Synthesis of 1,2,4,5-tetrasubstituted imidazoles using silica-bonded propylpiperazine N-sulfamic acid as a recyclable solid acid catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.06.105

A simple and efficient procedure for the preparation of silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA) by the reaction of 3-piperazine-N-propylsilica (3-PNPS) and chlorosulfonic acid in chloroform is described. Silica-bonded propylpiperazine-N-sulfamic acid is employed as a recyclable catalyst for the synthesis of highly substituted imidazoles from the reaction of benzil, aromatic aldehydes, ammonium acetate and amines under solvent-free conditions. The heterogeneous catalyst was recycled for five runs upon the reaction of benzil, 4-methylbenzaldehyde, benzylamine, and ammonium acetate without losing its catalytic activity.

Full text of DOI:10.1016/j.tetlet.2011.06.105

Tetrahedron Letters 52 (2011) 4642–4645
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,2,4,5-tetrasubstituted imidazoles using silica-bonded
propylpiperazine N-sulfamic acid as a recyclable solid acid catalyst
⇑
Khodabakhsh Niknam , Abdollah Deris, Fatemeh Naeimi, Fatemeh Majleci
Chemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient procedure for the preparation of silica-bonded propylpiperazine-N-sulfamic acid
(SBPPSA) by the reaction of 3-piperazine-N-propylsilica (3-PNPS) and chlorosulfonic acid in chloroform
is described. Silica-bonded propylpiperazine-N-sulfamic acid is employed as a recyclable catalyst for
the synthesis of highly substituted imidazoles from the reaction of benzil, aromatic aldehydes, ammo-
nium acetate and amines under solvent-free conditions. The heterogeneous catalyst was recycled for five
runs upon the reaction of benzil, 4-methylbenzaldehyde, benzylamine, and ammonium acetate without
losing its catalytic activity.
Received 7 May 2011
Revised 21 June 2011
Accepted 27 June 2011
Available online 2 July 2011
Keywords:
Silica-bonded propylpiperazine-N-sulfamic
acid
Ó 2011 Elsevier Ltd. All rights reserved.
1,2,4,5-Tetrasubstituted imidazoles
Aldehydes
Solvent-free
Catalyst
One-pot synthesis
The imidazole ring system is one of the most important substruc-
tures found in a large number of natural products and pharmacolog-
ically active compounds.1–5 The members of this class of compounds
are known to possess NO synthase inhibition and antifungal, anti-
mycotic, antibiotic, antiulcerative, antibacterial, antitumor, and
CB1 receptor antagonistic activities.6,7 Various substituted imida-
zoles act as inhibitors of p38 MAP kinase8 and B-Raf kinase,9 gluca-
gon receptors,10 plant growth regulators,11 therapeutic agents,1 and
pesticides.12 Industrial and academic studies for the preparation of
1,2,4,5-tetrasubstituted imidazoles have led to numerous method-
ologies for the synthesis of these compounds.13,14 The most well-
known and classical method for preparation of these compounds
involves four-component condensations of a 1,2-diketone deriva-
tive with an aldehyde, primary amine, and ammonium acetate in
refluxing HOAc, which is known to have poor yields and long
reaction times.15 Improvements occurred using other acidic condi-
tions, such as silica gel,16 zeolite,16 alumina,17 NaHSO4–SiO2,18
HClO4ÁSiO2,19 molecular iodine,20,21 FeCl3Á6H2O,22 BF3ÁSiO2,23 In-
Cl3Á3H2O,24 K5CoW12O40Á3H2O,25 copper acetate,26 trifluroacetic
In continuation of our studies on the design and application of
solid acid catalysts in organic transformations,34–38 herein, we de-
scribe the preparation of silica-bonded propylpiperazine-N-sulfa-
mic acid (SBPPSA) and its application as a catalyst for the
synthesis of 1,2,4,5-tetrasubstituted imidazoles.
Silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA) was
prepared by the reaction of 3-piperazine-N-propylsilica (3-PNPS)
with chlorosulfonic acid in chloroform as illustrated in Scheme 1.
To study the effect of catalyst loading on the four component
condensation reactions for the synthesis of 1,2,4,5-tetrasubstituted
imidazoles, the reaction of benzil, 4-methylbenzaldehyde, benzyl-
amine, and ammonium acetate was chosen as a model reaction
(Table 1). The results show clearly that SBPPSA is an effective cat-
alyst for this four component condensation reaction. The best cat-
alytic loading of SBPPSA was 0.25 g in terms of reaction time and
isolated yield. The optimized conditions were chosen as follows:
benzil (1 mmol), aldehyde (1 mmol), amine (1 mmol), ammonium
acetate (1 mmol), and SBPPSA (0.25 g, equal to 0.31 mmol of H+)
and heated under solvent-free conditions at 140 °C (Scheme 2).
The lower temperature gave the corresponding product in lower
yield and longer reaction time (Table 1, entries 5–6).
acid,27 -proline,28 zeolite supported reagents,29 mercaptopropylsil-
L
ica (MPS),30 Bronsted acidic ionic liquid,31 MCM-41 or p-TsOH,32 and
1-butyl-3-methylimidazolium bromide33 under microwave-irradi-
ation, solvent-free or classical conditions.
A wide range of aromatic aldehydes were employed and all
imidazoles were obtained in high to excellent yields, which
demonstrated that this is a general method that tolerates both elec-
tron-withdrawing and electron-donating constituents. Another
important aspect is that various aliphatic and aromatic amines,
such as aniline, benzyl, cyclohexyl, and ethyl amine were employed
⇑
Corresponding author. Fax: +98 771 4545188.
E-mail addresses: niknam@pgu.ac.ir, khniknam@gmail.com (K. Niknam).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.105

K. Niknam et al. / Tetrahedron Letters 52 (2011) 4642–4645
4643
O
Cl
OH
OH
(MeO)3Si
O Si
Cl
SiO2
SiO2
toluene, reflux, 18 h
O
OH
(3-SPCl)
H
N
N
H
O
O
1) ClSO3H/ CHCl3 /4 h
2) wash with EtOH
O Si
N
SiO2
O Si
N
SiO2
N-SO3H
NH
O
O
(SBPPSA)
(3-PNPS)
Scheme 1. Preparation of silica-bonded propylpiperazine-N-sulfamic acid (SBPPSA).
The possibility of recycling the catalyst was examined using the
reaction of benzil, benzaldehyde, aniline, and ammonium acetate
under optimized conditions. Upon completion, the reaction mix-
ture was filtered and the solid was washed with ethanol, and the
recycled catalyst was saved for the next reaction. The recycled cat-
alyst could be reused five times without any further treatment. No
observation of any appreciable loss in the catalytic activity of
SBPPSA was observed (Fig. 1).
Table 1
Condensation reaction of benzil, 4-methylbenzaldehyde, benzylamine, and ammo-
nium acetate in the presence of different amounts of SBPPSA as catalyst under
solvent-free conditions and temperaturesa
Entry Catalyst loading
(g)
Temperature
(°C)
Time
(h)
Conversionb,c
(%)
1
2
3
4
5
6
7
0.05
0.1
0.2
0.25
0.25
0.25
0.3
140
140
140
140
100
80
7
4
1.5
1
2
70 (63)
80 (74)
85 (80)
95 (90)
75 (69)
70 (65)
95 (89)
In conclusion, we have shown that silica-bonded propylpiper-
azine-N-sulfamic acid (SBPPSA), which can be prepared from com-
mercially available and cheap starting materials, catalyzed
efficiently this four component condensation reactions for the syn-
thesis of 1,2,4,5-tetrasubstituted imidazole derivatives. The sim-
plicity of the procedure, eco-friendly, non-volatile, easy handling,
safety and reusability of catalyst are the advantages of this method.
All the products were characterized by comparison of their IR,
1H NMR and 13C NMR spectroscopic data and their melting points
with reported values.11–32 3-piperazine-N-propylsilica (3-PNPS)
was prepared according to the procedure reported by Dey.39
Synthesis of silica-bonded propylpiperazine-N-sulfamic acid
(SBPPSA): To a magnetically stirred mixture of 3-piperazine-N-pro-
pylsilica (3-PNPS) (25 g) in CHCl3 (50 mL), chlorosulfonic acid
(25 mL) was added dropwise at 0 °C over 2 h. After the addition
was complete, the mixture was stirred for another 2 h and then,
the mixture was filtered and washed with ethanol (50 mL) and
dried at room temperature to afford silica-bonded propylpiper-
azine-N-sulfamic acid (SBPPSA) as a cream powder (26.8 g). Ele-
mental analysis showed the S content to be 2.85%; C, 8.70%; H,
2.4%; N, 2.1%. The number of H+ sites of SBPPSA was determined
by pH-ISE conductivity titration (Denver Instrument Model 270)
and found to be 1.25 H+ sites per 1 g of solid acid at 25 °C (pH 2.30).
General procedure: To a mixture of benzil (1 mmol), aldehyde
(1 mmol), amine (1 mmol), and ammonium acetate (2 mmol) was
added SBPPSA (0.25 g, equal to 0.31 mmol of H+) and heated at
3
1
140
a
Reaction conditions: benzil (1 mmol), 4-methylbenzaldehyde (1 mmol), ben-
zylamine (1 mmol), and ammonium acetate (2 mmol) under solvent-free conditions
at 140 °C.
b
Determined by GC analysis.
Isolated yields in parenthesis.
c
in this four component condensation reaction under optimized con-
ditions (Table 2). In each case, no side product formation (for exam-
ple, 2,4,5-trisubstituted imidazoles) was observed, as is normally
the case in such reactions under the influence of strong acids. This
method not only affords the products in excellent yields but also
avoids the problems associated with catalyst cost, handling, safety,
and pollution. The results illustrate the high ability of this method
for the synthesis of 1,2,4,5-tetrasubstituted imidazoles with differ-
ent groups.
To show the advantages of SBPPSA as a catalyst in this reaction,
our results and reaction conditions for synthesis of 1-benzyl-2-(4-
methylphenyl)-4,5-diphenylimidazole (1a) were compared with
previously reported data in Table 3. The results show that our
method is quite comparable with the former methods in yields
and reaction times.
O
O Si
O
N
SiO2
N-SO3H
(0.25 g)
Ph
Ph
N
N
Ph
Ph
O
O
Ar
+
NH4OAc
(2 mmol)
Ar-CHO
+
+
R-NH2
Solvent-free
140 oC
(1 mmol)
(1 mmol)
R
(1 mmol)
1
Scheme 2. Synthesis of 1,2,4,5-tetrasubstituted imidazoles catalyzed by SBPPSA.

4644
K. Niknam et al. / Tetrahedron Letters 52 (2011) 4642–4645
Table 2
Preparation of various 1,2,4,5-tetrasubstituted imidazoles in the presence of SBPPSA under solvent-free conditions at 140 °Ca
Entry
Ar
R
Product
Time (min)
Yieldb (%)
Mp (°C)
Lit. mp (°C)
1
2
3
4
5
6
7
8
4-Me-C6H4-
4-Cl-C6H4-
2-Cl-C6H4-
C6H5-CH2–
C6H5-CH2–
C6H5-CH2–
C6H5-CH2–
C6H5-CH2–
C6H5-CH2–
C6H5-CH2–
C6H5–
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
60
70
90
85
75
60
75
120
150
150
150
300
240
120
90
90
92
90
90
89
86
87
89
85
72
88
70
75
75
78
77
78
72
73
165–167
162–164
140–142
185–187
232–235
164–166
208–210
212–214
143–145
194–196
219–221
168–170
164–166
217–219
197–199
215–217
283–285
310–312
155–157
165–16622
162–16423
140–14223
3,4,5-(MeO)3-C6H2-
3-HO-C6H4-
4-MeS-C6H4-
4-NC-C6H4-
4-O2N-C6H4-
3-Br-C6H4-
4-NC-C6H4-
4-Me-C6H4-
C6H5-
4-Me-C6H4-
4-MeO-C6H4-
4-Cl-C6H4-
4-O2N-C6H4-
4-HO-C6H4-
4-Cl-C6H4-
184–18619
—
—
—
159–16027
9
C6H5–
C6H5–
4-Br-C6H4–
—
—
—
10
11
12
13
14
15
16
17
18
19
C6H11
C6H11
C6H11
C6H11
C6H11
C6H11
Et–
–
–
–
–
–
–
167–16922
162–16422
—
—
—
—
—
—
320
260
90
4-NC-C6H4-
Et–
90
a
Reaction conditions: benzil (1 mmol), aromatic aldehyde (1 mmol), amine (1 mmol), ammonium acetate (2 mmol), SBPPSA (0.25 g, equal to 0.31 mmol of H+), solvent-free
at 140 °C.
b
Isolated yield.
Table 3
Synthesis of 1-benzyl-2-(4-methylphenyl)-4,5-diphenyl-imidazole 1a using different catalysts and reaction conditions
Entry
Solvent and catalyst (loading)
Time (min)
Yielda (%)
Ref.
1
2
3
4
5
6
7
8
9
MW, solvent-free, zeolite HY (5 mol %)
Solvent-free, 140 °C, NaHSO4–SiO2 (18.6 g)
Solvent-free, 140 °C, HClO4.SiO2 (1 mol %)
MeOH, rt, InCl3.3H2O (10 mol %)
6
120
6
480
120
540
32
120
60
85
92
90
75
95
88
82
90
90
16
18
19
24
25
28
32
33
Solvent-free, 140 °C, K5CoW12O40.3H2O (0.1 mol %)
MeOH, 60 °C,
L-proline (15 mol %)
Reflux in AcOH, MCM-41(0.04 g)
[Bmim]Br (0.5 g, 2.28 mmol), solvent-free, 140 °C
Solvent-free, 140 °C, SBPPSA (equal to 0.31 mmol H+)
This work
a
Isolated yield.
Acknowledgment
We are thankful to Persian Gulf University Research Council for
partial support of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.105.
References and notes
1. Heers, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. J. Med. Chem. 1979, 22,
1003–1005.
2. Hunkeler, W.; Mohler, H.; Pieri, L.; Polc, P.; Bonetti, E. P.; Cumin, R.; Schaffner,
R.; Haefely, W. Nature 1981, 290, 514–516.
3. Brimblecombe, R. W.; Duncan, W. A. M.; Durant, G. J.; Emmett, J. C.; Ganellin, C.
R.; Parons, M. E. J. Int. Med. Res. 1975, 3, 86–92.
4. Tanigawara, Y.; Aoyama, N.; Kita, T.; Shirakawa, K.; Komada, F.; Kasuga, M.;
Okumura, K. Clin. Pharmacol. Ther. 1999, 66, 528–534.
Figure 1. Recyclability of SBPPSA in the reaction of benzil (1 mmol), 4-methyl-
benzaldehyde (1 mmol), benzylamine (1 mmol) and ammonium acetate (2 mmol)
under solvent-free conditions at 140 °C. Reaction time = 60 min.
5. Wauquier, A.; Van Den Broeck, W. A. E.; Verheyen, J. L.; Janssen, P. A. J. Eur. J.
Pharmacol. 1978, 47, 367–377.
6. Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.; Ursini, A. Bioorg. Med.
Chem. Lett. 1999, 9, 1023–1028.
7. Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.;
Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinsky-
Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697–
1711.
140 °C under solvent-free conditions. When the reaction was com-
plete as judged by TLC, ethanol (5 mL) was added and the reaction
mixture was filtered and the remaining solid was washed with
warm ethanol (3 Â 5 mL) in order to separate the catalyst. The
products were recrystallized from ethanol. The recovered catalyst
was dried and reused for subsequent runs.
8. Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; Green, D.;
McNulty, D.; Blumenthal, M. J.; Keys, J. R.; Vatter, S. W. L.; Strickler, J. E.;

K. Niknam et al. / Tetrahedron Letters 52 (2011) 4642–4645
4645
McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi, G. P.; White, J. R.; Adams, J.
L.; Young, P. R. Nature 1994, 372, 739–746.
23. Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron Lett. 2008, 49, 2575–
2577.
9. Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird, A.
W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman, J. G.; Wilson, D. M.
Bioorg. Med. Chem. Lett. 2006, 16, 378–381.
10. Laszlo, S. E. D.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantalo, N.; Pivnichny, J.
V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmenn, W. K. Bioorg. Med. Chem.
Lett. 1999, 9, 641–646.
11. Schmierer, R.; Mildenberger, H.; Buerstell, H. German Patent 361464, 1987;
Chem. Abstr. 1988, 108, 37838.
12. Maier, T.; Schmierer, R.; Bauer, K.; Bieringer, H.; Buerstell, H.; Sachse, B. U.S.
Patent 4820335, 1989; Chem. Abstr. 1989, 111, 19494w.
24. Sharma, S. D.; Hazarika, P.; Konwar, D. Tetrahedron Lett. 2008, 49, 2216–2220.
25. Nagarapu, L.; Apuri, S.; Kantevari, S. J. Mol. Catal. A: Chem. 2007, 266, 104–108.
26. Lipshutz, B. H.; Morey, M. C. J. Org. Chem. 1983, 48, 3745–3750.
27. Mohammadizadeh, M. R.; Hasaninejad, A.; Bahramzadeh, M. Synth. Commun.
2009, 39, 3232–3242.
28. Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. Tetrahedron 2009, 65, 10155–
10161.
29. Sivakumar, K.; Kathirvel, A.; Lalitha, A. Tetrahedron Lett. 2010, 51, 3018–3021.
30. Mukhopadhyay, C.; Tapaswi, P. K.; Drew, M. G. B. Tetrahedron Lett. 2010, 51,
3944–3950.
13. Siamaki, A. R.; Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128, 6050–6051.
14. Claiborne, C. F.; Liverton, N. J.; Nguyen, K. T. Tetrahedron Lett. 1998, 39, 8939–
8942.
15. Schubert, H.; Stodolka, H. J. Prakt. Chem. 1963, 22, 130–133.
16. Balalaie, S.; Arabanian, A. Green Chem. 2000, 2, 274–276.
17. Usyatinsky, A. Y.; Khmelnitsky, Y. L. Tetrahedron Lett. 2000, 41, 5031–5034.
18. Karimi, A. R.; Alimohammadi, Z.; Azizian, J.; Mohammadi, A. A.;
Mohammadizadeh, M. R. Catal. Commun. 2006, 7, 728–732.
19. Kantevari, S.; Vuppalapati, S. V. N.; Biradar, D. O.; Nagarapu, L. J. Mol. Catal. A:
Chem. 2007, 266, 109–113.
31. Davoodnia, A.; Heravi, M. M.; Safavi-Rad, Z.; Tavakoli-Hoseini, N. Synth.
Commun. 2010, 40, 2588–2597.
32. Hekmat Shoar, R.; Rahimzadeh, G.; Derikvand, F.; Farzaneh, M. Synth. Commun.
2010, 40, 1270–1275.
33. Hassaninejad, A.; Zare, A.; Shekouhy, M.; Rad, J. A. J. Comb. Chem. 2010, 12, 844–
849.
34. Niknam, K.; Saberi, D.; Nouri Sefat, M. Tetrahedron Lett. 2009, 50, 4058–4062.
35. Niknam, K.; Saberi, D. Tetrahedron Lett. 2009, 50, 5210–5214.
36. Niknam, K.; Saberi, D. Appl. Catal. A: Gen. 2009, 366, 220–225.
37. Niknam, K.; Saberi, D.; Sadegheyan, M.; Deris, A. Tetrahedron Lett. 2010, 51,
692–694.
38. Niknam, K.; Saberi, D.; Nouri Sefat, M. Tetrahedron Lett. 2010, 51, 2959–2962.
39. Dey, R. K.; Patnaik, T.; Singh, V. K.; Swain, S. K.; Airoldi, C. Appl. Surf. Sci. 2009,
255, 8176–8182.
20. Kidwai, M.; Mothsra, P.; Bansal, V.; Somvanshi, R. K.; Ethayathulla, A. S.; Dey,
S.; Singh, T. P. J. Mol. Catal. A: Chem. 2007, 265, 177–182.
21. Ren, Y. M.; Cai, C. J. Chem. Res. 2010, 133–134.
22. Heravi, M. M.; Derikv, F.; Haghighi, M. Monatsh. Chem. 2008, 139, 31–33.