Highly efficient one-pot synthesis of trisubstituted imidazoles under catalyst-free conditions

Article abstract of DOI:10.1139/v11-141

Operationally simple, atom economical, and scalable synthesis of 2,4,5-trisubstituted imidazoles from benzil, aldehydes, and ammonium acetate is shown to proceed readily in methanol with high yield. The scope of the reaction is quite broad; a variety of aromatic and aliphatic activated and unactivated aldehydes have all been shown to be viable substrates for this reaction. Excellent yields and purity were obtained by washing the products with hot ethanol.

Full text of DOI:10.1139/v11-141

195
Highly efficient one-pot synthesis of trisubstituted
imidazoles under catalyst-free conditions
Najmadin Azizi, Nairreh Dado, and Alireza Khajeh Amiri
Abstract: Operationally simple, atom economical, and scalable synthesis of 2,4,5-trisubstituted imidazoles from benzil, alde-
hydes, and ammonium acetate is shown to proceed readily in methanol with high yield. The scope of the reaction is quite
broad; a variety of aromatic and aliphatic activated and unactivated aldehydes have all been shown to be viable substrates
for this reaction. Excellent yields and purity were obtained by washing the products with hot ethanol.
Key words: aldehyde, benzil, imidazole, atom economic, solvent effect, catalyst free.
Résumé : On a montré qu’un procédé simple, économique d’un point de vue atomique et d’échelle variable peut être appli-
qué à la synthèse, avec un rendement élevé, dans le méthanol, d’imidazoles 2,4,5-trisubstitués à partir du benzile, d’aldéhy-
des et d’acétate d’ammonium. Le domaine d’application de la réaction est étendu; on a en effet montré qu’une variété
d’aldéhydes aromatiques et aliphatiques, activés et non activés, peuvent être utilisés comme substrats pour la réaction. On a
obtenu rendements élevés et une pureté excellente en lavant les produits avec de l’éthanol bouillant.
Mots‐clés : aldéhyde, benzile, imidazole, économique d’un point de vue atomique, effet de solvant, sans catalyseur.
[Traduit par la Rédaction]
catalyst-free imidazole formation with excellent yield has
been developed.
Introduction
Imidazole derivatives play an important role in chemical
and biological systems.1 Many of the substituted imidazoles
are known as inhibitors of fungicides and herbicides, plant
growth regulators, and therapeutic agents.2 Recent advances
in green chemistry have extended the boundary of imidazoles
as ionic liquids that can be used as electrolytes or green sol-
vents because of their low vapor pressure and wide chemical
stability.3 Furthermore, imidazolylidene carbenes have been
used in coordination chemistry, as ligands in transition-metal
and metal-free catalysts for organic synthesis.4,5
Results and discussion
Recently, we were interested in performing organic reac-
tions in water, and we have shown that the aqueous medium
can strongly favor the reactivity and selectivity, even when
they are carried out under heterogeneous conditions.11
Herein, we wish to report the simple synthesis of new imida-
zole derivatives with the reaction of 1,2-diketones and variety
of aldehydes performed in methanol with excellent yields and
without using any catalyst.
Owing to the wide applicability of imidazoles, preparative
methodologies for this class of compounds have been inten-
sively developed in the literature.6 Conventional methods for
imidazole core synthesis usually involve the reaction of a-
diketones and a-haloketones with formamide (Bredereck
synthesis),7 the base-promoted reaction of tosylmethyl iso-
cyanides and aldimines or imidoyl chlorides,8 and catalytic
multicomponent coupling reactions in the presence of a
Lewis acid9 and an organocatalyst.10
However, the use of high temperatures, expensive instru-
ments such as microwaves, and corrosive reagents limit these
methods, and there are few reports on practical methods for
preparing them, and no method is catalyst-free. Thus, highly
efficient and flexible protocols for the synthesis of imida-
zoles are still in need as there is a scope for further improve-
ment towards milder reaction conditions, development of
simple workup, inexpensive reagents, convenient procedures,
and higher product yields. In this article, a simple, rapid, and
First, we embarked upon a series of experiments to estab-
lish the optimum conditions. The one-pot three-component
reaction of benzaldehyde 2, benzil 1, and ammonium salts
were studied (Table 1). First findings indicated that the pres-
ence of ammonium acetate in methanol was an excellent sol-
vent without using any catalyst or promoter and 2,4,6-
triphenyimidazole 3 crystals were obtained in 97% yield by
reacting equimolar amounts of 1 and 2 at 60 °C for 4 h.
Other ammonium salts such as fluoride, chloride, nitrate,
and hydrogen sulfate and ammonia solution (32%) give low
yields of desired products for these reaction conditions. We
also investigated the effects of common organic solvents and
the influence of different solvents on the rate and the course
of these reactions. In dichloromethane, cyclohexane, and
THF the reaction did not take place and the starting materials
were recovered and low yield of the product was observed in
acetonitrile, water, ethanol, and solvent-free conditions (Ta-
ble 1).
Received 1 June 2011. Accepted 8 September 2011. Published at www.nrcresearchpress.com/cjc on 13 December 2011.
N. Azizi, N. Dado, and A.K. Amiri. Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran.
Corresponding author: Najmadin Azizi (e-mail: azizi@ccerci.ac.ir).
Can. J. Chem. 90: 195–198 (2012)
doi:10.1139/V11-141
Published by NRC Research Press

196
Table 1. Optimization of reaction conditions.
Can. J. Chem. Vol. 90, 2012
rials. To the best of our knowledge, this is the first report of
the catalyst-free synthesis of imidazoles under very mild con-
ditions. The procedure offers a simple experimental proce-
dure and a short reaction time, is catalyst-free, is low cost,
and provides efficient yields, which makes this method a use-
ful and attractive strategy in view of economic and environ-
mental advantages.
CHO
Ph
Ph
Ph
Ph
O
O
N
NH4X
Ph
+
N
H
Solvent, 60 oC, 4 h
1
3
2
Yield (%)
Solvent
CH2Cl2
C6H12
CH3CN
THF
Experimental section
0
0
Instrumentation, analyses, and starting material
35
5
60
10
70
97
NMR spectra were recorded on a Bruker ACF 500 (1H
NMR at 500 MHz and 13C NMR at 125 MHz) spectrometer
in pure deuterated solvents with tetramethylsilane (Supple-
mentary data). Melting points were determined in open capil-
lary tubes in a Buchi-535 melting-point apparatus. All
reagents, unless otherwise stated, were used as received from
suppliers. Solvents were distilled before use.
SFC
H2O
EtOH
MeOH
Amine/ammonium
NH3
NH4F
NH4Cl
NH4NO3
NH4SO4
NH4OAc
20
40
0
0
15
97
General procedure for the synthesis of imidazole
derivatives in methanol
To a well-stirred mixture of benzaldehyde (0.1 cm3,
1 mmol) and benzil (0.21 g, 1 mmol) in methanol (1 cm3)
ammonium acetate was added (0.23 g, 3 mmol) and the reac-
tion mixture was heated at 60 °C for 4–8 h. The reaction was
allowed to cool and the resulting precipitates were recrystal-
lized from ethanol to give pure imidazole derivatives.
Note: Reaction conditions: benzil (1 mmol), benzaldehyde (1 mmol),
ammonium salts (3 mmol), and solvent (1 mL), 4 h.
With optimal conditions in hand, the reaction of benzil
with different aldehydes was examined to explore the scope
of the reaction. First, ammonium actate and benzil were used
as model substrates (Table 2), and the results indicated that
all commercially available aldehydes were good substrates
for this system. Aromatic aldehydes bearing such functional
groups as fluoro, chloro, bromo, methyl, or methoxy were
able to effect the imidazole synthesis. We also observed that
electronic effect on the aldehydes had little influence on the
yield and the reaction conditions; that is, aryl aldehydes with
electron-withdrawing groups reacted rapidly, whereas the
substitution of electron-rich groups on the benzene ring did
not decreased the reactivity. Moreover, a good yield for 3,5-
dimethoxy benzaldehyde (Table 2, entry 24), the substrate
with a strong electron-donating group, was observed. In addi-
tion, the 2-furaldehyde, (Table 2, entry 29), thiophenaldehyde
(Table 2, entry 30), 2-naphthaldehyde (Table 2, entry 25),
and 1-naphthaldehyde (Table 2, entry 26) also gave good
yields of products. On the other hand, for the first time we
have shown that fluorene-9-carbaldehyde (Table 2, entry 27),
indole-3-carboxaldehyde (Table 2, entry 28), terephthalde-
hyde (Table 2, entry 31), isophthaldehyde (Table 2, entry
32), ferrocene carbaldehyde, (Table 2, entry 33), and ali-
phatic aldehydes still displayed high reactivity and clean re-
actions under these standard conditions.
Selected data for the new compounds
Table 1, entry 27
1H NMR (500 MHz, DMSO-d6) d: 3.98 (s, 2H), 7.19–7.58
(m, 13H), 7.89 (d, J = 7.3 Hz, 1H), 7.94 (d, J = 7.9 Hz,
1H), 8.01 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H), 12.66 (brs, NH,
1H). 13C NMR (125 MHz, DMSO-d6) d: 121.0, 122.7, 124.9,
126.0, 127.3, 127.7, 127.8, 127.9, 128.6, 129.0, 129.2, 129.5,
129.7, 131.9, 136.1, 138.0, 141.6, 142.0, 144.2, 144.3, 146.7.
Anal. calcd for C28H20N2: C 87.47, H 5.24, N 7.29; found: C
86.55, H 5.10, N 6.30.
Table 1, entry 28
1H NMR (500 MHz, DMSO-d6) d: 7.12–7.60 (m, 13H),
7.96 (s, 1H), 8.45 (s, 1H), 11.33 (brs, NH, 1H)), 12.23 (brs,
NH, 1H). 13C NMR (125 MHz, DMSO-d6) d: 107.7, 112.6,
120.5, 122.3, 122.7, 124.6, 125.9, 126.6, 127.0, 127.7,
128.2, 129.0, 129.5, 132.5, 136.2, 136.8, 137.12, 144.5.
HRMS: 334 (M+), 335 (100). Anal. calcd for C23H17N3: C
82.36, H 5.11, N 12.53; found: C 81.90, H 4.88, N 12.01.
Table 1, entry 33
1H NMR (500 MHz, DMSO-d6) d: 4.14 (s, 5H), 4.36 (t,
J = 1.6 Hz, 3H), 4.96 (t, J = 1.9 Hz, 2H), 7.20–7.52 (m,
10H), 12.19 (brs, NH, 1H). 13C NMR (125 MHz, DMSO-d6)
d: 67.1, 69.5, 70.0, 76.6, 127.1, 127.8, 128.3, 128.9, 129.1,
129.4, 136.2, 146.8. HRMS: 404 (100).
It is noteworthy that the present method is very simple and
that the process became even more attractive for large-scale
applications when we found that it could be run at large
scales without decreased yields and with the use of ethanol
as the organic solvent in the workup without tedious column
chromatography.
Supplementary data
In summary, we have described a simple, highly efficient,
and facile procedure for one-pot three-component synthesis
of imidazole derivatives from readily available starting mate-
Supplementary data (experimental details and spectro-
scopic characterization (1H and 13C NMR and mass) of the
compounds) are available with the article through the journal
Published by NRC Research Press

Azizi et al.
197
Table 2. Practical synthesis of new imidazoles under catalyst-free conditions.
H
Ph
Ph
Ph
Ph
O
O
N
MeOH
RCHO
NH4OAc
R
+
+
60 °C, 4-8 h
N
60%-97%
mp (°C)
Found
Entry
Aldehyde
X
Yield (%)
Reported
Ref.
1
2
3
4
5
6
7
8
Cl
F
Br
OH
OCH
CH
97
95
90
80
92
90
88
90
84
86
97
97
97
97
95
92
97
97
97
90
90
85
80
264
242
260
235
232
234
224
230
262–264
188–190
265
232–233
228–230
233–235
223–224
232–234
246–248
242
276–278
295
305–310
267–268
300
10c
10c
9m
10c
9n
10c
9o
10c
9o
9m
9n
9m
10c
9b
9c
9m
9n
X
CHO
3
3
C H
2
5
7
C H
3
9
CO CH
246
245
275
2
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NO
H
Cl
Br
OCH
CH
OH
Cl
F
Br
OCH
295–297
307–308
263–265
298–299
258
197–198
256
206–207
209–210
255
CHO
CHO
3
X
3
259
195–197
254.5–255
206–208
206–211
252.5–253.5
230–231
178
9a
9d
10c
9a
10c
9m
X
3
CH
NO
3
2
230–233
176
Cl
CHO
Cl
24
60
165–167
164–165
9e
MeO
CHO
OMe
CHO
25
26
72
80
279
290
277–278
9a
297
9m
CHO
27
28
75
82
281–283
CHO
307
CHO
N
H
CHO
29
30
31
32
80
84
70
74
245–247
264–266
>350
242
9m
9m
1d
O
S
260–262
442
CHO
OHC
CHO
CHO
288–290
294–296
1d
OHC
Fe
33
64
97–99
CHO
34
35
62
68
248
238
246
9c
9p
CHO
CHO
238–240
Ph
Published by NRC Research Press

198
Can. J. Chem. Vol. 90, 2012
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Acknowledgements
Financial support of this work by the Chemistry and
Chemical Research Center of Iran is gratefully appreciated.
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Published by NRC Research Press

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