Ytterbium triflate as an efficient catalyst for one-pot synthesis of substituted imidazoles through three-component condensation of benzil, aldehydes and ammonium acetate

Article abstract of DOI:10.1016/j.jfluchem.2006.08.005

Yb(OTf)₃ has been found to be an extremely efficient catalyst for the preparation of imidazoles derivatives via three-component coupling reactions of benzil, aldehydes and ammonium acetate under mild conditions. The process presented here is op

Full text of DOI:10.1016/j.jfluchem.2006.08.005

Journal of Fluorine Chemistry 127 (2006) 1570–1573
www.elsevier.com/locate/fluor
Ytterbium triflate as an efficient catalyst for one-pot synthesis of
substituted imidazoles through three-component condensation
of benzil, aldehydes and ammonium acetate
a,b,*
a
, Yong-Hong Wang , He Tian ,
a
Li-Min Wang
a
a
Yin-Fang Yao , Jue-Hua Shao , Bo Liu
a
a
Laboratory for Advanced Materials, Institute of Fine Chemicals, East China University of Science and Technology,
30 Meilong Lu, Shanghai 200237, People’s Republic of China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
54 Fenglin Lu, Shanghai 200032, People’s Republic of China
1
b
3
Received 28 April 2006; received in revised form 14 August 2006; accepted 22 August 2006
Available online 1 September 2006
Abstract
Yb(OTf)
3
has been found to be an extremely efficient catalyst for the preparation of imidazoles derivatives via three-component coupling
reactions of benzil, aldehydes and ammonium acetate under mild conditions. The process presented here is operationally simple, environmentally
benign and has excellent yield. Furthermore, the catalyst can be recovered conveniently and reused for at least three reaction cycles without any
loss of activity.
#
2006 Elsevier B.V. All rights reserved.
Keywords: Ytterbium trifluoromethanesulfonate [Yb(OTf)
3
]; Benzil; Aldehyde; Imidazole
1
. Introduction
The use of imidazoles and their derivatives in chemical
The original route to synthesize imidazole utilized glyoxal,
formaldehyde and ammonia. Synthetic methodology alter-
natives are varied and have resorted to harsh conditions (e.g.,
the formamide synthesis, which requires excess reagents,
H SO as a condensing agent, 150–200 8C, 4–6 h, 40–90%)
processes, especially in pharmaceuticals, is becoming increas-
ingly important, because of their possibility of hydrogen bond
formation and not-shared electron pair of nitrogen atom of the
imidazole cycle [1]. Among these imidazoles, 2,4,5-tripheny-
limidazoles can be used as light-sensitive materials in
photography and known as inhibitors, fungicides and herbi-
cides, plant growth regulators [2] and therapeutic agents, and so
on. In a word, the compounds with imidazole ring system,
2
4
[4]. Although classical methods were derived from this early
success, this method suffered from tedious and time-
consuming work-up and side-reactions leading to mixtures
of products (including reversed aldol condensations and
oxazole formation) [5], and lack of generality [6,7]. Later,
many other methodologies have been presented, among them,
the procedure of three components condensation of benzil,
benzaldehyde derivatives and ammonium acetate was fre-
quently employed, especially in the late decades. For example,
Saeed et al. reported that zeolite HY and silica gel efficiently
catalyzed the three-component condensation via microwave
irradiation under solvent-free conditions [2]. Recently Shapi
et al. described an improved process of the one-pot synthesis of
2
,4,5-triphenylimidazole derivatives respectively, have many
properties and play important roles in chemical and biochem-
ical processes [3].
*
Corresponding author at: Laboratory for Advanced Materials, Institute of
2
,4,5-triaryl imidazoles in a room temperature ionic liquid [3].
Fine Chemicals, East China University of Science and Technology, 130
Meilong Lu, Shanghai 200237, People’s Republic of China.
Tel.: +86 21 64252758/2288; fax: +86 21 64252758/2288.
E-mail address: wanglimin@ecust.edu.en (L.-M. Wang).
Much work has done to catalyze this reaction by some common
Lewis acid catalysts, but in many cases the yield is less than
satisfactory and moreover they acted against the concept of
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.08.005

L.-M Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1570–1573
1571
Table 2
‘
‘green chemistry’’. Therefore, based on the original work of
a
Effect of temperature on model reaction
other scientists, the development of convenient, environmen-
tally benign, high-yielding and clean approaches is highly
desirable.
b
Yield (%)
Entry
Temperature (8C)
Time (h)
1
2
3
4
25
45
70
90
12
12
2
43
86
95
93
Over the past decades, much work of the rare earth metal
catalysts, especially the triflates catalyzed organic reactions,
has been done. As a new type of Lewis acid, they have been
applied in a variety of organic reactions [8,9]. The most
characteristic feature of these rare earth metal triflates are that
they act as water-compatible strong Lewis acids in aqueous
solvents. Only catalytic amount of the catalysts is enough to
complete reactions in most cases. Moreover, they can be easily
recovered after reactions and reused without any loss of
activity. As a part of our program aiming at developing selective
and environmental friendly methodologies for the preparation
of fine chemicals and in continuation of our interest in
lanthanide triflates catalyzed organic reactions [10], in this
paper, we wish to highlight our finding about the Yb(OTf)3
catalyzed three-component reaction using HOAc as a solvent
under mild conditions.
2
a
All reactions were carried out using 5 mol% Yb(OTf) in HOAc.
3
b
Isolated yields.
afford the corresponding adduct in good to excellent yield.
Among them, Yb(OTf) was the most effective catalyst. The
3
effect of catalyst loading on the reaction efficiency was
evaluated next. While adding 2.5 mol% of Yb(OTf) into this
3
system under similar conditions, the speed of reaction was
obviously accelerated, but the yield was not yet satisfactory. We
have changed the amount of the catalyst from 2.5 mol% to
7.5 mol%, finding that the use of 5 mol% of Yb(OTf) was
3
optimal to ensure high reaction efficiency (95%, yield), in the
meanwhile maintaining a short reaction time (2 h). After the
reaction was completed, the product was filtered after washed
by water and the catalyst can be obtained from water, which
could be subsequently reused several times. As indicated in
2
. Result and discussion
Firstly, the mixture of benzil, benzaldehyde and ammonium
Table 1, in the presence of 5 mol% of Yb(OTf) , the reaction
3
acetate was chosen as the model reaction (Scheme 1) to detect
whether the use of ytterbium triflate and other Lewis acids was
efficient. The results were summarized in Table 1.
gave excellent yields in three consecutive cycles without
attenuated activity (with yields of product la being 95%, 93%,
92% yields, in the first, second and third run, respectively). In
view of environmental friendly methodologies, organic
It was found that the conventional Lewis acids such as AlCl3
and FeCl , as well as the condition of no catalyst gave low
transformations employing Yb(OTf) as Lewis acid catalyst
3
is currently of great research interest.
3
yields of the products. Even large amount of these catalysts was
used in this reaction, the results were still unsatisfied and many
side reactions could be detected. When using the rare earth
metal compounds, the model reaction proceeded smoothly to
In the following study of model reaction, we examined the
reaction at different temperature to find out the effect on the
reaction (Table 2). It was found that at lower temperature, even
if the reaction time was prolonged, it gave only low yield, and
the higher temperature, the higher yield. When the reaction
solution heated at 90 8C, such high temperature did not further
improve yield, whereas the reaction mixture became blacker
and many by-products occurred. From the comparative results,
it has been observed that this reaction proceeded at 70 8C to
give the desired product in 95% yield (Table 2, entry 3).
The investigation of reaction medium for the process
revealed that reaction solvents played a significant role in the
model reaction. It is noted that in HOAc, the desired product
(2a) was produced exclusively in 95% yield (Table 3, entry 6).
Obviously, the polar solvents such as HOAc and THF were
Scheme 1.
Table 1
a
Effect of catalysts on model reaction
b
Yield (%)
Entry
Catalyst
Amount of
Time
(h)
catalyst (mol%)
1
2
3
4
5
6
7
8
9
None
\
20
20
25
15
2.5
5
6
4
4
3
3
2
2
2
2
42
60
45
82
78
84
95
95
Table 3
a
AlCl
FeCl
3
Effect of solvents on model reaction
3
b
Yield (%)
Entry
Solvent
Time (h)
NdCl
LaCl
3
3
1
2
3
4
5
6
Toluene
12
4
65
67
86
83
87
95
Yb(OTf)
Yb(OTf)
Yb(OTf)
Yb(OTf)
3
3
3
3
3
CH CN
C
2
H
5
OH
4
7.5
5
CH
3
COOC
2
H
5
4
c
95, 93, 92
THF
2
HOAc
2
a
All reactions were carried out in HOAc at 70 8C.
Isolated yields.
b
c
a
All reactions were carried out using Yb(OTf)
3
at 70 8C.
b
Catalyst was reused three times.
Isolated yields.

1572
L.-M Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1570–1573
Table 4
a
Yb(OTf)
3
catalyzed synthesis of different imidazoles derivatives
b
Yield (%)
Entry
RCHO (1)
p-MeOC
Time (h)
Product (2)
1
2
3
4
5
6
7
8
9
6
H
4
2
2
2
2
2
2
2
2
2
2
6
6
2b
2c
2d
2e
2f
2g
2h
2i
97
94
88
83
79
73
92
94
86
89
17
24
p-HOC
p-(Me)
p-BrC
p-O NC
m-O NC
o-HOC
2,4-(HO) C H
6 4
H
2 6 3
NC H
Scheme 2.
6 4
H
2
6 4
H
2
6
H
4
much better than non-polar solvents. The results could be
interpreted as the much better solubility of the catalyst and the
reagents in the polar solvents. The results of the study prompted
us to select HOAc as reaction solvent for the subsequent
investigation.
6 4
H
2
6 3
2,4-(Cl) CH
2
2
C
6
H
3
2j
2k
2l
1
1
1
0
1
2
2-(HO)-5-(O
2
N)C
6
H
3
C
C
2
H
H
5
3
7
2m
Having established optimal reaction conditions, we probed
the generality of process (Table 3). The three-component
coupling reactions of benzil, aldehydes (1) and ammonium
a
All reactions were carried out in the presence of Yb(OTf)
3
in HOAc at
7
0 8C.
b
Isolated yields.
acetate in the presence of 5 mol% of Yb(OTf) in HOAc at
3
7
0 8C was conducted. The reactions of aromatic aldehydes with
benzil and ammonium acetate proceeded smoothly to afford
corresponding 2,4,5-triaryl imidazoles in good to excellent
yields (73–97%). It was found that electron-rich benzaldehydes
worked better than electron-deficient ones. On the other side,
even if reaction time was prolonged (6 h), aliphatic aldehydes
afforded relevant lower yields. Furthermore, for arylacetalde-
hyde, the corresponding products are obtained in high yields
coordinated by Yb(OTf) . Then nucleophilic attack of the
3
nitrogen of ammonia obtained from NH OAc on the activated
4
carbonyl group, resulted in formation of aryl aldimine (3) and
a-imino ketone (4), and it followed by the nucleophilic attack
of the in situ generated imine (4) to carbonyl of aryl aldimine
(3), giving the intermediate (5). Their subsequent intramole-
cular interaction leads to cyclizations and eventually to the
formation of intermediate (6), which dehydrates to the
trisubstituted imidazoles (2) (Table 4).
(
entry 9, 86% yield) (Scheme 2).
A probable mechanism for the synthesis may be postulated
as shown below (Scheme 3). Ytterbium triflate Yb(OTf) is
3
strong Lewis acid because of the hard character of its metal
cation and the strong withdrawing effect of trifluoromethane-
sulfonyl group, so that it can activate the carbonyl group (C O)
to decrease the energy of transition state. It is highly probable
that the carboxyl groups of benzil and aldehydes (1) have to
be activated which occurs when the carbonyl oxygen is
3. Conclusion
In conclusion, the present synthetic method is a simple,
efficient and green synthesis of the 2,4,5-trisubstituented
imidazole derivatives via three-component one pot reaction of
benzil, aldehydes and ammonium acetate using Yb(OTf) as a
3
catalyst. This procedure has many obvious advantages
compared to those reported in the previous literatures,
including the avoidance of discharging harmful catalysts,
low reaction temperature, high yield of products, the simplicity
of the methodology and the recycling of the catalyst. The strong
Lewis acid characteristic feature of triflic acid (TfOH) make
Re(OTf) good choices for practical applications.
3
4. Experimental
4.1. Methods and apparatus
1
Melting points were determined on a Kofler hot plate. H
NMR spectra were recorded at Bruker WP-500SY (500 MHz)
in CDCl using TMS as internal standard. Mass spectra were
determined on a Micromass GCT spectrometer.
3
4.2. One-pot preparation of substituted imidazoles
(
2a–2m): general procedure
To a stirred mixture of benzil (1 mmol) and Yb(OTf) (0.03 g,
3
5 mol%) in HOAc (2 mL), aldehyde (1 mmol) and ammonium
acetate (10 mmol) were added at room temperature. The reaction
Scheme 3.

L.-M Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1570–1573
1573
mixturewasstirredat70 8Cforcertainhours. Theresultingwhite
4.2.11. 2-(2-Hydroxyl-5-nitrophenyl)-4,5-
diphenylimidazole (2k)
solid was filtered, washed with 3 Â 5 mL water for three times
and recrystallized by ethyl acetate to give the pure product. The
filtrate containing the catalyst could be evaporated under reduced
pressure to give a solid, which could be reused without losing
catalytic activity.
1
Mp > 255 8C[260.5–262 8C, Ref. [13]], HNMR(500 MHz,
CDCl ): d = 7.40–8.20 (m, 13H, Ar), 8.55 (s, OH), 10.10 (s, NH).
3
4.2.12. 2-Ethyl-4,5-diphenylimidazole (2l)
1
Mp 223–224 8C [229 8C, Ref. [14]], H NMR (500 MHz,
CDCl ): d = 1.24 (t, 3H, CH ), 2.59 (m, 2H, CH ), 7.50–8.15
(m, 10H, Ph), 13.40 (s, NH).
4
.2.1. 2,4,5-Triphenylimidazole (2a)
Mp > 260 8C [274–278 8C, Ref. [4b]], H NMR (500 MHz,
CDCl ): d = 7.25–7.95 (m, 15H, Ph), 8.40 (s, NH).
3
3
2
1
3
4.2.13. 2-Propyl-4,5-diphenylimidazole (2m)
1
Mp 256–258 8C [206 8C, Ref. [15]], H NMR (500 MHz,
CDCl ): d = 0.96 (t, 3H, CH ), 1.66 (m, 2H, CH ), 2.55 (t, 2H,
CH ), 7.45–8.10 (m, 10H, Ph), 13.40 (s, NH).
4
.2.2. 2-(4-Methoxylphenyl)-4,5-diphenylimidazole (2b)
1
3
3
2
Mp 227–228 8C [227–228 8C, Ref. [4a]], H NMR
2
(
500 MHz, CDCl ): d = 3.85 (s, OCH ), 6.95 (d, 2H,
3 3
J = 8.7 Hz, Ar), 7.30–7.55 (m, 10H, Ph), 7.90 (d, 2H,
J = 8.7 Hz, Ar).
Acknowledgements
This research was financially supported by the National
Nature Science Foundation of China and Key Laboratory of
Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences.
4
.2.3. 2-(4-Hydroxylphenyl)-4,5-diphenylimidazole (2c)
1
Mp 240–242 8C [233 8C, Ref. [3]], H NMR (500 MHz,
CDCl ): d = 7.00–7.90 (m, 14H, Ar), 9.50 (s, NH).
3
4
.2.4. 2-(4-Dimethylaminophenyl)-4,5-diphenylimidazole
2d)
References
(
1
Mp 257–258 8C [258–259 8C, Ref. [12]], H NMR
500 MHz, CDCl ): d = 2.90 (s, 2CH ), 6.70 (d, 2H,
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(
3
3
[
[
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J = 8.4 Hz, Ar).
[
4] (a) S. Balalaie, A. Arabanian, M.S. Hashtroudi, Monatsh. Chem. 131
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4
.2.5. 2-(4-Bromophenyl)-4,5-diphenylimidazole (2e)
1
Mp 236–237 8C [248 8C, Ref. [3]], H NMR (500 MHz,
(
b) Y.U. Alexander, L.K. Yuri, Tetrahedron Lett. 41 (2000) 5031.
[
[
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CDCl ): d = 7.20 (d, 2H, J = 7.8 Hz, Ar), 7.30–7.60 (m, 10H,
Ph), 7.8 (d, 2H, J = 7.8 Hz, Ar).
3
[
7] (a) E.W. Scott, D.W. David, H.L. William, Y. Wang, Z.J. Zhao, W.L.
Craig, Org. Lett. 6 (2004) 1453;
4
.2.6. 2-(4-Nitrophenyl)-4,5-diphenylimidazole (2f)
Mp 241–242 8C [236–237 8C, Ref. [4a]], H NMR
1
(b) B. Saeed, M.H. Mohammed, A. Maryam, Tetrahedron Lett. 44 (2003)
(
1709).
8] S. Kobayashi, M. Sugiura, H. Kitagawa, L. William, Chem. Rev. 102
2002) 2227.
(500 MHz, CDCl ): d = 7.35–7.60 (m, 10H, Ph), 8.05–8.30
(m, 4H, J = 8.7 Hz, Ar).
3
[
[
(
9] (a) A. Janczuk, W. Zhang, W.H. Xie, S.Z. Lou, J.P. Cheng, P.G. Wang,
Tetrahedron Lett. 43 (2002) 4271;
4
.2.7. 2-(3-Nitrophenyl)-4,5-diphenylimidazole (2g)
1
Mp > 260 8C [>295 8C, Ref. [11]], H NMR (500 MHz,
(b) C. Massimo, E. Francesco, C.M. Maria, R. Ornelio, Tetrahedron Lett.
4
2 (2001) 3193;
CDCl ): d = 7.55–8.95 (m, 14H, Ar), 13.10 (br s, NH).
3
(
(
c) S. Kobayashi, T. Hamada, S. Nagayama, K. Manab, Org. Lett. 3
2001) 165.
[
10] (a) L.M. Wang, J. Xia, F. Qin, C.T. Qian, J. Sun, Synthesis 8 (2003) 1241;
(b) L.M. Wang, J. Sheng, J.W. Han, Z.Y. Fan, C.T. Qian, Synthesis 18
4
.2.8. 2-(2-Hydroxylphenyl)-4,5-diphenylimidazole (2h)
1
Mp 209–211 8C [208–209 8C, Ref. [4a]], H NMR
(
(
2004) 3060;
(500 MHz, CDCl ): d = 6.70–7.60 (m, 14H, Ar), 9.50 (br s,
NH).
3
c) L.M. Wang, J. Sheng, H. Tian, C.T. Qian, Synth. Commun. 34 (2004)
4
265;
(
(
d) L.M. Wang, J.J. Liu, H. Tian, C.T. Qian, J. Sun, Adv. Synth. Catal. 347
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4
.2.9. 2-(2,4-Dihydroxylphenyl)-4,5-diphenylimidazole (2i)
1
(e) L.M. Wang, J.J. Liu, H. Tian, C.T. Qian, Synth. Commun. 34 (2004)
349;
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Tetrahedron 61 (2005) 1539.
Mp > 260 8C, H NMR (500 MHz, DMSO-d ): d = 7.60–
6
1
8.00 (m, 13H, Ar), 9.40 (s, OH), 9.60 (s, OH), 12.90 (s, NH).
HRMS: anal. calcd. for C H N O : 328.3640, found:
(
2
1 16 2 2
3
28.3696.
[11] G.R. Coraor, L.A. Cescon, R. Dessauer, E.F. Silversmith, E.J. Urban, J.
Org. Chem. 36 (1971) 2262.
[
[
[
12] D.M. White, J. Sonnenberg, J. Org. Chem. 29 (1964) 1926.
13] Marschner, Frank, DE Patent 4,320,802 (1995).
14] Cook, Jones, J. Chem. Soc. (1941) 278.
4
.2.10. 2-(2,4-Dichlorobenzyl)-4,5-diphenylimidazole (2j)
1
Mp 176–178 8C [176.5–177, Ref. [12]],
H NMR
500 MHz, CDCl ): d = 7.35–8.40 (m, 13H, Ar), 10.20 (s, NH).
(
[15] Theilig, Chem. Ber. 86 (1953) 96.
3