Synthesis of 2,4,5-triarylimidazoles in aqueous solution, under microwave irradiation

Article abstract of DOI:10.1039/b925177d

A series of 2,4,5-triarylimidazoles was synthesized from a new, highly efficient and green method. The reaction is performed in water, without the presence of any catalyst, and under microwave irradiation. This provides new opportunities for the rapid scr

Full text of DOI:10.1039/b925177d

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www.rsc.org/greenchem | Green Chemistry
Synthesis of 2,4,5-triarylimidazoles in aqueous solution, under microwave
irradiation†
Edouard Chauveau, Catherine Marestin,* Fre´de´ric Schiets and Re´gis Mercier
Received 30th November 2009, Accepted 23rd February 2010
First published as an Advance Article on the web 8th April 2010
DOI: 10.1039/b925177d
A series of 2,4,5-triarylimidazoles was synthesized from a new, highly efficient and green method.
The reaction is performed in water, without the presence of any catalyst, and under microwave
irradiation. This provides new opportunities for the rapid screening of a wide range of compounds,
either for the development of new drugs, or original compounds for the material scientist.
the replacement of hazardous organic reaction media with water
1. Introduction
is particularly relevant.
Imidazoles and more specifically 2,4,5-triarylimidazoles have
It is well-known that at high temperature, water behaves like a
proven to be key compounds for the synthesis of ther-
pseudo-organic solvent.34,35 As a result, some organic reactions
apeutic agents (anti-inflamatory,1,2 analgesic,3 glucagon re-
can be performed at high temperature in a homogeneous
ceptor antagonists4…). In addition, their optical properties
medium, whereas the reactants and/or the products are not
(fluorescence5,6 and chemiluminescence) are of particular con-
soluble in water at room temperature. Since the pioneering work
cern for material scientists. In this context, they have received
of Strauss and co-workers,36–38 the development of new synthetic
great attention for the development of fluorescence labelling
protocols involving both water and microwave irradiation has
agents,7–9 materials for biological imaging application,10 blue-
recently received a considerable interest.39–41 Some reviews42,43
light emitting materials,11 luminophores for optoelectronic
report a wide range of chemical reactions (eliminations, re-
applications12 or chromophores for non linear optic systems.13
Recently, some distriarylimidazoles have been investigated for
ductions, cyclodehydration, Suzuki-coupling…) and recently,
a specific attention has been devoted to the synthesis of
their piezochromism, photochromism and thermochromism
heterocyclic compounds.44–48
properties, and the results reported suggest potential applica-
In continuation of our work related to the synthesis of aro-
tions in molecular photonics and sensing.14 The synthesis of
matic and heterocyclic structures by environmentally-friendly
2,4,5-triphenylimidazole (Lophine) has been known for a long
procedures,49,50 this paper reports a very efficient and green
time.15,16 Such a compound and its derivatives are principally
process for the synthesis of 2,4,5-triaryimidazoles, without any
obtained by a multi-component reaction involving benzil (or
catalyst, in water and under microwave irradiation.
a substituted benzil), an aryl aldehyde and ammonium acetate
as an ammonia source. In the last decade, increasing interest
2. Results and discussion
has been devoted to optimize the reaction conditions in order
to reach very high yields and highly pure products. For this
purpose, many catalysts have been investigated (silica/sulfuric
acid,17,18 Yb(OTf)3,19 NiCl2·6H2O,20 oxalic acid,21 iodine,22 sul-
fanilic acid,23 tetrabutyl ammonium bromide,24 cerium ammo-
nium nitrate,10 Zr(acac)4,25 InCl3·3H2O26…) as well as different
activation modes (thermal activation, microwave irradiation27,28
or ultrasounds10,25). These reactions are performed either in
solution (AcOH,19,28 EtOH,20,22 EtOH–H2O21,29,30), in solvent-
less conditions17,27,31 or in ionic liquids.32,33
In this work, a three-component reaction between benzil,
anisaldehyde and ammonium acetate was chosen as a bench-
mark reaction for the formation of a 2,4,5-triarylimidazole
compound (Scheme 1).
In order to face current environmental preoccupations, the
development of green organic syntheses, sustainable and envi-
ronmentally benign protocols appears essential. In this respect,
Scheme
1
Synthesis of 2-(4-methoxyphenyl)-4,5-diphenyl-1H-
imidazole.
Laboratoire des Mate´riaux Organiques a` Proprie´te´s Spe´cifiques UMR
5041 CNRS-Universite´ de Savoie, Chemin du Canal, 69 360, Solaize,
France. E-mail: marestin@lmops.cnrs.fr; Fax: 33 4 78 02 77 38;
Tel: 33 4 78 02 35 42
† Electronic supplementary information (ESI) available: Temperature
and pressure profiles during reactions, HPLC UV chromatograms,
NMR spectra, and synthesis and characterization of a benzoxazole
compound. See DOI: 10.1039/b925177d
Pressure and temperature were monitored during the whole
reaction by a pressure sensor and an optical fibre dipping in
the medium. For safety reasons, a maximum pressure threshold
was fixed at 30 bars. Owing to the direct in-core heating nature
of microwave irradiation and thanks to an efficient magnetic
stirring, a uniform temperature profile was produced in the
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Table 1 Optimization of 2,4,5-triarylimidazole synthesis in water,
under microwave irradiation
reaction mixture. The reaction temperature was varied from 180
to 210 ◦C.
During microwave irradiation, the temperature increase was
extremely rapid. One most probable reason is the very efficient
microwave heating of aqueous media. In the case of a high
irradiation power (800 W), the temperature increase was even
faster than the optical fibre time-delay, which results in slightly
higher temperatures than the initially fixed temperature (tem-
Reaction
Entry SC (%)b Power/W time/min T1/◦Cc T2/◦Cd Yield (%)e
1
15
15
15
15
15
15
27
27
27
27
500
500
800
500
500
500
500
800
800
800
10
15
10
10
5
180
180
180
200
210
210
210
210
210
210
188
190
185
205
212
215
216
214
220
219
74
86
79
87
73
89
93
90
88
98
2
3
4
◦
5
6
7
perature oscillations with maximum values up to 10 C above
the threshold—Fig. 1).
10
10
5
10
10
8
9a
10
a With 5 equivalents of NH4OAc instead of 10 equivalents. b Solid
content SC (%) = (theoretical mass of triarylimidazole formed /
(theoretical mass of triarylimidazole formed + volume of water)) ¥ 100.
c Reaction temperature. d Maximum observed temperature. e Isolated
yield, analytically pure compounds obtained after filtration and washing
with petroleum ether. For details, see the ESI.†
suggesting that 5 min reaction is not sufficient to complete
the reaction. This hypothesis was confirmed by the presence
of residual benzyl and aldehyde by HPLC. Besides the triaryl
imidazole product (elution time 10.8 min), excepted in entry
10, traces of a secondary product was evidenced (15.7 min).
On the basis of a mass spectroscopy analysis, this product was
identified as a benzoxazole. The formation of such a compound
has already been mentioned by Davidson and coworkers,51 by
the action of ammonia on esters of benzoin. An additional
experiment reacting exclusively benzyl and ammonium acetate
was performed, and the expected benzoxazole was isolated
and thoroughly characterized (see the ESI†), confirming the
formation of this species in the course of the reaction.
Whereas this benzoxazole was produced in significant
amounts when the reaction was performed in the absence of
aldehyde, its proportions remained almost negligible in the
typical reaction conditions studied in this work (Fig. 2a). In
order to remove any traces of this undesired compound, all crude
products were slightly rinsed with petroleum ether, yielding
analytically pure compounds (Fig. 2b).
Fig. 1 Typical temperature and pressure profiles recorded during a
synthesis of 2,4,5-triarylimidazole. (a) Reaction with 500 W irradiation.
(b) Reaction with 800 W irradiation. In red: temperature profile; in blue:
pressure profile; in black: irradiation power.
Typically, a maximum pressure of 27 bars was observed
during the reaction. The pressure profile (see Fig. 1) recorded
as a function of reaction time was not constant, which could
be accounted for by different phenomena. Indeed, besides the
autogenic pressure of water (leading to a near supercritical
character), gaseous ammonia is produced in situ (by the thermal
decomposition of ammonium acetate) and consumed in the
course of the reaction. After cooling, the product formed
precipitates, which can be simply isolated by filtration, and
rinsed with water. This very convenient work-up avoids time-
consuming or energy-costly additional steps such as column
chromatography, extraction or re-crystallization, and confers an
additional green character to this process. Different parameters
such as the reactiontime, reaction temperature, and solid content
were studied in order to provide optimized reaction conditions.
The results are reported in Table 1.
Each crude sample has been analyzed by high performance
liquid chromatography (HPLC). The analytical conditions were
set up in order to identify the presence of eventual residual
reagents as well as the final product. For a given microwave
irradiation power, a reaction time increase (entry 5 and 6
vs. entry 8 and 10) results in a systematic yield increase,
Fig. 2 HPLC traces of (a) crude product and (b) pure product (after
washing in petroleum ether).
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Table 2 High yield syntheses of various 2,4,5-triarylimidazoles
Entry
1
Product
Yield (%)a
98
Mp/◦C found
232–234
Mp/◦C (Lit.)
230–23152
2
81
275–277
275–27731,52,53
3
4
99
99
251–252
256–258
250–25152
256–25721
5
96
264–265
—
6
7
99
96
251–253
286–287
—
—
8
9
88
97
267–270
253–254
—
—
a Isolated yield, analytically pure compounds obtained after filtration and washing with petroleum ether. For details, see the ESI.†
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From the results obtained, it appeared that the reaction
strongly depends on the reaction medium temperature. When
the recorded temperature was less than 190 ◦C, the yields
were lower than 85%. The presence of benzil confirmed an
incomplete reaction. At higher temperatures (200–220 ◦C), the
yields are better. The reaction time appears also to be important
parameter as 5 min irradiation was not sufficient to complete
the reaction (entry 6 and 8). The last point concerns the
amount of ammonium acetate necessary: 10 equivalents were
required whereas 5 equivalents were not sufficient (entry 9).
Taking these parameters into account, the optimal reaction
conditions were found to be a 10 min reaction at 210 ◦C
(800 W microwave power), using 10 equivalents of ammonium
acetate, and in a highly concentrated medium (27 wt%). In
these conditions an analytically pure compound was isolated
with 98% yield. It is worth mentioning that these reactions
are performed using stoichiometric amounts of benzil and aryl
aldehyde, and can be realized in a highly concentrated medium,
which minimizes the amount of chemical waste. Based on these
experimental conditions, different aldehydes have been involved
in the three-component reaction to synthesize different 2,4,5-
triarylimidazoles. The results are reported in Table 2.
In all cases, excellent yields were obtained, whatever the nature
of the substituent present on the aldehyde (electron-donating
or electron-withdrawing). This confirms the reliability of the
synthetic method. Comparing the results obtained with those
reached in solvent-free conditions, in the presence of zeolite
HY,31 the yields obtained in this study are very similar (81% in
both cases for the synthesis of product 2, Table 2; 98 and 92%
for the synthesis of product 1, Table 2, respectively, in water and
in the presence of zeolite HY). This suggests that both processes
are very effective.
In these experimental conditions, the eventual presence of
anisaldehyde and benzyl were respectively evidenced by their
elution at 4.8 min and 10.4 min.
3.2 2,4,5-Triarylimidazole synthesis
Optimized general procedure for the preparation of 2,4,5-
triarylimidazole:
Benzil (1.8 g, 8.5 mmol), aldehyde (8.5 mmol) and ammonium
acetate (6.6 g, 85 mmol) were suspended in 7.5 mL of water in
a high pressure Teflon reactor equipped with a magnetic stir
bar, a pressure sensor and an optical fibre. The reaction mixture
was submitted to microwave irradiation in a Milestone Ethos
multi-mode cavity at 800 W for 10 min. For security reasons,
the maximum temperature allowed was set to 210 ◦C and
the maximum pressure was 25 bars. Pressure and temperature
were monitored during the whole reaction by a pressure sensor
and an optical fibre dipping in the medium. The temperature
and pressure profiles recorded for all compounds syntheses
are reported in supporting informations. After cooling, the
crude product was isolated by simple filtration. The resulting
compounds were further rinsed with water, petroleum ether and
dried under vacuum at 50 ◦C, to afford an analytically pure
products (see thorough characterization in the ESI†).
4. Conclusions
In this paper, the efficient synthesis of 2,4,5-triarylimidazoles
in water, under microwave irradiation and without catalyst has
been described. The three-component reaction involving benzil,
an aryl aldehyde and ammonium acetate proceed expeditiously
(completion of the reaction within 10 min) and with excellent
yields (from 88 to 99% yields, in analytically pure and isolated
compounds). A wide range of aromatic aldehydes were tested,
bearing either electron-donating or electron-withdrawing sub-
stituents, suggesting that this method can be used to synthesize
a large variety of compounds. It has therefore been demonstrated
that using water as the solvent and microwave irradiation
as the heating source is ideally suited for the synthesis of
2,4,5-triarylimidazoles. This high throughput method can be
considered as a green process, as it fulfils many required criteria,
including the use of an environmentally friendly solvent (water),
cost effectiveness thanks to microwave heating efficiency, a
convenient and rapid isolation procedure (simple filtration), no
catalyst, and minimum chemical waste. Such a green and efficient
process provides new opportunities for the rapid screening of
a wide range of compounds, either for the development of
new drugs, or original compounds for the material scientist.
In the emerging field of green chemistry, the synthetic strategies
involving processes associating water and microwave irradiation
open new perspectives for the sustainable development of
environmentally friendly chemistry and technology.
From an economical point of view, according to the results
reported by Gronnow et al.,54 the use of microwave irradiation
heating process is expected to significantly reduce (up to 85-
fold) the amount of energy required to perform the reaction
(by comparison with what would be necessary in a thermal
conventional way). In this respect, this procedure can also be
considered as a green process.
3. Experimental
3.1 Characterization and methods
Microwave experiments were performed with a Milestone
ETHOS multi-mode dedicated oven. NMR spectra were
recorded on a Bruker 200 MHz spectrometer. Deuterated
dimethylsulfoxide (DMSO-d6 + ATF) was used as solvent.
Tetramethylsilane (TMS) was used as chemical shift reference.
Melting points were measured by using the capillary method, on
◦
a STUART SMP3 melting-point apparatus, at 2 C min-1. All
spectra were recorded at 25 ◦C. HPLC analyses were carried out
using an Agilent Technologies instrument (1200 series) equipped
with a LC/MSD (1956A)VL mass detector. Separation was
performed on a Modulo-cart QK Uptisphere 5HDO column
(150*2.0 mm—5 microns). The experimental conditions were
the following: T = 0 min. 70% H2O (pH = 7)–30% CH3CN /
T = 15 min. 100% CH3CN—T = 20 min. 100% CH3CN—back
to initial conditions—oven temp. = 40 ◦C—flow: 0.4 ml min-1.
References
1 J. G. Lombardino and E. H. Wiseman, J. Med. Chem., 1974, 17,
1182–1188.
2 T. F. Gallagher, S. M. Fier-Thompson, R. S. Garigipati, M. E.
Sorenson, J. M. Smietana, D. Lee, P. E. Bender, J. C. Lee, J. T.
Laydon, D. E. Griswold, M. C. Chabot-Fletcher, J. J. Breton and
J. L. Adams, Bioorg. Med. Chem. Lett., 1995, 5, 1171–1176.
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 1018–1022 | 1021
©

View Article Online
3 U. Ucucu, N. G. Karaburun and I. Isikdag, Farmaco, 2001, 56, 285–
290.
27 M. Kidwai, S. Saxena Ruby and S. Rastogi, Bull. Korean Chem. Soc.,
2005, 26, 2051–2053.
28 S. E. Wolkenberg, D. D. Wisnoski, W. H. Leister, Y. Wang, Z. Zhao
and C. W. Lindsley, Org. Lett., 2004, 6, 1453–1456.
29 S. Kantevari, S. V. N. Vuppalapati, D. O. Biradar and L. Nagarapu,
J. Mol. Catal. A: Chem., 2007, 266, 109–113.
4 L. L. Chang, K. L. Sidler, M. A. Cascieri, S. de Laszlo, G. Koch, B.
Li, M. MacCoss, N. Mantlo, S. O’Keefe, M. Pang, A. Rolando and
W. K. Hagmann, Bioorg. Med. Chem. Lett., 2001, 11, 2549–2553.
5 K. Nakashima, Y. Fukuzaki, R. Nomura, R. Shimoda, Y. Nakamura,
N. Kuroda, S. Akiyama and K. Irgum, Dyes Pigm., 1998, 38, 127–
136.
30 K. F. Shelke, S. B. Sapkal and M. S. Shingare, Chin. Chem. Lett.,
2009, 20, 283–287.
6 F. E. Gostev, L. S. Kol’tsova, A. N. Petrukhin, A. A. Titov, A. I.
Shiyonok, N. L. Zaichenko, V. S. Marevtsev and O. M. Sarkisov,
J. Photochem. Photobiol., A, 2003, 156, 15–22.
7 H.-J. Zhu, J.-S. Wang, K. S. Patrick, J. L. Donovan, C. L. DeVane
and J. S. Markowitz, J. Chromatogr., B: Anal. Technol. Biomed. Life
Sci., 2007, 858, 91–95.
8 N. Kuroda, R. Shimoda, M. Wada and K. Nakashima, Anal. Chim.
Acta, 2000, 403, 131–136.
9 K. Nakashima, H. Yamasaki, N. Kuroda and S. Akiyama, Anal.
Chim. Acta, 1995, 303, 103–107.
31 S. Balalaie, A. Arabanian and M. S. Hashtroudi, Monatsh. Chem.,
2000, 131, 945–948.
32 S. A. Siddiqui, U. C. Narkhede, S. S. Palimkar, T. Daniel, R. J. Lahoti
and K. V. Srinivasan, Tetrahedron, 2005, 61, 3539–3546.
33 M. Xia and Y.-d. Lu, J. Mol. Catal. A: Chem., 2007, 265, 205–208.
34 M. Siskin and A. R. Katritzky, Science, 1991, 254, 231–237.
35 C. R. Strauss and R. W. Trainor, Aust. J. Chem., 1995, 48, 1665–1692.
36 C. R. Strauss, Aust. J. Chem., 1999, 52, 83–96.
37 J. An, L. Bagnell, T. Cablewski, C. R. Strauss and R. W. Trainor,
J. Org. Chem., 1997, 62, 2505–2511.
10 Y.-F. Sun, W. Huang, C.-G. Lu and Y.-P. Cui, Dyes Pigm., 2009, 81,
10–17.
11 Z. Fang, S. Wang, L. Zhao, Z. Xu, J. Ren, X. Wang and Q. Yang,
Mater. Chem. Phys., 2008, 107, 305–309.
12 L. Zhao, S. B. Li, G. A. Wen, B. Peng and W. Huang, Mater. Chem.
Phys., 2006, 100, 460–463.
38 L. Bagnell, T. Cablewski, C. R. Strauss and R. W. Trainor, J. Org.
Chem., 1996, 61, 7355–7359.
39 V. Polshettiwar and S. Varma Rajender, Chem. Soc. Rev., 2008, 37,
1546–1557.
40 V. Polshettiwar and S. Varma Rajender, Acc. Chem. Res., 2008, 41,
629–639.
13 M. Staehelin, D. M. Burland, M. Ebert, R. D. Miller, B. A. Smith,
R. J. Twieg, W. Volksen and C. A. Walsh, Appl. Phys. Lett., 1992, 61,
1626–1628.
41 W. Wei, C. C. K. Keh, C.-J. Li and R. S. Varma, Clean Technol.
Environ. Policy, 2004, 7, 62–69.
42 D. Dallinger and C. O. Kappe, Chem. Rev., 2007, 107, 2563–
14 N. Fridman, M. Kaftory and S. Speiser, Sens. Actuators, 2007, B126,
2591.
107–115.
43 C. R. Strauss and R. S. Varma, Top. Curr. Chem., 2006, 266, 199–
231.
15 F. K. Japp and H. H. Robinson, J. Chem. Soc. Trans., 1882, 41,
323–329.
44 V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2007, 48, 7343–
16 B. Radziszewski, Ber. Dtsch. Chem. Ges., 1882, 15, 1493.
17 A. Shaabani, A. Rahmati, E. Farhangi and Z. Badri, Catal.
Commun., 2007, 8, 1149–1152.
7346.
45 V. Polshettiwar and R. S. Varma, Tetrahedron Lett., 2008, 49, 397–
400.
18 A. Shaabani and A. Rahmati, J. Mol. Catal. A: Chem., 2006, 249,
46 T. A. Bryson, J. M. Gibson, J. J. Stewart, H. Voegtle, A. Tiwari, J. H.
Dawson, W. Marley and B. Harmon, Green Chem., 2003, 5, 177–180.
47 L. M. Dudd, E. Venardou, E. Garcia-Verdugo, P. Licence, A. J. Blake,
C. Wilson and M. Poliakoff, Green Chem., 2003, 5, 187–192.
48 V. Polshettiwar and R. Varma, S, Current Opinion in Drug Discovery
and Development, 2007, 10, 723–737.
246–248.
19 L.-M. Wang, Y.-H. Wang, H. Tian, Y.-F. Yao, J.-H. Shao and B. Liu,
J. Fluorine Chem., 2006, 127, 1570–1573.
20 M. M. Heravi, K. Bakhtiari, H. A. Oskooie and S. Taheri, J. Mol.
Catal. A: Chem., 2007, 263, 279–281.
21 N. D. Kokare, J. N. Sangshetti and D. B. Shinde, Synthesis, 2007,
2829–2834.
22 M. Kidwai, P. Mothsra, V. Bansal, R. K. Somvanshi, A. S. Ethay-
athulla, S. Dey and T. P. Singh, J. Mol. Catal. A: Chem., 2007, 265,
177–182.
23 A. E. Mohammed, N. D. Kokare, J. N. Sangshetti and D. B. Shinde,
J. Korean Chem. Soc., 2007, 51, 418–422.
24 M. V. Chary, N. C. Keerthysri, S. V. N. Vupallapati, N. Lingaiah and
S. Kantevari, Catal. Commun., 2008, 9, 2013–2017.
25 A. R. Khosropour, Ultrason. Sonochem., 2008, 15, 659–664.
26 S. Das Sharma, P. Hazarika and D. Konwar, Tetrahedron Lett., 2008,
49, 2216–2220.
49 E. Chauveau, C. Marestin, V. Martin and R. Mercier, Polymer, 2008,
49, 5209–5214.
50 R. Brunel, C. Marestin, V. Martin, R. Mercier and F. Schiets, High
Perform. Polym., 2008, 20, 185–207.
51 D. Davidson, M. Weiss and M. Jelling, J. Org. Chem., 1937, 2, 328–
334.
52 C. Yu, M. Lei, W. Su and Y. Xie, Synth. Commun., 2007, 37, 3301–
3309.
53 H. A. Oskooie, Z. Alimohammadi and M. M. Heravi, Heteroat.
Chem., 2006, 17, 699–702.
54 M. J. Gronnow, R. J. White, J. H. Clark and D. J. Macquarrie, Org.
Process Res. Dev., 2005, 9, 516–518.
1022 | Green Chem., 2010, 12, 1018–1022
This journal is
The Royal Society of Chemistry 2010
©