Multi-component synthesis of highly substituted imidazoles catalyzed by nanorod vanadatesulfuric acid

Article abstract of DOI:10.1515/chempap-2015-0156

Nanorod vanadatesulfuric acid (VSA NRs), as a recyclable and eco-benign catalyst, was used for one-pot synthesis of 2,4,5-trisubstituted imidazoles and 1,2,4,5-tetrasubstituted imidazoles using aldehydes, benzil, benzoin or 9,10-phenanthrenequinone and ammonium acetate or aniline under solvent-free conditions providing high to excellent yields. VSA is easily prepared by a simple reaction of chlorosulfonic acid and sodium metavanadate in high purity. As compared with the conventional procedures, the present protocol offers several advantages such as simplicity of procedure, short reaction time, high yields, easy workup, recoverability and reusability of the catalyst and simple purification of the products.

Full text of DOI:10.1515/chempap-2015-0156

Chemical Papers 69 (11) 1491–1499 (2015)
DOI: 10.1515/chempap-2015-0156
ORIGINAL PAPER
Multi-component synthesis of highly substituted imidazoles
catalyzed by nanorod vanadatesulfuric acid
Masoud Nasr-Esfahani*, Morteza Montazerozohori, Tooba Abdizadeh
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
Received 24 January 2015; Revised 22 April 2015; Accepted 9 May 2015
Nanorod vanadatesulfuric acid (VSA NRs), as a recyclable and eco-benign catalyst, was used for
one-pot synthesis of 2,4,5-trisubstituted imidazoles and 1,2,4,5-tetrasubstituted imidazoles using
aldehydes, benzil, benzoin or 9,10-phenanthrenequinone and ammonium acetate or aniline under
solvent-free conditions providing high to excellent yields. VSA is easily prepared by a simple reaction
of chlorosulfonic acid and sodium metavanadate in high purity. As compared with the conventional
procedures, the present protocol offers several advantages such as simplicity of procedure, short
reaction time, high yields, easy workup, recoverability and reusability of the catalyst and simple
purification of the products.
c
ꢀ 2015 Institute of Chemistry, Slovak Academy of Sciences
Keywords: vanadatesulfuric acid, 2,4,5-trisubstituted imidazoles, 1,2,4,5-tetrasubstituted imida-
zoles, reusable catalyst, heterogeneous catalyst, nanorod particles
Introduction
ing and fluorescence labeling agents in biological fields
(Sun et al., 2009), ionic liquids in green chemistry
(Davoodnia et al., 2011) and finally N-heterocyclic
carbenes in organometallic catalysis (Bourissou et al.,
2000) are some other applications of the imidazoles
family.
In recent years, chemical and biological usefulness
of multi-substituted imidazoles have attracted more
attention in the field of pharmaceutical industry. A
wide variety of biological properties have been found
for imidazole derivatives including antibacterial (An-
tolini et al., 1999), analgesic (Uc¸ucu et al., 2001),
glucagon receptor antagonism (Chang et al., 2001),
anticonvulsant (Wang et al., 2002), tuberculostatic
(Siddiqui et al., 2005) and anticancer activities (Wang
et al., 2003). Many biological inhibitors belong to the
trisubstituted imidazoles family (Takle et al., 2006).
Moreover, these kinds of imidazoles are also applied
in photography as photo sensitive compounds (Kidwai
et al., 2006). Tetrasubstituted imidazole frameworks
are the most active ones among many drug molecules
such as olmesartan, medoxomil, losartan, eprosartan
and trifenagrel (Abrahams et al., 1989; Norwood et al.,
2002; Wolkenberg et al., 2004) as well as other phar-
maceutical natural products (Lombardino & Wise-
man, 1974). Applications such as chromophores in
non-linear optic systems (Stähelin et al., 1992), imag-
The first synthesis of the poly-substituted imida-
zole was reported in 1882 using an aldehyde, 1,2-
dicarbonyl compound and ammonia (Radziszewski,
1882). In recent decades, various methods for the
preparation of trisubstituted and tetrasubstituted imi-
dazoles have been developed. 2,4,5-Trisubstituted imi-
dazoles are usually prepared by three-components cy-
clocondensation of 1,2-diketone or α-hydroxyketone,
an aldehyde and ammonium acetate in the presence of
a strong protic acid, such as H3PO4 (Liu et al., 2003)
or H2SO4 (Weinmann et al., 2002) or other catalysts
in HOAc (Frantz et al., 2004) under reflux conditions
or microwave irradiation (Oskooie et al., 2006), silica
sulfuric acid (Shaabani & Rahmati, 2006), ionic liq-
uids (Siddiqui et al., 2005), ceric ammonium nitrate
(CAN) (Sangshetti et al., 2008), K5CoW12O40 · 3H2O
(Nagarapu et al., 2007), Yb(OTf)3 (Wang et al., 2006)
*Corresponding author, e-mail: manas@yu.ac.ir
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M. Nasr-Esfahani et al./Chemical Papers 69 (11) 1491–1499 (2015)
Fig. 1. Synthesis of 2,4,5-trisubstituted imidazoles.
Fig. 2. Synthesis of 1,2,4,5-tetrasubstituted imidazoles.
and Cu(NO3)2–zeolite (Sivakumar et al., 2010). Tetra-
substituted imidazoles have also been synthesized via
four-component condensation reactions using various
Lewis or protic acidic reagents such as I2 (Kidwai et
al., 2007), heteropolyacid (Heravi et al., 2007), silica
gel/NaHSO4 (Karimi et al., 2006), L-proline (Samai
et al., 2009), BF3–SiO2 (Sadeghi et al., 2008) and
silica-supported Wells–Dawson acid (Karimi et al.,
2010). The reaction of 1,2-diketone with a nitrile
and a primary amine by N-alkylation of trisubsti-
tuted imidazoles (Davidson et al., 1937), under mi-
crowave irradiation (Balalaie et al., 2003), and by
hetero-Cope rearrangement (Lantos et al., 1993) is an-
other method for the synthesis of these compounds.
In spite of other imidazoles, there are a few reports
on the synthesis of phenanthroimidazoles, probably
due to their lower solubility in organic solvents and
the steric hindrance in these molecules (Yan et al.,
2009, 2010; Eseola et al., 2011). Most of the above
mentioned methods suffer from serious drawbacks,
such as mineral acids and hazardous and often ex-
pensive acid catalysts, long reaction time, laborious
and complex work-up and purification and moderate
yield. On the other hand, the use of polar solvents
such as EtOH, MeOH, CH3COOH, DMF and DMSO
leads to the complexity of product isolation and cat-
alyst recovery. Therefore, the design of new clean,
safe and eco-benign methods seems to be necessary.
Multi-component reactions (MCRs) provide an at-
tractive synthesis method because of the fast and
effective generation of products. Nowadays, organic
syntheses involving the MCRs strategy are of inter-
est because of a single step procedure, which is pre-
ferred to the multiple step one, with no harmful by-
products and easy work-up. Here, solid acid catalysts
have gained increasing importance in organic synthe-
ses due to their advantages including reusability, sim-
plicity, non-toxicity, low cost and simple isolation af-
ter the reaction completion (Clark, 2002). Thus, intro-
ducing new eco-friendly Brønsted and/or Lewis acidic
catalysts with appropriate reusability is important in
organic synthesis.
In continuation of our previous efforts toward
the development and application of new nanostruc-
ture heterogeneous catalysts in organic synthesis
(Nasr-Esfahani & Abdizadeh, 2013a, 2013b; Nasr-
Esfahani et al., 2014), a mild and efficient one-pot
four component synthesis of 2,4,5-trisubstituted im-
idazoles (Fig. 1) and 1,2,4,5-tetrasubstituted imida-
zoles (Fig. 2) in high yields using nanorod vanadate-
sulfuric acid (VSA NRs) as a novel solid acid cata-
lyst with high catalytic activity and reusability in very
short reaction time under solvent-free conditions is re-
ported herein.
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M. Nasr-Esfahani et al./Chemical Papers 69 (11) 1491–1499 (2015)
1493
Experimental
= 3 : 1 vol.). IR (KBr), ν˜/cm−1: 696, 765, 914, 970,
1150, 1489, 1504, 1602, 3029. 1H NMR (400 MHz,
CDCl3), δ: 2.30 (s, 3H), 2.59 (s, 3H), 7.10–7.68 (m,
13H), 12.38 (s, 1H). 13C NMR (125 MHz, DMSO-d6)
δ: 21.21, 21.54, 122.33, 124.51, 125.62, 127.35, 127.46,
127.54, 127.84, 127.99, 129.78, 132.38, 137.21, 135.92,
136.53, 136.95, 137.96, 146.71. Formula, C23H20N2;
calculated: C, 85.15; H, 6.21; N, 8.63; found: C, 85.05;
H, 6.16; N, 8.70.
All chemicals were provided from Merck, Fluka
and Aldrich chemical companies. Transmission elec-
tron microscopy images were recorded using a Philips,
CM-10 TEM instrument operated at 100 kV. Melting
points were measured by a Barnstead Electrothermal
(BI 9300) apparatus and are uncorrected. IR spec-
tra were obtained using a FT-IR JASCO-680 spec-
trometer instrument. NMR spectra were recorded by a
Bruker 400 MHz Ultrashield spectrometer at 400MHz
(1H) and 125 MHz (13C) using CDCl3 or DMSO-d6 as
the solvent with TMS as the internal standard.
2-(2,6-Dichlorophenyl)-4,5-diphenyl-1H-
imidazole IVu
MP = 232–233◦C; Rf = 0.59 (n-hexane/ethyl ac-
etate = 3 : 1 vol.). IR (KBr), ν˜/cm−1: 696, 777, 914,
973, 1194, 1480, 1501, 1603, 3056. 1H NMR (400 MHz,
CDCl3) δ: 7.23–7.65 (m, 13H), 12.75 (s, H, NH).
13C NMR (125 MHz, DMSO-d6) δ: 127.05, 127.63,
127.80, 128.15, 128.25, 128.69, 128.79, 129.25, 130.91,
131.33, 132.36, 135.56, 136.16, 137.02, 141.21. For-
mula, C21H14Cl2N2; calculated: C, 69.05; H, 3.86; Cl,
19.41; N, 7.67; found: C, 68.96; H, 3.79; N, 7.73.
Preparation of vanadatesulfuric acid
Anhydrous sodium metavanadate was obtained by
drying of sodium metavanadate monohydrate in an
oven at 250◦C for 4 h. To a mixture of chlorosulfonic
acid (0.1 mol, 11.6 g) and dry CHCl3 (25 mL) in a
round bottom flask in an ice-bath, anhydrous sodium
metavanadate (0.1 mol, 12.2 g) was gradually added
under rigorous stirring. After the addition completion,
the reaction mixture was shaken for 1 h. Then, 50 mL
of cold water were added to the reaction mixture and
it was stirred for 15 min. Finally, the reaction mixture
was filtered and a dark red solid of vanadatesulfuric
acid was obtained (16.1 g, 90 %). MP = 256◦C (de-
composition). Characteristic IR bands (KBr, cm−1):
2-(3-Ethoxy-4-hydroxyphenyl)-4,5-diphenyl-
1H-imidazol IVv
MP = 261–263◦C. Rf = 0.63 (hexane/ethyl acetate
= 3 : 1 vol.). IR (KBr), ν˜/cm−1: 696, 764, 932, 1194,
1
1496, 1602, 3030, 3316. H NMR (400 MHz, CDCl3)
—
3540–3300 (OH, bs), 1640 (OH, m), 1250–1140 (S O,
δ: 1.36 (t, 3H, J = 6.2 Hz), 4.08 (q, 2H, J = 6.5 Hz),
6.83–7.64 (m, 13H), 9.18 (s, 1H), 12.39 (s, 1H). 13C
NMR (125 MHz, DMSO-d6) δ: 15.25, 64.41, 111.03,
116.16, 118.86, 122.38, 126.82, 127.49, 128.04, 128.60,
128.85, 129.11, 131.82, 135.83, 137.04, 146.53, 147.29,
147.77. Formula, C23H20N2O2; calculated: C, 77.51;
H, 5.66; N, 7.86; O, 8.98; found: C, 77.42; H, 5.71; N,
7.91.
—
—
—
—
bs), 1050 (S—O, m), 960 (V O, m), 840 (V O, m),
630 (V—O, m) (Nasr-Esfahani & Abdizadeh, 2013a,
2013b).
—
General procedure for the preparation of multi-
substituted imidazoles
In a round-bottom flask, the aldehyde (1 mmol),
benzil or benzoin (1 mmol), ammonium acetate
(2 mmol for 2,4,5-trisubstituted imidazoles and
1 mmol for 1,2,4,5-tetrasubstituted imidazoles) or ani-
line (1 mmol for 1,2,4,5-tetrasubstituted imidazoles)
and VSA (10 mol %) were mixed thoroughly. The flask
was heated at 80◦C under continuous stirring. After
the its completion, the reaction as monitored by TLC
(eluent/EtOAc/hexane = 1 : 4 vol.), acetone (10 mL)
was added and the solid catalyst was then filtered and
separated. The solvent was evaporated and the crude
products were purified by column chromatography or
recrystallization from ethanol (Tables 2 and 3). Then,
2-(2,4-Dimethylphenyl)-1H-phenanthro[9,10-
d]imidazole VIg
MP = 207–209◦C. Rf = 0.65 (hexane/ethyl acetate
= 3 : 1 vol.); IR (KBr), ν˜/cm−1: 631, 753, 918, 963,
1149, 1483, 1552, 1617, 3054. 1H NMR (400 MHz,
CDCl3) δ: 2.35 (s, 3H), 2.68 (s, 3H), 7.10–7.68 (m,
11H), 12.38 (s, H). 13C NMR (125 MHz, DMSO-
d6) δ: 21.29, 21.53, 122.33, 122.44, 122.96, 124.16,
124.51, 125.40, 125.62, 126.97, 127.35, 127.46, 127.63,
127.94, 129.78, 132.38, 137.27, 138.89, 150.31. For-
mula, C23H18N2; calculated: C, 85.68; H, 5.63; N, 8.69;
found: C, 85.58; H, 5.58; N, 8.76.
1
the products were characterized by IR, H NMR, 13C
NMR and also the comparison of their melting points
with those reported in literature.
Results and discussion
2-(2,4-Dimethylphenyl)-4,5-diphenyl-1H-
imidazole IVt
Synthesis of a new and efficient acidic catalyst was
attempted, and anhydrous sodium metavanadate was
proved to be able to react with chlorosulfonic acid to
give nanorod vanadatesulfuric acid (VSA NRs) (Nasr-
MP = 221–223◦C. Rf = 0.67 (hexane/ethyl acetate
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M. Nasr-Esfahani et al./Chemical Papers 69 (11) 1491–1499 (2015)
Fig. 3. Synthesis of nanorod vanadatesulfuric acid.
Esfahani & Abdizadeh, 2013a, 2013b). The reaction
was simple and routine so that the product was ob-
tained by simple filtration (Fig. 3).
Synecek and co-worker have shown that in the
structure of metavanadate ion, the oxygen atoms are
tetrahedrally coordinated to the vanadium atoms and
the tetrahedral VO4 units form infinite chains in the
direction of the [001] axis (Syneček & Hanic, 1954). In
this structure, the VO4 chains are mutually bonded by
electrostatic bonds of the positive ions.
Fig. 4. TEM image of VSA NRs (needle-like, size of 15–
20 nm).
Scherrer equation from the XRD pattern of VSA NRs
(Fig. 4) (Nasr-Esfahani & Abdizadeh, 2013a, 2013b).
IR spectrum of nanorod vanadatesulfuric acid
showed two absorption bands at 3450 cm−1 and
1640 cm−1 assigned to the stretching and bending vi-
brations of the hydroxy group, respectively. The ab-
sorption peaks at 1050 cm−1 and 1180 cm−1 were at-
Effect of solvent, catalyst concentration and
heat on the synthesis of multi-substituted imi-
dazoles
—
tributed to the sulfonic acid bonds of S—OH, S
O
In order to find the best experimental conditions,
catalytic activity of nanorod vanadatesulfuric acid in
the synthesis of 2,4,5-trisubstituted imidazoles and
1,2,4,5-tetrasubstituted imidazoles under different re-
action conditions was first investigated. As a typi-
cal reaction in a comparable study, the condensation
of benzaldehyde (1 mmol), benzil (1 mmol), ammo-
nium acetate (2 mmol for trisubstituted imidazole and
1 mmol for tetrasubstituted imidazole) and aniline
(1 mmol for tetrasubstituted imidazole) in the pres-
ence of VSA NRs (5 mol %) was performed in a solvent
and under solvent-free conditions. As shown in Ta-
—
—
—
stretching and the S O asymmetric stretching, re-
spectively. These signals, not present in the IR spec-
trum sodium metavanadate, confirm the synthesis of
the target catalyst. The absorption peaks appearing
at 960 cm−1, 840 cm−1 and 603 cm−1 are related
—
—
to the V O and V—O stretching vibrations, respec-
tively (Nasr-Esfahani & Abdizadeh, 2013a, 2013b).
Based on the TEM image, the solid acid catalyst
has needle-like morphology with a narrow size distri-
bution in the range of 15 nm to 20 nm and the mean
size of 17 nm, confirming the data calculated using the
Table 1. Catalytic activity evaluation and effect of temperature and solvent on the synthesis of multi-substituted imidazolesa
A and B
Temperature
A
B
A
B
Entry
Catalyst
mole %
Solvent
Yieldb
%
Time
min
◦C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5
7
100
100
100
100
100
100
100
100
100
RT
40
–
–
–
–
76
82
92
88
43
35
30
32
50
25
55
68
80
90
68
74
85
80
35
30
26
30
40
20
40
56
67
82
45
40
30
75
60
50
10
15
10
10
10
10
10
10
10
10
10
10
35
55
Ethanol
Methanol
Water
Acetonitrile
200
340
380
360
400
120
85
50
42
40
250
380
430
400
450
150
100
75
Chloroform
–
–
–
–
–
60
80
120
62
60
a) Reaction conditions: benzaldehyde (1 mmol), benzil (1 mmol), ammonium acetate (2 mmol) for trisubstituted imidazole (con-
dition A) and benzaldehyde (1 mmol), benzil (1 mmol), ammonium acetate (1 mmol) and aniline (1 mmol) for tetrasubstituted
imidazole (condition B); b) isolated yields.
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M. Nasr-Esfahani et al./Chemical Papers 69 (11) 1491–1499 (2015)
Table 2. Preparation of 2,4,5-trisubstituted imidazoles catalyzed by VSA NRs using benzil (II) or benzoin (III)
Benzil Benzoin Benzil Benzoin Founda Reported
1495
Entry
R
Product
Yieldb
%
Time
min
MP
◦C
Reference
1
2
C6H5
4-NO2C6H4
IVa
IVb
92
89
90
30
30
40
35
272–274 274–275 Samai et al. (2009)
241–243 242–243
87
85
85
3
4
3-NO2C6H4
3-ClC6H4
IVc
IVd
87
88
35
25
39
38
298–300 299–300 Shaabani and Rahmati (2006)
233–235 234–236 Zang et al. (2010)
5
6
2-ClC6H4
4-ClC6H4
IVe
IVf
86
90
82
87
40
25
53
36
182–184 183–184 Samai et al. (2009)
260–262 261–263
7
8
9
4-BrC6H4
2,4-Cl2C6H3
4-(CH3)2NC6H3
IVg
IVh
IVi
94
86
92
90
85
90
35
35
30
36
46
37
264–266 265–266 Zang et al. (2010)
177–179 178–179
255–257 256–257
10
11
2-HOC6H4
4-HOC6H4
IVj
IVk
85
84
82
82
45
40
52
52
201–203 200–203 Zhao et al. (2005)
232–234 233–235
12
2-CH3C6H4
IVl
80
81
50
59
203–205 205–207 Sivakumar et al. (2010)
13
14
15
16
4-CH3C6H4
4-HO-3-CH3OC6H3
4-CH3OC6H4
IVm
IVn
IVo
IVp
82
83
80
91
86
80
82
89
45
42
40
35
50
56
55
45
230–232 233–235 Zhao et al. (2005)
241–243 243–244
229–231 230–233
3,4-(CH3O)2C6H3
141–143 142–143
17
18
19
2-Furyl
2-Thienyl
CH3CH2CH2
IVq
IVr
IVs
80
78
71
80
80
69
45
50
65
55
70
75
232–234 233–235 Samai et al. (2009)
254–256 255–256
205–207 206–208
20
21
2,4-(CH3)2C6H3
2,6-Cl2C6H3
IVt
IVu
IVv
79
90
88
76
89
86
60
40
55
62
50
65
221–223
232–233
261–263
–
–
–
–
–
–
22 4-HO-3-CH3CH2OC6H3
a) All products were characterized by 1H NMR and IR spectroscopy and compared with literature; b) isolated yields.
ble 1, the tested solvents included ethanol, methanol,
water, acetonitrile, chloroform and were compared
with a solvent-free system; the best results were ob-
served after 30 min or 50 min for the reactions un-
der solvent-free conditions for the synthesis of trisub-
stituted and tetrasubstituted imidazoles in excellent
yields, 92 % and 85 %, respectively.
With these results, the best reaction conditions
were studied by using different amounts of the cat-
alyst. It was found that an increase in the quantity
of the catalyst causes higher product yields (Table 1),
thus, the concentration of 10 mol % of nanorod vana-
datesulfuric acid was found to be the optimum amount
of catalyst. This optimization achievement showed
that the catalyst concentration plays a major role in
the product yields. It is to be noted that higher load-
ings of catalyst did not increase the rate and yields
of the reactions. Moreover, the effect of temperature
on the reaction product yields was also investigated.
Higher yields in shorter reaction times were obtained
after increasing the temperature to 100◦C, while the
product yields decreased at higher temperatures (Ta-
ble 1). To improve the yields, the reactions were per-
formed using different amounts of reagents. The best
results were obtained with the 1 : 1 : 2 molar ra-
tio of benzaldehyde, benzyl and ammonium acetate
in the synthesis of trisubstituted imidazole, while the
1 : 1 : 1 : 1 molar ratio of benzaldehyde, benzyl, am-
monium acetate and aniline for tetrasubstituted imi-
dazole was found as suitable for efficient synthesis of
tetrasubstituted imidazole.
A wide variety of aromatic, heterocyclic and
aliphatic aldehydes as well as benzil, benzoin and 9,10-
phenanthrenequinone were investigated under these
optimized conditions to extend the scope of the cat-
alytic transformation. As shown in Table 2, VSA
NRs catalyzed the three-components condensation re-
actions of an aldehyde (1 mmol), benzil or benzoin
(1 mmol), and ammonium acetate (2 mmol) gave the
desired products of 2,4,5-trisubstituted imidazoles in
high to excellent yields in short reaction times. To
study the substituent effect under optimized reac-
tion conditions, aldehydes bearing various functional
groups such as nitro, halogen, methyl, methoxy and
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M. Nasr-Esfahani et al./Chemical Papers 69 (11) 1491–1499 (2015)
Table 3. Preparation of 2,4,5-trisubstituted imidazoles catalyzed by VSA NRs using 9,10-phenanthrenequinone (V )
Founda
Reported
MP
◦C
Entry
R
Product
Yieldb
%
Time
min
Reference
1
2
C6H5
4-ClC6H4
VIa
VIb
90
92
30
30
35
35
321–323
273–275
322–324
275–276
Saffari Jourshari et al. (2013)
Damavandi (2011)
3
4
5
6
4-NO2C6H4
4-OCH3C6H4
4-CH3C6H4
4-OHC6H4
VIc
VId
VIe
VIf
91
84
85
82
35
25
40
25
32
45
48
50
337–339
254–256
268–270
348–350
336–338
255–256
270–271
350–352
7
2,4-(CH3)2C6H3
VIg
85
35
40
207–209
–
–
a) All products were characterized by 1H NMR and IR spectroscopy and compared with literature; b) isolated yields.
Table 4. Catalytic synthesis of 1,2,4,5-tetrasubstituted imidazoles using VSA NRs and benzil or benzoin
Benzil Benzoin Benzil Benzoin Founda Reported
Entry
R
Product
Yieldb
%
Time
min
MP
◦C
Reference
1
2
C6H5
4-NO2C6H4
VIIa
VIIb
85
85
83
81
50
45
60
55
219–221 218–220 Teimouri and Chermahini (2011)
183–185 184–186
3
4
4-ClC6H4
4-BrC6H4
VIIc
VIId
88
84
85
82
46
45
58
54
162–164 164–166 Wang et al. (2009)
151–153 152–154 Teimouri and Chermahini (2011)
5
7
4-HOC6H4
4-CH3C6H4
VIIe
VIIf
80
81
80
80
58
60
69
75
284–286 287–289 Wang et al. (2009)
185–187 186–188
22
4-CH3OC6H4
VIIg
79
77
75
80
183–185 180–182 Teimouri and Chermahini (2011)
a) All products were characterized by 1H NMR and IR spectroscopy and compared with literature; b) isolated yields.
hydroxy were used. It was observed that the reactions
with aldehydes possessing an electron-withdrawing
group give excellent yields of products in shorter re-
action times as compared with the reactions employ-
ing aldehydes with electron-donating groups (Table 2).
Aliphatic aldehydes afforded the corresponding imida-
zoles in moderate yield at low reaction rate (Table 2,
entry 19). The same reactions with benzoin (III ) in-
stead of benzil (II ) showed lower reactivity (Tables 2
and 4). Also, the optimized conditions were applied
for the synthesis of phenanthro[9,10-d]imidazoles (VI )
using 9,10-phenanthrenequinone (V ) providing prod-
ucts in good to excellent yields in short reaction times
(Table 3).
the optimized conditions applied.
For these multi-component reactions, different
mechanistic pathways have been proposed in the
Brønsted or Lewis acidic catalysis (Davidson et al.,
1937; Wang et al., 2006; Kokare et al., 2007). A
plausible mechanism for the synthesis of imidazoles
from benzil, aldehyde, and ammonium acetate by VSA
catalysis may be similar to that of the acid-catalyzed
synthesis (Siddiqui et al., 2005), which involves the
formation of a diamine intermediate (VIII ) (Fig. 5).
The condensation of VIII with benzil leads to inter-
mediate IX which is rearranged via a [1,5]-sigmatropic
proton shift to afford the corresponding imidazole
(IV ).
The synthesis of 1,2,4,5-tetrasubstituted imida-
zoles was also carried out by condensation of an alde-
hyde (1 mmol), benzil or benzoin (1 mmol), aniline
(1 mmol) and ammonium acetate (1 mmol) under the
same conditions. The results are provided in Table 4.
In spite of some other reports, no by-products such as
2,4,5-trisubstituted imidazoles were produced under
On the other hand, intermediate VIII reacts with
benzoin to form intermediate of dihydroimidazole (X )
that undergoes aerobic oxidation to give the fully con-
jugated system IX and is subsequently rearranged via
a [1,5]-sigmatropic proton shift to give the final prod-
uct. Therefore, the necessity of an oxidation step in
the production of intermediate IX can be explained
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Fig. 5. Plausible mechanism for the catalytic synthesis of multi-substituted imidazoles.
Table 5. Reusability of nanorod vanadatesulfuric acid in the
recovered from the reaction mixture and dried in an
oven at 120◦C for 3 h prior to use. Afterwards, con-
sidering the amount of the dried recovered catalyst,
the required amounts of fresh substrates were added.
It is noteworthy that VSA NRs acts as the catalyst
for four consecutive runs without a noticeable activity
loss (Table 5). Therefore, we suggest that the structure
of the catalyst remains unchanged after its recycling
which is confirmed by comparison of the XRD diffrac-
tion patterns and infrared spectra of fresh and used
VSA nanorods (Nasr-Esfahani & Abdizadeh, 2013a,
2013b).
synthesis of multi-substituted imidazoles
Cycle
Time/min
Isolated yield/%a
Fresh
30
32
35
37
40
92
90
87
85
82
1
2
3
4
a) Catalyst recyclable by washing with ethanol dried at 100◦C
for 2 h.
by the lower reaction rate observed when using ben-
zoin (Tables 2 and 4) (Kokare et al., 2007).
Conclusions
From the industrial point of view, the recovery
and reusability of the catalyst is important for large
scale operations. Therefore, catalytic activity of recy-
cled VSA was examined in the reaction of benzalde-
hyde, benzil and ammonium acetate producing trisub-
stituted imidazole. The catalyst can be separated from
the reaction mixture using simple filtration without
any acidic or basic work-up after the dilution of the
reaction mixture with ethanol. Therefore, after the
completion of the typical reaction, the catalyst was
In summary, a procedure using nonorod vanadate-
sulfuric acid (VSA) as an efficient novel catalyst for
the synthesis of 2,4,5-trisubstituted imidazoles and
1,2,4,5-tetrasubstituted imidazoles in a one-pot four-
component condensation of benzyl, benzoin or 9,10-
phenanthrenequinone with an aldehyde, ammonium
acetate and/or aniline under solvent-free conditions
has been developed. This method provided the desired
products in high yields in short reaction times, follow-
ing a simple work-up procedure. Also, the catalyst can
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1498
M. Nasr-Esfahani et al./Chemical Papers 69 (11) 1491–1499 (2015)
be readily recycled and reused at least four times with-
out any considerable loss of its activity and change in
the structure. Moreover, this catalytic system demon-
strates some advantages such as environmentally be-
nign character, mild reaction conditions, easy han-
dling, lower catalyst loading and cost efficiency. This
approach can be a valuable contribution to the re-
ported processes in the field of poly-substituted imi-
dazoles syntheses.
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