Efficient multi-component synthesis of highly substituted imidazoles utilizing P2O5/SiO2 as a reusable catalyst

Article abstract of DOI:10.1002/cjoc.201180293

Phosphorus pentoxide supported on silica gel (P₂O ₅/SiO₂) has been used as an efficient and reusable catalyst for the one-pot pseudo four-component synthesis of 2,4,5-trisubstituted imidazoles from benzil or benzoin, aldehydes, and ammonium acetate. It was also used for four-component preparation of 1,2,4,5-tetrasubstituted imidazoles from benzil or benzoin, aldehydes, primary amine, and ammonium acetate under thermal solvent-free conditions. The remarkable features of this new procedure are high conversions, cleaner reaction, simple experimental and work-up procedures and also the catalyst can be easily separated from the reaction mixture and reused several times without any loss of its activity.

Full text of DOI:10.1002/cjoc.201180293

FULL PAPER
Efficient Multi-component Synthesis of Highly Substituted
Imidazoles Utilizing P2O5/SiO2 as a Reusable Catalyst
Shaterian, Hamid Reza*
Ranjbar, Mohammad
Azizi, Kobra
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan,
PO Box 98135-674, Zahedan, Iran
Phosphorus pentoxide supported on silica gel (P2O5/SiO2) has been used as an efficient and reusable catalyst for
the one-pot pseudo four-component synthesis of 2,4,5-trisubstituted imidazoles from benzil or benzoin, aldehydes,
and ammonium acetate. It was also used for four-component preparation of 1,2,4,5-tetrasubstituted imidazoles from
benzil or benzoin, aldehydes, primary amine, and ammonium acetate under thermal solvent-free conditions. The
remarkable features of this new procedure are high conversions, cleaner reaction, simple experimental and work-up
procedures and also the catalyst can be easily separated from the reaction mixture and reused several times without
any loss of its activity.
Keywords multicomponent reactions, domino reactions, phosphorus pentoxide supported on silica gel,
2,4,5-trisubstituted imidazoles, 1,2,4,5-tetrasubstituted imidazoles, heterogeneous catalysis
Introduction
Scheme 1
Multi-component reactions (MCRs) are powerful
tools in generating products in organic and medicinal
chemistry for their high degree of atom economy and
application in the diversity-oriented convergent synthe-
sis of complex organic molecules from simple and read-
ily available substrates in a single synthetic operation.1,2
Imidazoles are an important class of heterocycles
being the core fragment of different natural products
and biological systems.3,4 Substituted imidazoles used
as light-sensitive materials in photography are known as
inhibitors, fungicides and herbicides,5 plant growth
regulators and therapeutic agents.6 Phosphorus pentox-
ide-methanesulfonic acid was used for the first time as a
convenient alternative to polyphosphoric acid by Eaton
et al. to escape the difficulties encountered with poly-
phosphoric acid (PPA).7 In continuation of researcher
works8 on supported materials, P2O5/SiO2 as an inex-
pensive, heterogeneous stable, free flowing, and white
powder was prepared. P2O5/SiO2 was used for several
transformations.9-15 We report herein, a simple pseudo
four-component synthesis of 2,4,5-trisubstituted imida-
zoles from benzil or benzoin, aldehydes, and ammo-
nium acetate (Scheme 1) and also four-component
preparation of 1,2,4,5-tetrasubstituted imidazoles from
benzil or benzoin, aldehydes, primary amine, and am-
monium acetate (Scheme 2) in high yields using cata-
lytic amount of P2O5/SiO2 as a catalyst under sol-
vent-free conditions for the first time.
Scheme 2
Experimental
All reagents were purchased from Merck and Al-
drich and used without further purification. P2O5/SiO2
was prepared according to the reported procedure.16 All
yields refer to isolated products after purification.
*
E-mail: hrshaterian@chem.usb.ac.ir; Tel.: 0098-541-2447010, Fax: 0098-541-2431067
Received February 24, 2011; revised April 21, 2011; accepted April 21, 2011.
Project supported by the University of Sistan and Baluchestan Research Council.
Chin. J. Chem. 2011, 29, 1635—1645
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Shaterian, Ranjbar & Azizi
FULL PAPER
Products were characterized by comparison with au-
thentic samples and by spectroscopy data (IR, 1H NMR
and 13C NMR spectra). The NMR spectra were recorded
on a Bruker Avance DPX 500 MHz instrument, and
measured in DMSO-d6 relative to TMS. FT-IR spectra
were recorded on a JASCO FT-IR 460 plus spectropho-
tometer. Mass spectra were recorded on an Agilent
technologies 5973 network mass selective detector
(MSD) operating at an ionization potential of 70 eV.
TLC was performed on a silica-gel Poly Gram SIL
G/UV 254 plates.
room temperature. The resulting mixture was heated to
100 ℃ for the appropriate time reported in Table 2.
Completion of the reaction was indicated by TLC. After
completion of the reaction, the mixture was cooled to
room temperature, and the crude solid product was dis-
solved in ethylacetate. The mixture was filtered for
separation of the catalyst. The catalyst was washed
twice with ethylacetate (5 mL×2), and then recovered
catalyst was dried in an oven at 100 ℃ for 3 h. The
filtrate organic solution was concentrated. The solid
product was purified by recrystallization procedure in
ethanol. All of the desired product(s) were characterized
by comparison of their physical data with those of
known compounds. Some characterization data for se-
lected known products are given below.
Preparation of P2O5/SiO2
A mixture of SiO2 (2 g) and P2O5 (1 mmol, 0.142 g)
was ground vigorously to give P2O5/SiO2 catalytic sys-
tem as a white powder (2.142 g).16
1,4,5-Triphenyl-2-p-tolyl-1H-imidazole (Table 2,
1
Entry 6): H NMR (DMSO-d6, 500 MHz) δ: 2.26 (s,
General procedure for preparation of 2,4,5-trisub-
stituted imidazoles
3H), 7.08 (d, J＝8.0 Hz, 2H), 7.16—7.18 (m, 1H),
7.22—7.25 (m, 6H), 7.26—7.28 (m, 5H), 7.31—7.32
(m, 3H), 7.50 (d, J＝8.0 Hz, 2H); 13C NMR (DMSO-d6,
125 MHz) δ: 21.5, 127.2, 128.4, 128.9, 129.0, 129.2,
129.50, 129.58, 129.6, 129.9, 131.3, 131.9, 132.0, 135.3,
137.60, 137,63, 138.6, 147.0; IR (KBr) ν: 2935, 1590,
Benzil or benzoin (1 mmol), aldehyde (1 mmol) and
ammonium acetate (4 mmol) were added to P2O5/SiO2
(0.05 g, 7 wt%)16 in an oil bath at room temperature.
The resulting mixture was heated to 100 ℃ for the
appropriate time reported in Table 1. Completion of the
reaction was indicated by TLC. After completion of the
reaction, the mixture was cooled to room temperature,
and the crude solid product was dissolved in ethylace-
tate. The mixture was filtered for separation of the cata-
lyst. The catalyst was washed twice with ethylacetate (5
mL×2), and then recovered catalyst was dried in oven
at 100 ℃ for 3 h. The filtrate organic solution was
concentrated. The solid product was purified by recrys-
tallization procedure in ethanol. All of the desired
product(s) were characterized by comparison of their
physical data with those of known compounds. Some
characterization data for selected known products are
given below:
－
1
1577, 1492 cm .
1,2-Bis(4-chlorophenyl)-4,5-diphenyl-1H-imidazole
1
(Table 2, Entry 10): H NMR (DMSO-d6, 500 MHz):
δ: 7.17—7.19 (m, 1H), 7.23—7.25 (m, 4H), 7.29—7.32
(m, 5H), 7.38—7.42 (m, 6H), 7.50 (d, J＝7.0 Hz, 2H);
13C NMR (DMSO-d6, 125 MHz) δ: 127.2, 127.4, 129.44,
129.49, 129.9, 130.1, 130.8, 130.9, 131.3, 132.0, 132.3,
134.1, 134.3, 135.0, 136.2, 145.8; IR (KBr) ν: 2987,
－
1
1596, 1499, 1411 cm .
Results and discussion
Owing to the versatile biological activities of substi-
tuted imidazoles, numerous classical methods for the
synthesis of these compounds have been reported.3-6 In
a typical procedure, benzil or benzoin, aldehydes,
amines, and ammonium acetate are condensed in the
presence of strong protic acid such as H3PO4,17 H2SO4,18
HOAc19 as well as organo catalyst in HOAc20 under
reflux conditions and silica structure MCM-41 or
p-toluenesulfonic acid (p-TsOH).21 These catalysts pre-
sent limitations due to the use of corrosive reagents and
the necessity of neutralization of the strong acid media.
In addition, the synthesis of these heterocycles in polar
organic solvents such as ethanol, methanol, acetic acid,
DMF and DMSO leads to complex isolation and recov-
ery procedures.
In our research for selection of appropriate reaction
conditions, we chose the reaction of benzil (1 mmol),
benzaldehyde (1 mmol) and ammonium acetate (2
mmol) as a model with 0.05 g of P2O5 /SiO2 as catalyst
at 100 ℃ under solvent-free conditions. We avoid us-
ing pure phosphorus pentoxide (P2O5) for the reaction,
because it is a flammable, dangerous, corrosive to metal
and extremely deliquescent compound. It reacts vigor-
2-(4-Methoxyphenyl)-4,5-diphenylimidazole (Table
1, Entry 4): 1H NMR (DMSO-d6, 500 MHz) δ: 12.48 (s,
1H), 8.00 (dt, J＝8.80, 2.0 Hz, 2H), 7.51 (d, J＝7.2 Hz,
4H), 7.35 (t, J＝7.2 Hz, 4H), 7.27 (t, J＝7.2 Hz, 2H),
7.04 (dt, J＝8.8, 2.0 Hz, 2H), 3.80 (s, 3H); 13C NMR
(DMSO-d6, 125 MHz) δ: 55.2, 114.1, 122.9, 126.7,
127.0, 127.7, 128.4, 145.6, 159.4; IR (KBr) ν: 3400,
－
1
3060, 1611, 1490, 1179, 1028, 830, 761 cm .
2-(2,4-Dichlorophenyl)-4,5-diphenylimidazole (Ta-
ble 1, Entry 18): 1H NMR (DMSO-d6, 500 MHz) δ: 12.8
(s, 1H), 7.80 (d, J＝8.4 Hz, 2H), 7.81 (s, 1H), 7.61—
7.22 (m, 12H); 13C NMR (DMSO-d6, 125 MHz) δ:
126.7, 127.2, 127.4, 127.9, 128.2, 128.3, 128.7, 128.8,
129.6, 130.6, 132.4, 132.6, 133.9, 134.8, 137.1, 142.4;
－
1
IR (KBr) ν: 3427, 3068, 1593, 824, 767 cm .
General procedure for preparation of 1,2,4,5-tetra-
substituted imidazoles
Benzil or benzoin (1 mmol), aldehyde (1 mmol),
amine (1 mmol), and ammonium acetate (1 mmol) were
added to P2O5/SiO2 (0.05 g, 7 wt%)16 in an oil bath at
1636
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Chin. J. Chem. 2011, 29, 1635—1645

Efficient Multi-component Synthesis of Highly Substituted Imidazoles
ously with water and water-containing substances, lib-
erates much heat and may even cause fire. P2O5 is dif-
ficult to handle due to moisture sensitivity. However,
the preparation of P2O5 on silica gel (P2O5/SiO2) is
straight forward to escape from disadvantages of P2O5.
The stoichiometric amount of ammonium acetate in
preparation of 2,4,5-trisubstituted imidazoles is 2. We
can prepare 2,4,5-trisubstituted imidazoles using two
equivalent of ammonium acetate, but we observed in
our experiment and other published papers, if we use
inexpensive and available ammonium acetate having
more than two equivalent, the reaction will show better
results. Thus, a slight excess of the ammonium acetate
was found to be advantageous and hence the molar ratio
of benzil or benzoin to ammonium acetate was kept at
1∶4. So, the condensation reaction of benzil or benzoin
(1 mmol), aldehydes (1 mmol), and ammonium acetate
(4 mmol) in the presence of P2O5/SiO2 as the catalyst
for synthesis of 2,4,5-trisubstituted imidazoles under
solvent-free conditions at 100 ℃ was studied (Scheme
1, Table 1).
Table 1 Synthesis of 2,4,5-trisubstituted imidazoles via a one-pot pseudo four-component condensation reaction in the presence of
P2O5/SiO2 (0.05 g) as heterogeneous catalyst under thermal solvent-free condition at 100 ℃
Reaction time/h
Yielda/%
m.p./℃
Reported [Ref.]
Entry
Aldehyde
Benzil
Benzoin
Benzil Benzoin
Found
1
1
1.5
1.5
2
1.5
95
85
87
80
72
80
90
80
80
76
78
85
270
269 [24]
2
3
4
5
6
2
233—236
203—206
231—233
210
232—235 [25]
205—207 [26]
230—232 [26]
210—210.5 [26]
216—218 [27]
2.5
3
2
2.5
3.5
2
217—220
7
8
9
1
1
1
2.5
1.5
1.5
90
94
98
93
97
95
233
233 [24]
205 [28]
204—207
270—273
272 [22]
Chin. J. Chem. 2011, 29, 1635—1645
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Shaterian, Ranjbar & Azizi
FULL PAPER
Continued
Reaction time/h
Yielda/%
m.p./℃
Entry
10
Aldehyde
Benzil
Benzoin
Benzil Benzoin
Found
Reported [Ref.]
1
1
2
95
92
96
98
261—263
260.5—262 [29]
11
12
13
14
1.5
1.5
1.5
1.5
287—289
176—178
196—198
263
285—287 [23,30]
176.5—177 [31]
195—197 [32]
262—264 [26]
1
1
1
97
94
95
98
90
97
15
16
17
1
1
1.5
2
97
92
90
95
95
89
242—243
＞265
241—242 [23]
＞260 [23]
270 [22]
1.5
2.5
269—271
18
19
20
1
1.5
1
1.5
2
89
87
92
90
93
96
176—178
200—202
261—263
176.5—177 [31]
201—202 [33]
1.5
261.5—263.5 [26]
1638
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Chin. J. Chem. 2011, 29, 1635—1645

Efficient Multi-component Synthesis of Highly Substituted Imidazoles
Continued
Reaction time/h
Yielda/%
Benzil Benzoin
m.p./℃
Reported [Ref.]
Entry
21
Aldehyde
Benzil
Benzoin
Found
1.5
2
95
89
189—191
189—190 [32]
22
23
24
2
1
2
3
2
92
88
94
92
95
98
256—258
202—204
242—243
257—258 [32]
202—203 [33]
243 [22]
2.5
25
26
1.5
1
2
2
89
85
92
95
290—292
242—243
291.5—292 [26]
241—242 [34]
27
1.5
2
96
98
243—244
242—244 [35]
28
29
2
3
2
92
90
90
94
260—262
200—201
260—261 [32]
200—201 [32]
1.5
30
1.5
2
89
90
199
197 [36]
31
2
3
84
80
261—262
261 [22]
1
a Yields refer to isolated pure products. The known products were characterized by comparing their physical properties (m.p., H NMR,
13C NMR and FT-IR) with authentic samples.
The efficiency and versatility of the P2O5/SiO2 as
catalyst for the preparation of 2,4,5-trisubstituted imi-
dazoles were demonstrated by the wide rang of substi-
tuted and structurally divers aldehydes to synthesize the
corresponding products in high to excellent yields. The
presence of electron donating groups on the aromatic
Chin. J. Chem. 2011, 29, 1635—1645
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Shaterian, Ranjbar & Azizi
FULL PAPER
aldehyde resulted in the corresponding products in low
yields and the reaction was sluggish, however the pres-
ence of electron-withdrawing groups afforded the cor-
responding 2,4,5-trisubstituted imidazoles in shorter
reaction time with higher yields. Also, benzil in com-
parison with benzoin gives corresponding products in
shorter reaction time but there was no effect in the yield
of corresponding 2,4,5-trisubstituted imidazoles.
useful new synthesis methods based on the use of men-
tioned P2O5/SiO2 as a catalyst, we have studied the
four-component one-pot synthesis of 1,2,4,5-tetrasub-
stituted imidazoles by condensing benzil or benzoin (1
mmol), aldehyde (1 mmol), primary amines (1 mmol),
and ammonium acetate (1 mmol) using a catalytic
amount of P2O5/SiO2 (0.05 g) under solvent-free condi-
tions at 100 ℃ (Scheme 2, Table 2).
Next, as part of our program aimed at developing
Table 2 Synthesis of 1,2,4,5-tetrasubstituted imidazoles via a one-pot four component condensation reaction in the presence of
P2O5/SiO2 as heterogeneous catalyst (0.05 g) under thermal solvent-free conditions at 100 ℃
Reaction time/min
Yielda/%
m.p./℃
Reported [Ref.]
Entry
Aldehyde
Amine
Benzil
35
Benzoin
40
Benzil Benzoin
Found
1
89
88
90
80
87
83
85
89
215—217
218 [37]
2
3
4
30
40
45
45
50
55
161—163
212—214
121—123
158—160 [37]
208—211 [38]
124—126 [38]
CH3NH2
C2H5NH2
5
6
7
8
9
25
20
15
30
25
60
55
20
40
35
85
78
96
95
87
80
85
98
89
93
156—157
192—193
164—165
197—198
174—177
151—153 [38]
189 [37]
165—166 [37]
201—202 [37]
170—172 [39]
CH3NH2
1640
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Chin. J. Chem. 2011, 29, 1635—1645

Efficient Multi-component Synthesis of Highly Substituted Imidazoles
Reaction time/min
Continued
Yielda/%
m.p./℃
Reported [Ref.]
Entry
Aldehyde
Amine
Benzil
Benzoin
Benzil Benzoin
Found
10
15
25
98
92
95
89
95
92
96
89
90
93
97
85
189—202
187—189 [38]
149—151 [38]
219—220 [38]
156—158 [38]
196—197 [38]
163—165 [39]
11
12
13
14
15
30
25
20
15
20
35
30
25
20
25
152—154
222—225
160—162
198—200
167—169
16
17
18
45
45
30
50
60
35
85
87
93
78
90
95
192—194
132—135
149—152
188—191 [38]
128—130 [39]
146—148 [39]
19
20
55
20
60
25
87
89
82
92
164—167
156—158
164 [39]
156—157 [39]
Chin. J. Chem. 2011, 29, 1635—1645
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Shaterian, Ranjbar & Azizi
FULL PAPER
Continued
Reaction time/min
Yielda/%
m.p./℃
Entry
Aldehyde
Amine
Benzil
Benzoin
Benzil Benzoin
Found
Reported [Ref.]
CHO
OH
21
20
30
92
80
92
95
90
89
90
95
89
82
97
85
96
92
95
87
92
92
87
89
135—137
155—158
283—286
227—230
203—205
294—297
205—207
227—229
214—216
219—221
134—135 [39]
22
23
24
25
26
27
28
29
30
40
20
30
30
30
30
45
45
35
45
25
40
40
35
45
50
60
45
157—160 [40]
280—281 [41]
226—228 [42]
199—202 [21]
289—290 [21]
198—201 [21]
230—232 [42]
215—217 [21]
218—220 [21]
CHO
OH
1642
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Efficient Multi-component Synthesis of Highly Substituted Imidazoles
Reaction time/min
Continued
Yielda/%
m.p./℃
Reported [Ref.]
Entry
Aldehyde
Amine
Benzil
Benzoin
Benzil Benzoin
Found
31
45
60
75
72
78
76
188—190
185—187 [42]
184—186 [39]
32
50
60
188—190
33
34
35
36
37
30
50
25
25
20
40
60
30
35
30
85
80
92
90
87
89
87
92
85
85
250—253
100—104
162—165
145—147
154—155
248—251 [42]
104—105 [39]
165—167 [38]
140—142 [39]
150—152 [39]
CH3CH2CHO
38
39
40
25
25
50
40
30
60
85
92
89
86
92
83
180—182
140—141
117—119
183—185 [42]
144—146 [42]
112—115 [38]
1
a Yields refer to isolated pure products. The known products were characterized by comparing their physical properties (m.p., H NMR,
13C NMR and FT-IR) with authentic samples.
To show the merit of the present work in comparison
with reported results in the literature, we compared re-
sults of P2O5/SiO2 with reported catalysts in the synthe-
sis of 2,4,5-trisubstituted imidazoles and 1,2,4,5-tetra-
substituted imidazoles. As shown in Tables 3 and 4, the
P2O5/SiO2 can act as a suitable catalyst with respect to
reaction times and yields of the products.
Chin. J. Chem. 2011, 29, 1635—1645
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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1643

Shaterian, Ranjbar & Azizi
Table 3 Comparison of the efficiency of various catalysts with P2O5/SiO2 in the synthesis of 2,4,5-trisubstituted imidazolesa
FULL PAPER
Entry
Catalyst
InCl3•3H2O
Condition
MeOH/r.t.
Time/min
492
60
Yield/%
76
Ref.
1
2
3
4
5
6
8
9
43
KH2PO4
EtOH/Reflux
C10F18/80 ℃
EtOH/Reflux
Methanol/60 ℃
100 ℃
89
44
Yb(OPf)3
360
120
540
60
80
45
Zr(acac)4
95
46
L-Proline
87
28
[Hbim]BF4
NiCl2•6H2O/Al2O3
P2O5/SiO2
94
24
47
EtOH/Reflux
90
89
100 ℃
60
98
Present work
a Based on the preparation of 2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole (Table 1, Entry 15).
Table 4 Comparison of the efficiency of various catalysts with P2O5/SiO2 in the synthesis of 1,2,4,5-tetrasubstituted imidazolesa
Entry
Catalyst
BF3/SiO2
Condition
140 ℃
Time/min
120
120
120
440
9h
Yield/%
92
Ref.
1
2
45
SiO2
CH2Cl2/r.t.
140 ℃
90
48
3
NaHSO4/ SiO2
InCl3•3H2O
L-Proline
AlCl3
92
38
4
140 ℃
79
41
5
Methanol/r.t.
Methanol/ 60 ℃
140 ℃
88
28
6
120
120
120
120
15
53
45
7
MgCl2
50
45
8
SnCl4
140 ℃
60
37
42
9
K5CoW12O40•3H2O
P2O5/SiO2
140 ℃
95
10
100 ℃
98
Present work
a Based on the preparation of 1-benzyl-4,5-diphenyl-2-p-tolyl-1H-imidazole (Table 2, Entry 7).
We also investigated the recycling of the catalyst
under solvent-free conditions using a model reaction of
4-methylbenzaldehyde, benzylamine, benzil and ammo-
nium acetate (Table 2, Entry 7). In this procedure, after
completion of the reaction, the mixture was cooled to
room temperature, and the crude solid product was dis-
solved in ethylacetate. The mixture was filtered for
separation of the catalyst. The catalyst was washed
twice with ethylacetate (5 mL×2), and then recovered
catalyst was dried in an oven at 100 ℃ for 3 h. The
recovered catalyst was used for the subsequent catalytic
runs. The recovered catalyst could be recycled six times
without significant loss of catalytic activity (Figure 1)
Figure 1 The study of the recovered catalyst, P2O5/SiO2, activi-
ties
Conclusions
P2O5/SiO2 efficiently catalyzes the condensation re-
action of benzil or benzoin, aldehydes and ammonium
acetate in a pseudo four-component reaction and affords
the corresponding 2,4,5-trisubstituted imidazoles in high
yields. Also this recyclable catalyst has been used for
preparation of 1,2,4,5-tetrasubstituted imidazoles by
one-pot condensation reaction of benzil or benzoin, al-
dehydes, primary amines and ammonium acetate in ex-
cellent yields under solvent-free and conventional heat-
ing conditions. The recovered catalyst was reused
for six cycles without loss of its activities.
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