849.

17 M. A. Zolfigol and M. Safaiee, Synlett, 2004, 827–828.18 M. A. Zolfigol, P. Salehi andM. Safaiee, Lett. Org. Chem., 2006, 3,

153–156.19 Y. K. Sun, M. Ma, Y. Zhang and N. Gu, Colloids Surf., A, 2004,

245, 15–19.20 Z. Xu, C. Shen, Y. Tian, X. Shi and H. J. Gao, Nanoscale, 2010, 2,

1027–1032.21 K. V. S. Ranganath and F. Glorius, Catal. Sci. Technol., 2011, 1,

13–22.22 Y. Cudennec and A. Lecerf, Solid State Sci., 2005, 7, 520–529.23 R. Grau-Crespo, A. Y. Al-Baitai, I. Saadoune and N. H.

De Leeuw, J. Phys.: Condens. Matter, 2010, 22, 255401.24 H. Zhu, Y. Ma, H. Yang, C. Ji, D. Hou and L. Guo, J. Phys.

Chem. Solids, 2010, 71, 1183–1186.25 P. Li, et al., Phys. D: Appl. Phys., 2011, 44, 075003.26 G. Pacchioni, Surf. Rev. Lett., 2000, 7, 277–306.27 Y. Zhao and K. Aoki, Chem. Phys. Lett., 2006, 430, 117–120.28 General procedure for the synthesis of 1,4-dihydropyridine

compounds: All reactions were carried out in an oil-bath (oil-bathtemperature 90 1C). The aldehyde (1 mmol), b-keto compound(2 mmol), ammonium acetate (1.5 mmol) and nano-Fe2O3

(0.15 mmol) were added to a glass reactor (ca. 25 mL). Thereaction mixture was vigorously stirred. After completion of thereaction (monitored by TLC), the mixture was cooled to roomtemperature and triturated with ethyl acetate (10 mL). In thepresence of a magnetic stirrer bar, nano-Fe2O3 moved onto thestirrer bar steadily and the reaction mixture turned clear within10 s. The catalyst can be isolated by simple decantation.The reaction mixture was treated with brine, extracted withethyl acetate (2�20 mL). After evaporation of the solvent, thecrude product was recrystallized from EtOH–H2O to give a puresolid.

Table 2 ‘‘Free’’ nano-g-Fe2O3 catalyzed Hantzsch synthesis of1,4-dihydropyridinesa

Entry R1 R2 Product t/min Yieldb (%)

1 Ph OEt 4a 15 982 p-MeC6H4 OEt 4b 25 903 p-ClC6H4 OEt 4c 15 924 p-HOC6H4 OEt 4d 20 815 p-O2NC6H4 OEt 4e 32 946 p-FC6H4 OEt 4f 25 937 p-CNC6H4 OEt 4g 40 908 p-BrC6H4 OEt 4h 30 889 o-MeOC6H4 OEt 4i 15 9010 m-ClC6H4 OEt 4j 15 9111 4-HO-3-MeOC6H3 OEt 4k 20 8712 n-Pr OEt 4l 20 9213 2-Furyl OEt 4m 12 8914 Ph OMe 5a 15 9515 o-MeOC6H4 OMe 5b 10 9416 p-O2NC6H4 OMe 5c 20 9617 p-MeC6H4 OMe 5d 25 9318 p-ClC6H4 OMe 5e 12 9019 p-HOC6H4 OMe 5f 10 8820 p-FC6H4 OMe 5g 20 8521 p-NCC6H4 OMe 5h 35 9122 p-BrC6H4 OMe 5i 40 9423 o-ClC6H4 OMe 5j 15 9624 4-HO-3-MeOC6H3 OMe 5k 19 8925 n-Pr OMe 5l 15 8026 2-Furyl OMe 5m 25 8627 m-O2NC6H4 OMe 5n 30 91

a All products were characterized by IR, 1H NMR and 13C NMR

spectroscopic data, and melting points. b Yields refer to isolated

products.

Table 3 Reuse of ‘‘free’’ nano-g-Fe2O3 in the synthesis of1,4-dihydropyridinesa

Run 1 2 3 4 5

Yieldb (%) 98 98 96 96 92

a Benzaldehyde–ethyl acetoacetate–NH4OAc= 1 : 2 : 1.5, solvent-free,

90 1C, 0.15 mmol ‘‘free’’ nano-g-Fe2O3; the weight loss of catalyst after

5 runs was 9 wt%. b Isolated yields.