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
Li-Min Wang a,b,*, Yong-Hong Wang a, He Tian a,
Yin-Fang Yao a, Jue-Hua Shao a, Bo Liu a
a
Laboratory for Advanced Materials, Institute of Fine Chemicals, East China University of Science and Technology,
130 Meilong Lu, Shanghai 200237, People’s Republic of China
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, People’s Republic of China
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 original route to synthesize imidazole utilized glyoxal,

The use of imidazoles and their derivatives in chemical
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,
2,4,5-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
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).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.08.005
formaldehyde and ammonia. Synthetic methodology alter-
natives are varied and have resorted to harsh conditions (e.g.,
the formamide synthesis, which requires excess reagents,
H2SO4 as a condensing agent, 150–200 8C, 4–6 h, 40–90%)
[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-triaryl imidazoles in a room temperature ionic liquid [3].
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
 L.-M Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1570–1573 1571

‘‘green chemistry’’. Therefore, based on the original work of Table 2

Effect of temperature on model reactiona
other scientists, the development of convenient, environmen-
tally benign, high-yielding and clean approaches is highly Entry Temperature (8C) Time (h) Yieldb (%)
desirable. 1 25 12 43
Over the past decades, much work of the rare earth metal 2 45 12 86
catalysts, especially the triflates catalyzed organic reactions, 3 70 2 95
has been done. As a new type of Lewis acid, they have been 4 90 2 93
applied in a variety of organic reactions [8,9]. The most a
All reactions were carried out using 5 mol% Yb(OTf)3 in HOAc.
b
characteristic feature of these rare earth metal triflates are that Isolated yields.
they act as water-compatible strong Lewis acids in aqueous
solvents. Only catalytic amount of the catalysts is enough to afford the corresponding adduct in good to excellent yield.
complete reactions in most cases. Moreover, they can be easily Among them, Yb(OTf)3 was the most effective catalyst. The
recovered after reactions and reused without any loss of effect of catalyst loading on the reaction efficiency was
activity. As a part of our program aiming at developing selective evaluated next. While adding 2.5 mol% of Yb(OTf)3 into this
and environmental friendly methodologies for the preparation system under similar conditions, the speed of reaction was
of fine chemicals and in continuation of our interest in obviously accelerated, but the yield was not yet satisfactory. We
lanthanide triflates catalyzed organic reactions [10], in this have changed the amount of the catalyst from 2.5 mol% to
paper, we wish to highlight our finding about the Yb(OTf)3 7.5 mol%, finding that the use of 5 mol% of Yb(OTf)3 was
catalyzed three-component reaction using HOAc as a solvent optimal to ensure high reaction efficiency (95%, yield), in the
under mild conditions. meanwhile maintaining a short reaction time (2 h). After the
reaction was completed, the product was filtered after washed
2. Result and discussion by water and the catalyst can be obtained from water, which
could be subsequently reused several times. As indicated in
Firstly, the mixture of benzil, benzaldehyde and ammonium Table 1, in the presence of 5 mol% of Yb(OTf)3, the reaction
acetate was chosen as the model reaction (Scheme 1) to detect gave excellent yields in three consecutive cycles without
whether the use of ytterbium triflate and other Lewis acids was attenuated activity (with yields of product la being 95%, 93%,
efficient. The results were summarized in Table 1. 92% yields, in the first, second and third run, respectively). In
It was found that the conventional Lewis acids such as AlCl3 view of environmental friendly methodologies, organic
and FeCl3, as well as the condition of no catalyst gave low transformations employing Yb(OTf)3 as Lewis acid catalyst
yields of the products. Even large amount of these catalysts was is currently of great research interest.
used in this reaction, the results were still unsatisfied and many In the following study of model reaction, we examined the
side reactions could be detected. When using the rare earth reaction at different temperature to find out the effect on the
metal compounds, the model reaction proceeded smoothly to 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).
Scheme 1. The investigation of reaction medium for the process
revealed that reaction solvents played a significant role in the
Table 1 model reaction. It is noted that in HOAc, the desired product
Effect of catalysts on model reactiona (2a) was produced exclusively in 95% yield (Table 3, entry 6).
Entry Catalyst Amount of Time Yieldb (%) Obviously, the polar solvents such as HOAc and THF were
catalyst (mol%) (h)
1 None \ 6 42 Table 3
2 AlCl3 20 4 60 Effect of solvents on model reactiona
3 FeCl3 20 4 45
Entry Solvent Time (h) Yieldb (%)
4 NdCl3 25 3 82
5 LaCl3 15 3 78 1 Toluene 12 65
6 Yb(OTf)3 2.5 2 84 2 CH3CN 4 67
7 Yb(OTf)3 5 2 95 3 C2H5OH 4 86
8 Yb(OTf)3 7.5 2 95 4 CH3COOC2H5 4 83
9 Yb(OTf)3 5 2 95, 93, 92c 5 THF 2 87
a 6 HOAc 2 95
All reactions were carried out in HOAc at 70 8C.
b a
Isolated yields. All reactions were carried out using Yb(OTf)3 at 70 8C.
c b
Catalyst was reused three times. Isolated yields.
1572 L.-M Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1570–1573

Table 4
Yb(OTf)3 catalyzed synthesis of different imidazoles derivativesa
Entry RCHO (1) Time (h) Product (2) Yieldb (%)
1 p-MeOC6H4 2 2b 97
2 p-HOC6H4 2 2c 94
3 p-(Me)2NC6H3 2 2d 88
Scheme 2.
4 p-BrC6H4 2 2e 83
5 p-O2NC6H4 2 2f 79
6 m-O2NC6H4 2 2g 73
much better than non-polar solvents. The results could be 7 o-HOC6H4 2 2h 92
interpreted as the much better solubility of the catalyst and the 8 2,4-(HO)2C6H3 2 2i 94
reagents in the polar solvents. The results of the study prompted 9 2,4-(Cl)2CH2C6H3 2 2j 86
us to select HOAc as reaction solvent for the subsequent 10 2-(HO)-5-(O2N)C6H3 2 2k 89
11 C2H5 6 2l 17
investigation.
12 C3H7 6 2m 24
Having established optimal reaction conditions, we probed
a
the generality of process (Table 3). The three-component All reactions were carried out in the presence of Yb(OTf)3 in HOAc at
70 8C.
coupling reactions of benzil, aldehydes (1) and ammonium b
Isolated yields.
acetate in the presence of 5 mol% of Yb(OTf)3 in HOAc at
70 8C was conducted. The reactions of aromatic aldehydes with
benzil and ammonium acetate proceeded smoothly to afford coordinated by Yb(OTf)3. Then nucleophilic attack of the
corresponding 2,4,5-triaryl imidazoles in good to excellent nitrogen of ammonia obtained from NH4OAc on the activated
yields (73–97%). It was found that electron-rich benzaldehydes carbonyl group, resulted in formation of aryl aldimine (3) and
worked better than electron-deficient ones. On the other side, a-imino ketone (4), and it followed by the nucleophilic attack
even if reaction time was prolonged (6 h), aliphatic aldehydes of the in situ generated imine (4) to carbonyl of aryl aldimine
afforded relevant lower yields. Furthermore, for arylacetalde- (3), giving the intermediate (5). Their subsequent intramole-
hyde, the corresponding products are obtained in high yields cular interaction leads to cyclizations and eventually to the
(entry 9, 86% yield) (Scheme 2). formation of intermediate (6), which dehydrates to the
A probable mechanism for the synthesis may be postulated trisubstituted imidazoles (2) (Table 4).
as shown below (Scheme 3). Ytterbium triflate Yb(OTf)3 is
strong Lewis acid because of the hard character of its metal 3. Conclusion
cation and the strong withdrawing effect of trifluoromethane-
sulfonyl group, so that it can activate the carbonyl group (C O) In conclusion, the present synthetic method is a simple,
to decrease the energy of transition state. It is highly probable efficient and green synthesis of the 2,4,5-trisubstituented
that the carboxyl groups of benzil and aldehydes (1) have to imidazole derivatives via three-component one pot reaction of
be activated which occurs when the carbonyl oxygen is benzil, aldehydes and ammonium acetate using Yb(OTf)3 as a
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)3 good choices for practical applications.

4. Experimental

4.1. Methods and apparatus

Melting points were determined on a Kofler hot plate. 1H

NMR spectra were recorded at Bruker WP-500SY (500 MHz)
in CDCl3 using TMS as internal standard. Mass spectra were
determined on a Micromass GCT spectrometer.

4.2. One-pot preparation of substituted imidazoles

(2a–2m): general procedure

To a stirred mixture of benzil (1 mmol) and Yb(OTf)3 (0.03 g,

5 mol%) in HOAc (2 mL), aldehyde (1 mmol) and ammonium
Scheme 3. acetate (10 mmol) were added at room temperature. The reaction
 L.-M Wang et al. / Journal of Fluorine Chemistry 127 (2006) 1570–1573
mixture was stirred at 70 8C for certain hours. The resulting white
solid was filtered, washed with 3  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.
4.2.1. 2,4,5-Triphenylimidazole (2a)
Mp > 260 8C [274–278 8C, Ref. [4b]], 1H NMR (500 MHz,
CDCl3): d = 7.25–7.95 (m, 15H, Ph), 8.40 (s, NH).
4.2.2. 2-(4-Methoxylphenyl)-4,5-diphenylimidazole (2b)
Mp 227–228 8C [227–228 8C, Ref. [4a]], 1H NMR
(500 MHz, CDCl3): d = 3.85 (s, OCH3), 6.95 (d, 2H,
J = 8.7 Hz, Ar), 7.30–7.55 (m, 10H, Ph), 7.90 (d, 2H,
J = 8.7 Hz, Ar).
4.2.3. 2-(4-Hydroxylphenyl)-4,5-diphenylimidazole (2c)
Mp 240–242 8C [233 8C, Ref. [3]], 1H NMR (500 MHz,
CDCl3): d = 7.00–7.90 (m, 14H, Ar), 9.50 (s, NH).
4.2.4. 2-(4-Dimethylaminophenyl)-4,5-diphenylimidazole
(2d)
Mp 257–258 8C [258–259 8C, Ref. [12]], 1H NMR
(500 MHz, CDCl3): d = 2.90 (s, 2CH3), 6.70 (d, 2H,
J = 8.4 Hz, Ar), 7.20–7.50 (m, 10H, Ph), 7.80 (d, 2H,
J = 8.4 Hz, Ar).
4.2.5. 2-(4-Bromophenyl)-4,5-diphenylimidazole (2e)
Mp 236–237 8C [248 8C, Ref. [3]], 1H NMR (500 MHz,
CDCl3): 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).
4.2.6. 2-(4-Nitrophenyl)-4,5-diphenylimidazole (2f)
Mp 241–242 8C [236–237 8C, Ref. [4a]], 1H NMR
(500 MHz, CDCl3): d = 7.35–7.60 (m, 10H, Ph), 8.05–8.30
(m, 4H, J = 8.7 Hz, Ar).
4.2.7. 2-(3-Nitrophenyl)-4,5-diphenylimidazole (2g)
Mp > 260 8C [>295 8C, Ref. [11]], 1H NMR (500 MHz,
CDCl3): d = 7.55–8.95 (m, 14H, Ar), 13.10 (br s, NH).
4.2.8. 2-(2-Hydroxylphenyl)-4,5-diphenylimidazole (2h)
Mp 209–211 8C [208–209 8C, Ref. [4a]], 1H NMR
(500 MHz, CDCl3): d = 6.70–7.60 (m, 14H, Ar), 9.50 (br s,
NH).
4.2.9. 2-(2,4-Dihydroxylphenyl)-4,5-diphenylimidazole (2i)
Mp > 260 8C, 1H NMR (500 MHz, DMSO-d6): d = 7.60–
8.00 (m, 13H, Ar), 9.40 (s, OH), 9.60 (s, OH), 12.90 (s, NH).
HRMS: anal. calcd. for C21H16N2O2: 328.3640, found:
328.3696.
4.2.10. 2-(2,4-Dichlorobenzyl)-4,5-diphenylimidazole (2j)
Mp 176–178 8C [176.5–177, Ref. [12]], 1H NMR
(500 MHz, CDCl3): d = 7.35–8.40 (m, 13H, Ar), 10.20 (s, NH).
1573
4.2.11. 2-(2-Hydroxyl-5-nitrophenyl)-4,5-
diphenylimidazole (2k)
Mp > 255 8C [260.5–262 8C, Ref. [13]], 1H NMR (500 MHz,
CDCl3): d = 7.40–8.20 (m, 13H, Ar), 8.55 (s, OH), 10.10 (s, NH).
4.2.12. 2-Ethyl-4,5-diphenylimidazole (2l)
Mp 223–224 8C [229 8C, Ref. [14]], 1H NMR (500 MHz,
CDCl3): d = 1.24 (t, 3H, CH3), 2.59 (m, 2H, CH2), 7.50–8.15
(m, 10H, Ph), 13.40 (s, NH).
4.2.13. 2-Propyl-4,5-diphenylimidazole (2m)
Mp 256–258 8C [206 8C, Ref. [15]], 1H NMR (500 MHz,
CDCl3): d = 0.96 (t, 3H, CH3), 1.66 (m, 2H, CH2), 2.55 (t, 2H,
CH2), 7.45–8.10 (m, 10H, Ph), 13.40 (s, NH).
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.
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