Nano Fe3O4: A novel and magnetically recyclable catalyst for the synthesis of 1,2,4,5-tetrasubstituted imidazoles in solvent-free conditions

Article abstract of DOI:10.14233/ajchem.2013.13963

A convenient and efficient one-pot four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles using nano Fe₃O₄ as magnetically recyclable catalyst is reported. The results show that the methodology has several advantages such as low loading of catalyst, excellent yield, short reaction time, operational simplicity and solvent-free conditions.

Full text of DOI:10.14233/ajchem.2013.13963

Asian Journal of Chemistry; Vol. 25, No. 6 (2013), 3463-3466
http://dx.doi.org/10.14233/ajchem.2013.13963
Nano Fe3O4: A Novel and Magnetically Recyclable Catalyst for the Synthesis
of 1,2,4,5-Tetrasubstituted Imidazoles in Solvent-Free Conditions
1,*
1
1
1,2
NASER MONTAZERI , KHALIL POURSHAMSIAN , HAMIDEH REZAEI , MAHDI FOULADI1,2 and SASAN RAHBAR
1Department of Chemistry, Faculty of Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
2Islamic Azad University, Tonekabon Branch, Young Researchers Club, Tonekabon, Iran
*Corresponding author: Fax: +98 192 4274409; Tel: +98 192 4274415; E-mail: montazer50@toniau.ac.ir; montazer1350@gmail.com
(Received: 25 April 2012; Accepted: 26 December 2012) AJC-12615
A convenient and efficient one-pot four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles using nano Fe3O4 as magnetically
recyclable catalyst is reported. The results show that the methodology has several advantages such as low loading of catalyst, excellent
yield, short reaction time, operational simplicity and solvent-free conditions.
Key Words: Nano Fe3O4, Tetrasubstituted imidazoles, Solvent-free conditions, Reusable catalyst.
harmful to environment and moderate yields. Therefore, to avoid
these limitations there is still a need for the development of a
new protocol for the synthesis of 1,2,4,5-tetrasubstituted
imidazoles in terms of operational simplicity, reusability of the
catalyst, high-yielding and economic viability.
INTRODUCTION
Imidazoles are very important compounds with wide
spectrum of biological activities such as antiinflammatory1,
anti-allergic2, antibacterial3, antitumor4 and plant growth
regulators5, activities. Furthermore, they act as glucagon
receptors6. Recent advances in green chemistry and organo-
metallic catalysis has extended the application of imidazoles
as ionic liquids7 and N-heterocyclic carbenes8.
Recently, metal nanoparticles have attracted a great
attention as heterogeneous catalysts because of their interesting
structure and high catalytic activities22a,b. In particular, magnetite
nanoparticles have emerged as one of the most useful hetero-
geneous catalysts due to their numerous applications in bio-
technology and medicine23a,b. Of these, Fe3O4 nanoparticles
are the most promising catalysts because of their ease of handing,
ease of recovery with external magnetic field, high catalytic
The design and development of multi component reactions
for the generation of heterocycles receive growing interest9a,b
.
One example of multi component reactions is four-component,
one-pot synthesis of tetrasubstituted imidazoles.
activities and reactivates in various organic transformations24a,b
.
In view of different biological and chemical applications
of imidazoles, the development of suitable synthetic method-
ologies for their generation has been a topic of great interest in
recent times. The general method involves four component con-
densation of 1,2-diketones, aromatic aldehydes, primary amines
and ammonium acetate in the presence of various catalysts, such
as zinc oxide10, carbon-based solid acid11, Bronsted acidic ionic
liquid12, silica gel/NaHSO413, K5CoW12O4.3H2O14, BF3-SiO215,
molecular iodine16, HClO4-SiO217 and L-proline18. In addition,
they can also be accessed by the condensation of a 1,2-diketone
with an aryl nitrile and primary amine under microwave irradi-
ation19, cycloaddition reaction of mesoionic 1,3-oxazolium-5-
olates with N-(arylmethylene)-benzensulfonamide20 and N-(2-
oxo)amides with ammonium trifluroracetate21. However, in spite
of their potential utility, some of the reported methods suffer
from certain drawbacks such as expensive reagents, harsh
conditions, use of toxic catalysts and organic solvents that are
However, there are no reports on the use of Fe3O4 nanoparticles
for one-pot four-component synthesis of 1,2,4,5-tetrasubstituted
imidazoles.
In continuation of our previous works on the applications
of reusable catalysts in the synthesis of heterocyclic compounds25a-c
,
in this article, we report nano-Fe3O4 as a highly efficient, (iron
oxide (Fe3O4), 98 %, 20-30 nm; nanostructured and amorphous
materials, Inc. USA), clean and economically valuable catalyst
fortheone-pot, four-componentsynthesisof1,2,4,5-tetrasubstituted
imidazoles 5a-m from reaction of benzil 1, aromatic aldehydes
2, primary amines 3 and ammonium acetate 4 under solvent-
free conditions (Scheme-I).
EXPERIMENTAL
All chemicals were available commercially and used with-
out additional purification. Melting points were recorded on

3464 Montazeri et al.
Asian J. Chem.
an electrothermal type 9100 melting point apparatus. The IR
spectra were obtained using 4300 Shimadzu spectrophoto-
efficiency of this nanoparticles (Fe3O4) as heterogeneous
catalyst in the synthesis of 1,2,4,5-tetrasubstituted imidazoles
under solvent-free condition. Initially, the one-pot four-
component coupling of benzil, benzaldehyde, aniline and
ammonium acetate as a simple model substrates was investi-
gated to establish the feasibility of the strategy and optimize
the reaction conditions.
1
meter as KBr disks. The H NMR, 400 MHz spectra were
recorded with a Bruker DRX 400 spectrometers.
O
N
nano-Fe3O4
Ar
ArCHO RNH
+
A mixture of benzil (1 mmol), benzaldehyde (1 mmol),
aniline (1 mmol) and ammonium acetate (1 mmol) was heated
on the oil bath at different temperatures in the presence of
various amounts of nano Fe3O4 as heterogeneous catalyst
under solvent-free conditions (Table-1). As can be seen from
this Table, the yield of compound 5a is affected by the catalyst
amount and reaction temperature. No product was obtained in
the absence of the catalyst (Entry 1) or in the presence of the
catalyst at room temperature (Entry 2) indicating that the
catalyst and temperature are necessary for the reaction.
Increasing the amount of the catalyst and reaction temperature
up to 15 mol % and 140 ºC, respectively, increased the yield
of the product 5a. Further increase in both catalyst amount
and temperature did not increase the yield noticeably (entries
1-18).
+
O
+
2
CH3COONH4
Solvent-free
N
R
1
2
3
4
5a-m
Scheme-I: Synthesis of 1,2,4,5-tetrasubstituted imidazoles using Fe3O4 as
catalyst
Synthesis of 1,2,4,5-tetrasubstituted imidazoles:A mixture
of benzil (1 mmol), aromatic aldehydes (1 mmol), primary amine
(1 mmol), ammonium acetate (1 mmol) and nano-Fe3O4 (0.15
mmol) was heated on the oil bath at 140 ºC for 30-60 min. The
reaction was monitored by TLC.After completion of the reaction,
the reaction mixture was cooled to room temperature, boiling
ethanol 95 % was added and the mixture was heated under reflux
for 1 min. The Fe3O4 nanoparticles were absorbed on to the
magnetic stirring bar.After cooling to room temperature, the crude
product was collected and recrystallized from ethanol to give
compounds 5a-m in high to excellent yields. All products were
known and characterized by comparison of their physical and
spectroscopic data with those of reported techniques.
TABLE-1
EFFECT OF NANO FE3O4 AMOUNT AND TEMPERATURE
ON THE MODEL REACTION
Entry
Amount of catalyst
(mol. %)
T (ºC)
Time
(min)
Yieldb (%)
Recycling and reusing of the catalyst: The recyclability
of the catalyst in the reaction of benzil, benzaldehyde, aniline,
ammonium acetate in the presence of nano Fe3O4 was checked.
The separated catalyst can be reused after washing twice with
ethanol 95 %, drying at 100 ºC under vacuum and reused in
another reaction. It showed the same activity as fresh catalyst
without any loss of its activity.
1
2
None
15
10
10
10
10
15
15
15
15
20
20
20
20
25
25
25
25
110
r.t.
60
60
40
20
20
20
26
20
20
20
20
20
20
20
40
20
15
15
None
None
62
3
110
130
140
150
110
130
140
150
110
130
140
150
110
130
140
150
4
76
5
89
6
82
7
68
2-(4-chlorophenyl)-1-(4-nitrophenyl)-4,5-diphenyl-1H-
imidazole (5g): m.p. 167-169 ºC; IR (KBr, νmax, cm-1): 3100,
8
82
9
94
1
10
11
12
13
14
15
16
17
18
88
1530, 1475, 1350; H NMR (DMSO-d6 400 MHz) δ: 6.76-
7.71 (m, 18H, ArH); 13C NMR (DMSO-d6 100 MHz) δ :
146.35, 137.59, 137.50, 134.81, 134.06, 131.29, 131.07,
130.87, 130.66, 130.04, 129.47, 129.16, 129.06, 128.60,
127.74, 126.84, 126.58, 126.10.
54
72
79
77
42
1-Benzyl-2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole
(5h): m.p. 166-168 ºC; IR (KBr, cm-1): 3100, 1520, 1470, 1350;
1H NMR (DMSO-d6 400 MHz) δ: 5.27 (s, 2H, CH2), 6.79-
8.30 (m, 19H,ArH); 13C NMR (DMSO-d6 100 MHz) δ: 147.50,
145.25, 138.30, 137.27, 137.20, 134.51, 132.36, 131.28,
130.51, 129.73, 129.69, 129.57, 129.13, 129.07, 129.01,
128.67, 127.86, 127.11, 126.67, 126.15, 126.09, 124.32.
2-(4-Methoxyphenyl)-1,4,5-triphenyl-1H-imidazole
(5k): m.p. 157-160 ºC ; IR (KBr, νmax, cm-1): 3120, 1475; 1H
NMR (DMSO-d6 400 MHz) δ : 3.73 (s, 3H, CH3), 6.84-7.51
(m, 19H, ArH); 13C NMR (DMSO-d6 100 MHz) δ : 159.68,
146.48, 137.26, 137.02, 134.98, 131.61, 131,31, 131.00,
130.12, 129.63, 129.26, 129.17, 128.92, 128.81, 128.62,
126.84, 126.81, 123.28, 114.08, 55.59.
52
71
76
a1 mmol benzil, 1 mmol benzaldehyde, 1 mmol aniline and 1 mmol
ammonium acetate under neat conditions. b Isolated yields
Also, the model reaction was carried out in various
solvents such as EtOH, H2O, CHCl3 and CH2Cl2 using 15
mol % of the catalyst. The use of H2O gave the product 5a in
low yield (48 %). MeOH, CH2Cl2 and CHCl3 gave moderate
yields 60, 60 and 63 % respectively. In addition the use of
EtOH gave the product 5a in good yield (84 %).
We next made a study on the catalytic activity of powdered
Fe3O4 loading in model reaction. In comparison with Fe3O4
nanoparticles, the reaction times were longer and the yield
were considerably lower.
RESULTS AND DISCUSSION
Under the above optimized conditions, the scope of this
MCR process was next examined using various aromatic aldehydes
Due to the increasing demand in modern organic proce-
sses for reusability of catalysts, we decided to investigate the

Vol. 25, No. 6 (2013)
Nano Fe3O4: A Novel and Magnetically Recyclable Catalyst 3465
TABLE-2
NANO FE3O4 CATALYZED SYNTHESIS OF 1, 2, 4, 5-TETRASUBSTITUTEDa
m.p. (ºC)
Entry
Ar
R
Productb
Time (min)
Yieldc (%)
Found
Reported
213-21512
161-16312
22010
146-14812
16710
1
2
C6H5
C6H5
20
30
45
45
45
30
60
45
45
30
60
60
45
94
92
80
85
75
91
79
81
87
82
92
93
80
215-218
162-164
221-222
149-150
165-166
180-183
167-169
166-168
160-162
163-165
157-160
158-160
142-144
5a
5b
5c
5d
5e
5f
C6H5
CH2C6H5
4-MeC6H4
C6H5
3
4-NO2C6H4
4-ClC6H4
4-MeC6H4
4-CH3C6H4
4-ClC6H4
4-NO2C6H4
4-CH3C6H4
4-ClC6H4
4-CH3OC6H4
4-CH3OC6H4
C6H5
4
5
CH2C6H5
C6H5
6
183-18412
7
4-NO2C6H4
CH2C6H5
CH2C6H5
CH2C6H5
C6H5
-
5g
5h
5i
8
-
9
163-16512
163-16410
-
10
11
12
13
5j
5k
5l
CH2C6H5
155-15712
144-14518
CH3
5m
a1 mmol benzil, 1 mmol aromatic aldehyde, 1 mmol primary amine, 1 mmol ammonium acetate and 0.15 mmol nano Fe3O4 at 140 °C under
solvent-free conditions. bThe products were characterized by comparison of their spectroscopic and physical data with authentic sample synthesized
by reported procedures. CIsolated yields
and primary amines (Table-2). In all cases, the obtained yields
were excellent without formation of any side products such as
Fe O
3
4
I
NH
NH OAC
4
O
2
O
2,4,5-trisubstituted imidazoles.Aromatic aldehydes containing
electron-donating or electron-withdrawing groups and various
primary amines reacted efficiently and gave the expected prod-
ucts with excellent yields in relatively short reaction times. While
aliphatic aldehydes such as pentanal and butanal produced only
trace amounts of imidazoles that could not be isolated, aliphatic
amines, such as methyl amine, produced high yield of the corres-
ponding imidazole (Table-2, entry 13).
nano-Fe3O4
NH
3
RNH
+
2
Ar
H
Ar
NHR
Ar
H
II
O
Fe O
3
4
Ph
Ph
N
O
Ar
Ph
nano-Fe3O4
I
Ph
Ph
H
Ph
N
O
HO
O
R
O Fe
4
3
The principle advantage of the use of heterogeneous solid
acid catalysts in organic transformations is their reusability.
Hence, we decided to study the catalytic activity of recycled nano
Fe3O4 in the synthesis of compound 5a. After the completion
of the reaction, the catalyst was recovered according to the proce-
dure mentioned in experimental part and reused for a similar
reaction. The catalyst could be reused at least five times with
only slight reduction in the catalytic activity (Table-3).
N
Ph
Ar
N
Ph
R
Scheme-II: Plausible mechanism for the synthesis of 1,2,4,5-tetrasubstituted
imidazoles using Fe3O4 as catalyst
Conclusion
TABLE-3
RECOVERY AND REUSE OF NANO FE3O4
FOR THE SYNTHESIS OF 5a
In conclusion, nano Fe3O4 has shown to be an excellent
catalyst for one pot four-component synthesis of 1,2,4,5-
tetrasubstituted imidazoles under solvent-free conditions. Easy
isolation and recycling of the catalyst, simple work up proce-
dure, short reaction time and excellent yields are some advan-
tages of this method. Henceforth, this methodology works well
and is environmentally benign and may prove beneficial to
both academia and industry for the socio-econom change.
Cycle
Yielda (%)
1
2
93
93
91
90
90
88
86
86
84
83
3
4
5
6
7
ACKNOWLEDGEMENTS
8
9
The authors are thankful to Islamic Azad university,
Tonekabon branch for financial support.
10
aisolated yield
REFERENCES
N-nucleophilic attack of the primary amine and ammonia,
obtained from NH4OAc, at activated carbonyl group in aryl
aldehyde by nano Fe3O4 yields the intermediate (I) which subse-
quently reacts with activated benzil to form intermediate (II).
Dehydration of this intermediate produces the final products
(Scheme-II).
1. M. Misono, Chem. Commun., 1141 (2001).
2. J.W. Blank, G.J. Durant, J.C. Emmett and C.R. Ganellin, Nature, 248,
65 (1974).
3. M.Antolini, A. Bozzoli, C. Ghiron, G. Kennedy, T. Rossi andA. Ursini,
Bioorg. Med. Chem. Lett., 9, 1023 (1999).
4. L. Wang, K.W. Woods, Q. Li, K.J. Barr, R.W. McCroskey, S.M.
Hannick, L. Gherke, R.B. Credo, Y.-H. Hui, K. Marsh, R. Warner, J.Y.

3466 Montazeri et al.
Asian J. Chem.
Lee, N. Zielinsky-Mozng, D. Frost, S.H. Rosenberg and H.L. Sham, J.
Med. Chem., 45, 1697 (2002).
17. S. Kantevari, S.V.N. Vuppalapati, D.O. Biradar and L. Nagarapu, J. Mol.
Catal. A, 266, 109 (2007).
5. R. Schmierer, H. Mildenberger and H. Buerstell, Ger 3614364, (1987);
Chem. Abstr., 108, 37838 (1988).
18. S. Samai, G.C. Nandi, P. Singh and M.S. Singh, Tetrahedron, 65, 10155
(2009).
6. S.E. De Laszlo, C. Hacker, B. Li, D. Kim, M. MacCoss, N. Mantlo,
J.V. Pivnichny, L. Colwell, G.E. Koch, M.A. Cascieri and W. Hagmann,
Bioorg. Med. Chem. Lett., 9, 641 (1999).
19. S. Balalaie, M.M. Hashemi and M. Akhbari, Tetrahedron Lett., 44,
1709 (2003).
20. I. Lantos, W.Y. Zhang, Y. Shui and D.S. Eggleston, J. Org. Chem., 58,
7092 (1993).
7. S. Chowdhury, R.S. Mohan and J.L. Scott, Tetrahedron, 63, 2363 (2007).
8. D. Bourissou, O. Guerret, F.P. Gabbai and G. Bertrand, Chem. Rev.,
100, 39 (2000).
21. C.F. Claiborne, N.J. Liverton and K.T. Nguyen, Tetrahedron Lett., 39,
8939 (1998).
9. (a) R.V.A. Orru and M. de Greef, Synthesis, 1471 (2003); (b) H. Bienayme,
C. Hulme, G. Oddon and P. Schmitt, Chem. Eur. J., 6, 3321 (2000).
10. K. Bahrami, M.M. Khodaei andA. Nejati, Monatsh. Chem., 142, 159 (2011).
11. N. Tavakoli-Hoseini andA. Davoodnia, Chin. J. Chem., 29, 203 (2011).
12. A. Davoodnia, M.M. Heravi, Z. Safavi-Rad and N. Tavakoli-Hoseini,
Synth. Commun., 40, 2588 (2010).
22. (a) F. Shi, M.K.Tse, S.L. Zhou, M.M. Pohl, J. Radnik, S. Hubner, K. Jahnisch,
A. Bruckner and M. Beller, J. Am. Chem. Soc., 131, 1775 (2009); (b)
M.J.Aliaga, D.J. Ramon and M.Yus, Org. Biomol. Chem., 8, 43 (2010).
23. (a)V. Polshettiwar, B. Baruwati and R.S. Varma, Chem. Commun., 1837
(2009); (b)V. Polshettiwar and R.S.Varma, Chem. Eur. J., 15, 1582 (2009).
24. (a) B. Sreedhar, A.S. Kumar and P.S. Reddy, Tetrahedron Lett., 50,
2322 (2009); (b) M.M. Mojtahedi, M.S. Abaee and T. Alishiri, Tetra-
hedron Lett., 50, 2322 (2009).
13. A.R. Karimi, Z.Alimohammadi, J.Azizian,A.A. Mohammadi and M.R.
Mohammadizadeh, Catal. Commun., 7, 728 (2006).
14. L. Nagarapu, S.Apuri and S. Kantevari, J. Mol. Catal. A, 266, 104 (2007).
15. B. Sadeghi, B.B.F. Mirjalili and M.M. Hashemi, Tetrahedron Lett., 49,
2575 (2008).
25. (a) N. Montazeri and K. Rad-Moghadam, Chin. Chem. Lett., 19, 1143
(2008); (b) N. Montazeri, S. Khaksar,A. Nazari, S.S.Alavi, S.M. Vahdat
and M. Tajbakhsh, J. Fluorine Chem., 132, 450 (2011); (c) N. Montazeri
and K. Rad-Moghadam, Phosphorus, Sulfur, Silicon Rel. Elem., 179,
2533 (2004).
16. M. Kidwai, P. Mothsra, V. Bansal, R.K. Somvanshi, A.S. Ethayathulla,
S. Dey and T.P. Singh, J. Mol. Catal. A., 265, 177 (2006).