One-pot synthesis of 2,4,5-triaryl-1 H -imidazoles from arylaldehydes, benzyl alcohols, or benzyl halides with hexamethyldisilazane in molten tetrabutylammonium bromide

Article abstract of DOI:10.1055/s-0030-1258393

A simple and efficient method for the synthesis of 2,4,5-triaryl-1H- imidazole derivatives in good to excellent yields by reaction between hexamethyldisilazane and arylaldehydes, benzyl alcohols, benzyl halides in molten tetrabutylammonium bromide as an inexpensive and non toxic solvent has been developed. The remarkable advantages of this method are the simple workup procedure, high yields of products, the use of an ionic liquid as a green solvent, and the availability of reagents. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258393

PAPER
459
One-Pot Synthesis of 2,4,5-Triaryl-1H-imidazoles from Arylaldehydes, Benzyl
Alcohols, or Benzyl Halides with Hexamethyldisilazane in Molten Tetrabutyl-
ammonium Bromide
O
ne-Pot
S
a
ynthesis of
v
2,4,5-Triary
a
l-1
H
-imidaz
d
ole
s
Salehi,*a Mohammad M. Khodaei,b Ahmad R. Khosropourb
a
Department of Pharmacology, Hamadan University of Medical Science, Hamadan, Iran
Department of Chemistry, Razi University of Kermanshah, Kermanshah, Iran
Fax +98(811)8276299; E-mail: javadsalehi_58@yahoo.com
b
Received 15 November 2010; revised 25 November 2010
spite a number of precedents, an efficient, practical and
facile method for these transformations is desired.
Abstract: A simple and efficient method for the synthesis of 2,4,5-
triaryl-1H-imidazole derivatives in good to excellent yields by reac-
tion between hexamethyldisilazane and arylaldehydes, benzyl alco-
hols, benzyl halides in molten tetrabutylammonium bromide as an
inexpensive and non toxic solvent has been developed. The remark-
able advantages of this method are the simple workup procedure,
high yields of products, the use of an ionic liquid as a green solvent,
and the availability of reagents.
Today, one of the biggest problems of chemists is the use
of hazardous and unrecoverable chemicals that pollute the
world. The use of ionic liquids as reaction media and cat-
alyst can offer a solution to solvent emission and catalyst
recycle problems.19 Ionic liquids possess a number of in-
teresting properties, especially their lack of vapor pres-
sure, a widely accessible temperature range with lack of
flammability, and ease of product recovery that reduce en-
vironmental emissions.20
Key words: 2,4,5-triaryl-1H-imidazole,
hexamethyldisilazane,
ionic liquids, aldehydes
In a further extension of our work in the context of eco-
nomical chemistry,21 herein, we would like to report the
use of molten tetrabutylammonium bromide as an inex-
pensive ionic liquid for the efficient one-pot synthesis of
2,4,5-triaryl-1H-imidazoles 1 (Table 1) in high yields.
2,4,5-Triaryl-1H-imidazoles have gained the remarkable
importance due to their widespread biological activity and
their use in synthetic chemistry. The imidazole ring sys-
tem is one of the most important substructures found in a
large number of natural products and pharmacologically
active compounds, such as the antiulcerative agent cime-
tidine,1 inhibitors of P38MAP kinase,2 fungicides and her-
bicides,3 plant growth regulators,4 and therapeutic
agents.5 Trifenagrel6 is a 2,4,5-triaryl-1H-imidazole that
reduces platelet aggregation in several animal species and
humans.
Among the various ionic liquids {tetrabutylphosphonium
bromide, tetrabutylammonium chloride, tetrabutylammo-
nium fluoride, and butylpyridinium tetrachloroferrate
([bpy]FeCl4)} studied for this reaction, molten tetrabutyl-
ammonium bromide gave better yields with short reaction
times. However, in the absence of an ionic liquid, the re-
action did not yield any product even after a long reaction
time (15–20 h).
Due to their great importance, many synthetic strategies
have been developed. In 1882, Adziszewski and Japp
reported the first synthesis of an imidazole from a 1,2-di-
carbonyl compound, various aldehydes, and ammonia,
giving 2,4,5-triphenyl-1H-imidazoles.7,8 Also, Grimmett
et al. proposed the synthesis of imidazole using nitriles
and esters.9
We initially performed the reaction with benzaldehyde de-
rivatives and hexamethyldisilazane in molten tetrabutyl-
ammonium bromide at 100 °C in presence of
trifluoromethanesulfonic acid–silica gel as catalyst, 2,4,5-
triaryl-1H-imidazole derivatives 1 were formed in high
yields (Table 1).
Recently, there have been several methods reported in the
literature for the synthesis of 2,4,5-triaryl-1H-imidazoles
from benzil/benzoin, aldehydes, and ammonium acetate
using different catalyst such as zeolite HY/silica gel,10 zir-
conium tetrachloride,11 nickel(II) chloride hexahydride,12
iodine,13 sodium bisulfite,14 acidic aluminum oxide,15 ace-
tic acid,16 ammonium acetate,17 ytterbium triflate.18,19 The
application of these methods suffer from some disadvan-
tages such as the use of costly or less easily available re-
agents, harsh reaction conditions, long reaction times,
poor yields, and the use of toxic solvents. Therefore, de-
The proposed mechanism for this reaction is given in
Scheme 1.
In continuation of this work, we were interested in ex-
panding this method by using benzylic alcohols and ben-
zylic halides. These reagents were separately treated with
bismuth(III) nitrate pentahydrate and hexamethyldisila-
zane in molten tetrabutylammonium bromide at 100 °C;
2,4,5-triaryl-1H-imidazole derivatives 1 were formed in
high yields (Table 1).
In conclusion, we have demonstrated a new, straightfor-
ward, and efficient method for the one-pot synthesis of
2,4,5-triaryl-1H-imidazole derivatives using molten tet-
rabutylammonium bromide as a commercially available
SYNTHESIS 2011, No. 3, pp 0459–0462
Advanced online publication: 11.01.2011
DOI: 10.1055/s-0030-1258393; Art ID: Z27410SS
x
x
.
x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

460
J. Salehi et al.
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Table 1 Reaction of Arylaldehydes, Aryl Alcohols, Aryl Halides with Hexamethyldisilazane To Form 2,4,5-Triaryl-1H-imidazoles
TfOH-SiO2, 100 °C
Ar
2–5.5 h, 70–95%
molten TBAB
HN
Ar
N
Ar-X + HMDS
Ar
Bi(NO3)3⋅5H2O, 100 °C
1
5–10 h, 65–92%
Entry
1
Ar
X
Producta
1a
1b
1c
Time (h)
Yieldb (%)
90
Ph
CHO
3.5
3.5
3
2
4-ClC6H4
4-O2NC6H4
2-ClC6H4
3-O2NC6H4
2-furyl
CHO
92
3
CHO
90
4
CHO
1d
1e
3.5
3
95
5
CHO
92
6
CHO
1f
2
95
7
4-MeC6H4
CHO
1g
1h
1a
1b
1c
5.5
5
70
8
4-MeOC6H4
Ph
CHO
75
9
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2Br
CH2Cl
CH2OH
CH2OH
CH2OH
CH2OH
5
87
10
11
12
13
14
15
16
17
18
19
20
4-ClC6H4
4-O2NC6H4
2-ClC6H4
3-O2NC6H4
2-furyl
5.5
10
5
92
65
1d
1e
92
10
5
60
1f
90
Ph
1a
1a
1b
1c
5
90
Ph
5.5
5
88
4-ClC6H4
4-O2NC6H4
4-O2NC6H4
3-O2NC6H4
90
10
10.5
7
60
1c
62
1e
87
a All products were characterized with IR and 1H and 13C NMR.
b Isolated yields.
Compound 1a is known;22 spectral data for new compounds are giv-
en below.
ionic liquid. The significant features of this method in-
clude: (a) operational simplicity, (b) the use of available
and inexpensive reagents, (c) high yields of products, and
(d) the use of an ionic liquid as a green solvent.
Trifluoromethanesulfonic Acid on Silica Gel Support
To MeCN (20 mL) were added TfOH (1.5 mg) and silica gel (0.5 g)
and the mixture was stirred at r.t. for 30 min. Evaporation of MeCN
gave the corresponding TfOH-silica gel.
Reaction progress was monitored by TLC using silica gel Poly-
grams SIL G/UV254 plates. IR spectra were obtained using a
1
2,4,5-Triaryl-1H-imidazoles 1 from Arylaldehyde Derivatives;
General Procedure
To the molten salt TBAB (321 mg, 1 mmol) were added arylalde-
hyde (1 mmol), HMDS (1 mmol), and TfOH-silica gel (0.06–0.1 g);
the mixture was stirred at 100 °C for the appropriate time (Table 1).
After completion of the reaction as indicated by TLC, H2O–EtOH
(2:1) was added to mixture and the solid thus formed was filtered
Shimadzu 470 spectrophotometer. H NMR spectra were run on a
Bruker Avance 200 MHz NMR spectrometer. Melting points were
determined in open capillaries with a Gallenkamp melting point ap-
paratus and are corrected. Chemicals were either prepared in our
laboratories or purchased from Fluka and Merck chemical compa-
nies.
Synthesis 2011, No. 3, 459–462 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 2,4,5-Triaryl-1H-imidazoles
461
CHO
CHO
OTMS
NH(TMS)
OTMS
TMSO
OTMS
– TMSOH
N
N
H
HMDS
+
CHO
NH(TMS)
N
H
N
N
– TMSOH
OTMS
HMDS
H
N
N
Ph
Ph
HN
Ph
N
HN
Ph
N
oxidation
Ph
Ph
Scheme 1
and then washed with cooled EtOH (2 × 10 mL). The solid was re-
IR (KBr): 3200, 1635, 1475, 1420, 1084, 785 cm–1.
crystallized (EtOH) to give the pure product in 70–95% yield.
1H NMR (DMSO, CDCl3): d = 7.42 (d, J = 10 Hz, 3 H, Ar), 7.33 (d,
J = 10 Hz, 3 H, Ar), 7.20 (t, J = 10 Hz, 3 H, Ar), 7.10 (t, J = 10 Hz,
3 H, Ar), 12.6 (br s, 1 H, NH).
13C NMR (DMSO, CDCl3): d = 124.1, 127, 128.4, 129.3, 129.9,
132.1, 136, 136.7.
2,4,5-Triaryl-1H-imidazoles 1 from Benzyl Alcohols or Benzyl
Halides; General Procedure
To the molten salt TBAB (1 mmol, 321 mg) were added benzyl al-
cohol or benzyl halide (1 mmol), HMDS (1 mmol), and
Bi(NO3)3·5H2O (1.2 mmol); the mixture was stirred at 100 °C for
the appropriate time (Table 1). After completion of the reaction as
indicated by TLC, Et2O (10 mL) was added to the mixture, which
was filtered and then H2O–EtOH (2:1) was added to the filtrate, the
solid thus formed was filtered and washed with cooled EtOH
(2 × 10 mL). The solid was recrystallized (EtOH) to give the pure
product in 62–92% yield.
2,4,5-Tris(3-nitrophenyl)-1H-imidazole (1e)
Mp (decomposed before melting).
IR (KBr): 3405, 1600, 1520, 1347, 1089, 900, 820, 710 cm–1.
1H NMR (DMSO, CDCl3): d = 7.2–8.3 (m, 12 H), 12.41 (br s, 1 H,
NH).
13C NMR (DMSO, CDCl3): d = 122.1, 124.1, 128.6, 133.2, 136.2,
137.6, 148.7.
2,4,5-Triphenyl-1H-imidazole (1a)
Mp 273–276 °C.
IR (KBr): 3434, 2993, 2470, 1638, 1216 cm–1.
1H NMR (DMSO, CDCl3): d = 7.42–8.12 (m, 15 H, Ar), 12.61 (br
s, 1 H, NH).
2,4,5-Tri-2-furyl-1H-imidazole (1f)
Mp (decomposed before melting).
IR (KBr): 3040, 1601, 1445, 850, 718 cm–1.
1H NMR (DMSO, CDCl3): d = 6.13–6.18 (d, J = 7.5 Hz, 3 H, Ar),
6.85–6.89 (d, J = 8 Hz, 3 H, Ar), 7.18 (s, 3 H, Ar), 12.42 (br s, 1 H,
NH).
13C NMR (DMSO, CDCl3): d = 103, 112, 122, 136.2, 143.1, 153.3.
13C NMR (DMSO, CDCl3): d = 122.1, 127.2, 128.5, 129.1, 136.5.
2,4,5-Tris(4-chlorophenyl)-1H-imidazole (1b)
Mp 275–276 °C.
IR (KBr): 3417, 1600, 1481, 1411, 1094, 810 cm–1.
1H NMR (DMSO, CDCl3): d = 7.35 (d, J = 10 Hz, 6 H, Ar), 7.85 (d,
J = 10 Hz, 6 H, Ar), 12.51 (br s, 1 H, NH).
13C NMR (DMSO, CDCl3): d = 123.3, 128.8, 129.2, 133.2, 134.2,
136.5.
2,4,5-Tri-4-tolyl-1H-imidazole (1g)
Mp 256–258 °C.
IR (KBr): 3451, 2990, 2450, 1625, 1210 cm–1.
1H NMR (DMSO, CDCl3): d = 2.36 (s, 9 H, CH3), 7.14–7.18 (m, 12
H, Ar), 12.58 (br s, 1 H, NH).
13C NMR (DMSO, CDCl3): d = 21.2, 122, 127, 129.1, 133.2, 136.2,
138.1.
2,4,5-Tris(4-nitrophenyl)-1H-imidazole (1c)
Mp 273–274 °C.
IR (KBr): 3408, 1612, 1523, 1347, 1091, 820 cm–1.
1H NMR (DMSO, CDCl3): d = 7.78 (d, J = 9 Hz, 6 H, Ar), 8.50 (d,
J = 9 Hz, 6 H, Ar), 12.55 (br s, 1 H, NH).
13C NMR (DMSO, CDCl3): d = 122.1, 124.1, 127.1, 136.2, 141.1,
147.1.
2,4,5-Tris(4-methoxyphenyl)-1H-imidazole (1h)
Mp 225–228 °C.
IR (KBr): 3418, 2856, 2435, 1625, 1214 cm–1.
1H NMR (DMSO, CDCl3): d = 3.85 (s, 9 H, CH3), 6.93–6.96 (d,
J = 8.8 Hz, 6 H, Ar), 8.02–8.05 (d, J = 8.8 Hz, 6 H, Ar), 12.52 (br s,
1 H, Ar).
13C NMR (DMSO, CDCl3): d = 58, 114.2, 122, 128, 128.7, 136,
161.
2,4,5-Tris(2-chlorophenyl)-1H-imidazole (1d)
Mp 268–270 °C.
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PAPER
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Acknowledgment
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Synthesis 2011, No. 3, 459–462 © Thieme Stuttgart · New York