Cyclic phosphoric acid catalyzed one-pot, four-component synthesis of 1,2,4,5-tetrasubstituted imidazoles

Article abstract of DOI:10.1016/j.cclet.2011.09.018

Cyclic phosphoric acid catalyzed one-pot, four component reactions of benzil, aldehydes, primary amines and ammonium acetate in refluxing ethanol were developed, giving highly substituted imidazoles in excellent yield.

Full text of DOI:10.1016/j.cclet.2011.09.018

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 13–16
www.elsevier.com/locate/cclet
Cyclic phosphoric acid catalyzed one-pot, four-component
synthesis of 1,2,4,5-tetrasubstituted imidazoles
a
Xiang Bo Wang , Lin He , Teng Yue Jian , Song Ye
a,
b
b,*
*
a
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan and School of Chemistry
and Chemical Engineering, Shihezi University, Shihezi 832000, China
b
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Received 26 May 2011
Available online 8 November 2011
Abstract
Cyclic phosphoric acid catalyzed one-pot, four component reactions of benzil, aldehydes, primary amines and ammonium
acetate in refluxing ethanol were developed, giving highly substituted imidazoles in excellent yield.
#
2011 Lin He. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Cyclic phosphoric acid; Multicomponent reactions; Tetrasubstituted imidazoles
Multicomponent reactions (MCRs) have been used widely in organic synthesis and medicinal chemistry due to
their high synthetic efficiency and atom economy in the preparation of complex compounds from simple substrates
[
1]. The synthesis of highly substituted imidazoles is a very good application for MCRs. Tetrasubstituted imidazoles
are important heterocycles in pharmaceutical and biochemical processes [2]. Many methods have been developed for
the synthesis of this type of essential compounds [3]. Among them, the four component condensations of diones,
aldehydes, primary amines and ammonium acetate were the most well known processes for the construction of this
important moiety. Careful investigation of literatures revealed that highly substituted imidazoles can be synthesized
under catalysis of trifluoroacetic acid [4], FeCl Á6H O [5], BF ÁSiO [6], InCl Á3H O [7], K CoW O Á3H O [8],
3
2
3
2
3
2
5
12
4
2
silica-gel/NaHSO [9], heteropoly acids [10], molecular iodine [11], ZrCl [12], AlPO [13], silica gel or zeolite HY
4
4
4
[
14]. However, the harsh reaction conditions, unavoidable metal pollution, poor yields and other serious drawbacks
restrain the potential application of these methods. Therefore, it is very meaningful to develop more efficient and
environmentally friendly catalytic system for this reaction. Very recently, Singh et al. reported [15] that L-proline can
be used as organocatalyst to promote this four-component condensation efficiently, providing highly substituted
imidazoles in high yield.
Recently, as one type of strong Brønsted acids, cyclic phosphoric acids have been shown to be excellent
nonmetal organocatalyst for a series important transformations [16] such as nucleophilic addition to aldimines
[
17], aza-Diels-Alder reaction [18], transfer hydrogenations [19], MCRs [20] based on the activation of imines,
*
Corresponding authors.
E-mail addresses: helin@shzu.edu.cn (L. He), songye@iccas.ac.cn (S. Ye).
1001-8417/$ – see front matter # 2011 Lin He. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.09.018

14
X.B. Wang et al. / Chinese Chemical Letters 23 (2012) 13–16
Table 1
Reaction conditions evaluation for imidazole synthesis.
a
c
Entry
Cat. (loading)
Solvent
Time (h)
Yield (%)
b
1
6 (10 mol%)
6 (10 mol%)
6 (10 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
6 (20 mol%)
7 (20 mol%)
EtOH
EtOH
EtOH
EtOH
MeOH
THF
12
12
20
20
20
20
20
20
20
20
35
51
65
93
80
45
56
69
78
83
2
3
4
5
6
7
8
9
DCM
3
CH CN
1:1 EtOH/H
2
O
1
0
EtOH
a
b
c
Reactions were carried out in refluxing solvent using benzil/benzaldehyde/aniline/ammonium acetate, molar ratio of 1/1/1/1.
Reaction was run at room temperature.
Isolated yield after recrystallization from ethanol.
enamides, ketones as well as aziridines. However, to the best of our knowledge, four-component reactions
promoted by this strong Brønsted acid have not been reported so far. Herein, we would like to report our
preliminary results on cyclic phosphoric catalyzed one-pot, four-component condensation of diones, aldehydes,
primary amines and ammonium acetate to the access of tetrasubstituted imidazoles.
At the outset, the condensation of benzil, benzaldehyde, aniline and ammonium acetate was chosen as the model
reaction for the optimization of reaction conditions (Table 1). We found that in the presence of 10 mol% catalyst 6,
(Fig. 1) tetrasubstituted imidazole was isolated in 35% yield after 12 h at room temperature (entry 1). When the reaction
was carried out in refluxing ethanol, the yield was improved to 51% (entry 2). Prolonged reaction time to 20 h led the
desired product in 65% yield (entry 3). To our delight, increasing the catalyst loading to 20 mol%, excellent yield was
obtained (entry 4). An evaluation of solvents indicated that the reaction can proceed in MeOH, THF, DCM, CH CN and
3
EtOH/H O but no improvement of yield was observed (entries 5–9). It is noteworthy that catalyst 7 derived from BINOL
2
was also suitable for this MCRs but afforded tetrasubstituted imidazole in relatively lower yield (entry 10).
With the optimized reaction conditions in hand, different aldehydes and primary amines were then evaluated [21]
and the results were summarized in Table 2. Avariety of aromatic aldehydes were found to be good reactant to form the
corresponding tetrasubstituted imidazoles in high yields. Both electron-donating and electron-withdrawing groups on
the aromatic ring were well tolerated (entries 1–4). Interestingly, heliotropine as well as 2-naphthaldehyde were also
very good candidates for the reaction, providing highly substituted imidazoles in excellent yields (entries 5–6). In
addition, both aniline and aliphatic primary amines such as benzyl amine and ethylamine were all suitable substrates
for the multi-component cyclocondensations, affording the desired products in high yield (entries 7–9).
We also compared the catalytic activity of cyclic phosphoric acid 6 with various protonic acids and Lewis acids for
the synthesis of 1-benzyl-2,4,5-triphenyl-1H-imidazole (5g). As shown in Table 3, simple protonic acids such as HCl,
HOAc and TFA could promote the condensation but in low efficiency (Table 3, entries 1–3). Interestingly, Lewis acids
such as AlCl , ZnCl , InCl Á4H O and Cu(OAc) could mediate the reaction efficiently, giving the product in good
3
2
3
2
2
yield (Table 3, entries 4–7).
Based on the pioneering work of cyclic phosphoric acid-catalyzed reactions [16], we proposed the Brønsted acid–
Brønsted base dual-catalysis mechanism. As depicted in Scheme 1, the phosphoric acid hydrogen activated the
carbonyl compounds as a Brønsted acid, while the phosphoryl oxygen activated the nucleophiles by coordinating with
Ts
N
N
O
O
O
P
P
OH
OH
O
Ts
7
6
Fig. 1. Structures of catalysts 6 and 7.

X.B. Wang et al. / Chinese Chemical Letters 23 (2012) 13–16
15
Table 2
Synthesis of tetrasubstituted imidazoles under catalysis of cyclic phosphoric acid.
a
1
2
b
Entry
R
C
R
Product
Yield (%)
M.P. (8C)
Lit. (8C)
216–218 [13]
1
2
3
4
5
6
7
8
9
6
H
5
C
C
C
C
C
C
C
C
6
6
6
6
6
6
6
6
H
5
5
5
5
5
5
5
5
5a
5b
5c
5d
5e
5f
93
91
81
82
92
95
93
91
80
216–218
183–185
183–185
148–150
193–195
241–243
156–158
167–168
220–221
4-CH
4-CH
3
–C
6
H
4
H
H
H
H
H
H
H
185–188 [13]
184–185 [11a]
149–151 [6]
3
O–C
6
H
4
4-Cl–C
6 4
H
Furyl
194–195 [11b]
2-Naphtyl
244 [5]
C
6
H
5
CH
CH
2
5g
5h
5i
158–160 [13]
165–166 [13]
218–220 [13]
4-CH
4-CH
3
–C
–C
6
H
H
4
4
2
3
6
CH
3
a
Reactions were carried out in refluxing ethanol for 20 h, using benzil/aldehyde/amine/ammonium acetate with molar ratio of 1/1/1/1.
Isolated yield after recrystallization in ethanol.
b
Table 3
Comparison of cyclic phosphoric acid 6 with other protonic acids and Lewis acids for the synthesis of 1-benzyl-2,4,5-triphenyl-1H-imidazole (5g,
a
Table 2, entry 7).
b
Entry
Catalyst
Temp/time
Yield (%)
1
2
3
4
5
6
7
8
HCl (20 mol%)
HOAc (20 mol%)
TFA (20 mol%)
Reflux/20 h
Reflux/20 h
Reflux/20 h
Reflux/20 h
Reflux/20 h
Reflux/20 h
Reflux/20 h
Reflux/20 h
62
65
75
AlCl
ZnCl
InCl
Cu(OAc)
6 (20 mol%)
3
(20 mol%)
66
2
(20 mol%)
80
3
Á4H
2
O (10 mol%)
(20 mol%)
85
2
75
93 (this work)
a
Reactions were carried out in refluxing ethanol for 20 h, using benzil/aldehyde/amine/ammonium acetate with molar ratio of 1/1/1/1.
Isolated yield after recrystallization in ethanol.
b
TsN
O
NTs
TsN
NTs
TsN
O
NTs
P
P
P
R2
N
TsN
NTs
R2
N
R2
N
O
H
P
O
H
O
H
NH2
O
H
OH
H2O
Ph
Ph
Ph
Ph
Ph
- H+
O
H
O
H
H
+ H+
H
H
HN
R2
R1
H
N
R1
O
Ph
Ph
O
R1 - H O
NHR2
HO
- H O
2
- H2O
N
R1
N
2
N
R1
Ph
O
Ph
R1
R1
NHR2
NHR2
O
N
Ph
Scheme 1. Proposed reaction mechanism.
the hydrogen of the amines as a Brønsted base. And therefore, the catalytic activity of cyclic phosphoric acid was
improved efficiently by this dual-catalysis.
1
All of the products are known compounds and characterized by H NMR, IR, melting point and assigned through
comparison with literature data.
In conclusion, we have developed an organocatalyst promoted one-pot, four-component condensation of diones,
aldehydes, primary amines and ammonium acetate. Several advantages of the reaction, such as environmentally
benignity, easy purification and high yields offer a valuable access to tetrasubstituted imidazoles. Further studies on
the scope and generality of this methodology are underway in our laboratory.
Acknowledgments
We are grateful to CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences for generous financial support.

16
X.B. Wang et al. / Chinese Chemical Letters 23 (2012) 13–16
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[21] General procedure: A solution of benzil (0.63 g, 3 mmol), benzaldehyde (0.318 g, 3 mmol), aniline (0.28 g, 3 mmol), ammonium acetate
(0.231 g, 3 mmol) and catalyst 6 (0.286 g, 0.6 mmol) in 5.0 mL ethanol was stirred at 78 8C for 20 h. Then, the mixture was cooled to room
temperature and the precipitated crude product was separated by vacuum filtration. Pure tetrasubstituted imidazole 5a was obtained after
À1
recrystallising the crude product from hot ethanol. Data for 5a: Yield: 93%; white solid; mp 217–218 8C; IR (KBr, cm ) n 3013, 1600, 1461,
1
370; H NMR (400 MHz, CDCl
1
3
): d 7.65–7.55 (m, 2H), 7.48–7.35 (m, 2H), 7.28–7.15 (m, 12H), 7.14–7.10 (m, 2H), 7.06–7.00 (m, 2H).