Simple and efficient method for the synthesis of highly substituted imidazoles catalyzed by benzotriazole

Article abstract of DOI:10.1002/jhet.1818

Benzotriazole is an efficient, readily available, and simple catalyst for the synthesis of 2,4,5-trisubstituted imidazoles in high yields from 1,2-diketones and aldehydes in the presence of NH₄OAc via multi-components reaction. The significant features of this one-pot procedure are very simple operation, easy work-up and purification of products.

Full text of DOI:10.1002/jhet.1818

668
Simple and Efficient Method for the Synthesis of Highly Substituted
Vol 50
Imidazoles Catalyzed by Benzotriazole
*
Feng Xu, Nige Wang, Youping Tian, and Gaoqiang Li
Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering
Science, Shaanxi Normal University, Xi’an, Shaanxi 710062, People’s Republic of China
*
E-mail: fengxu@snnu.edu.cn
Received April 17, 2012
DOI 10.1002/jhet.1818
Published online in Wiley Online Library (wileyonlinelibrary.com).
N
Ph
Ph
Ph
O
5mol% benzotriazole
R
+
+
R-CHO
1eq.
NH4OAc
2eq.
NH
n-BuOH, 80oC
O
Ph
1eq.
Benzotriazole is an efficient, readily available, and simple catalyst for the synthesis of 2,4,5-trisubstituted
imidazoles in high yields from 1,2-diketones and aldehydes in the presence of NH4OAc via multi-components
reaction. The significant features of this one-pot procedure are very simple operation, easy work-up and
purification of products.
J. Heterocyclic Chem., 50, 668 (2013).
INTRODUCTION
NiCl2•6H2O/Al2O3,[28] ZrCl4,[29] ionic liquids,[30] ceric
ammonium nitrate,[31] InCl3•3H2O,[32] and DABCO[33].
Moreover, some of these synthetic protocols suffer from
one or more serious drawbacks, such as longer reaction
times, large amount of catalyst loadings, significant amounts
of waste materials, low selectivity or low yields, and the use
of expensive reagents. Simple efficient and flexible protocol
for the synthesis of imidazoles still needs to be pursued for
further improvement towards milder reaction conditions,
development of simple and inexpensive reagents, convenient
procedures, and higher product yields. However, despite in-
tensive effort, only a handful of general methodologies exist
for the direct construction of highly substituted imidazoles.
Replacement of conventional toxic and pollutant Bronsted
and metal Lewis acid catalysts with environmentally benign or-
ganic molecular catalysts is an active area of current research.
The use of organic molecules as catalysts has provided attrac-
tive alternatives to the more traditional metal-catalyzed. In
recent years, benzotriazole has wide application as a synthetic
auxiliary in a multitude of synthetic endeavors [34], such as
nitrogen ligand[35], reactive promotion reagents[36], or cata-
lyst[37]. But it has not been studied as a catalyst in the synthe-
sis of imidazoles until now. In continuation of our efforts
toward the development of organic molecules, catalyst using
organic synthesis, herein, we report a mild, efficient, and facile
one-pot synthesis of highly substituted imidazole derivatives
by the multi-component reaction of 1,2-diketone, amine
source, and aldehyde using benzotriazole as the catalyst.
Imidazole ring system is one of the most important
substructure found in a large number of natural products and
pharmacologically active compounds.[1–5] The potency and
wide applicability of the imidazole pharmacophore can be at-
tributed to its hydrogen bond donor-acceptor capability as
well as affinity for metals (e.g., Zn, Fe, and Mg), which are
present in many protein active sites[6]. Various substituted
imidazole act as inhibitor of p38 MAP kinase,[7] glucagon
receptors,[8] plant growth regulators,[9] therapeutic agents,
[10] antibacterial,[11] and also antitumor.[12] Recent
advances in green chemistry and organometallic chemistry
have extended the boundary of imidazole to the synthesis
and application of a large class of imidazoles as ionic liquids
and imidazole related N-heterocyclic carbenes.[13,14] In
addition, the optical properties (fluorescence[15] and chemilu-
minescence) of imidazole derivatives are of particular concern
for material scientists. Because of their wide range of biolog-
ical, synthetic, and potential industrial applications, synthesis
imidazoles, especially high substituted imidazoles, have re-
ceived a great deal of attention.
Accordingly, a number of synthetic methods have been
reported for synthesis imidazoles and its derivates. Among
these method, multicomponent reactions are very smart and
convenient method with unique merit.[16] Multicomponent
condensation of 1,2-diketones, aromatic aldehydes, and ammo-
nium acetate can be carried out in the presence of several
catalysts systems, which include microwaves radiation,[17] mo-
lecular iodine,[18] HClO4-SiO2,[19] heteropolyacid,[20] silica
gel/NaHSO4,[21] L-proline,[22] FeCl3•6H2O,[23] BF3•SiO2,[24]
K5CoW12O40-3H2O,[20b], and silica-supported Wells-Dawson
acid.[25] They can also be accessed by refluxing in acetic
acid,[26] silica sulfuric acid[27] and catalyzed by
RESULTS AND DISCUSSION
Three component condensation reactions of benzaldehyde
(1.0 mmol) with ammonium acetate (2.0 mmol) and benzil
© 2013 HeteroCorporation

May 2013
Simple and Efficient Method for the Synthesis of Highly
669
Substituted Imidazoles Catalyzed by Benzotriazole
Table 1
(1.0 mmol) for the synthesis of imidazole were used as a
model reaction (Scheme 1).
DMAP catalyzed-condensation of 1,2-diketone, benzaldehyde, and
ammonium acetate in different solvents and with different catalyst loadings.
Initially, in continuation of our previous work on the
applications of Ph3P, PPh3 (10 mol%) was used as a catalyst
for model reaction in n-butanol solvent at 80ꢀC, which led to
the 2,4,5-trisubstituded imidazole in 80% yield for 24 h. But
the reaction time is long, and catalyst loadings is also large,
even the yield is good. Encouraged by this result, we moved
our attention to nitrogen containing organic molecules that
have great choice spaces and belong to the same group with
phosphorus. First object is 4-dimethylaminopyridine
(DMAP), it also works for the model reaction and gives the
desire product in 76% yield when 5 mol% DMAP was used
in n-butanol solvent at 80ꢀC for 12 h (Table 1, entry 4).
When increased the catalyst loading to 10 mol%, the yield
of the desired product showed a slight increase to 80%
(Table 1, entry 2). The temperature effect of this model reac-
tion also was evaluated by using 5 mol% DMAP as catalyst
in n-butanol solvent at 50, 80ꢀC and reflux (118ꢀC). The
experiment results that exhibit the yields of product are 62,
76 and 55%, respectively (Table 1, entries 3–5). Reaction
solvent also was a very crucial factor for this reaction. In
order to determine the most appropriate solvent system for
this DMAP-catalyzed synthesis of substituted imidazoles,
the model reaction was tested in a variety of protic and
aprotic solvents, such as EtOH, MeOH i-PrOH, t-BuOH,
CH3CN, CH2Cl2, CHCl3, and toluene. But none of the above
solvent was found to be effective than n-butanol for this
reaction (Table 1). Considering the initial experimental
outcomes, it was worthwhile to investigate the other nitrogen
containing organic molecules. We screen the catalyzed
performance of several commercially available nitrogen
organic molecules for model reaction in n-butanol solvent
at 80ꢀC. The results are shown in Table 2. To our surprise,
benzotriazole gave excellent yield to 88% among the selected
catalyst for this model reaction. Then, benzotriazole was se-
lected as the best candidate for 2,4,5-trisubstituded imidazole
by 5 mol% catalyst loading at 80ꢀC in n-butanol solvent.
After optimizing the best reaction conditions for the syn-
thesis 2,4,5-trisubstituded imidazole, the scope and effi-
ciency of the process was explored under the optimized
conditions. For this purpose, a broad range of structurally
diverse aromatic aldehydes as well as aliphatic aldehydes
was condensed with 1,2-diketones and ammonium acetate
under the best conditions (Scheme 2). Ortho-substituted,
Entry Catalyst (%) Solvent Temp (ꢀC) Time (h) Yield (%)
1
2
3
4
5
6
7
8
10
10
5
5
5
5
5
5
5
5
5
5
5
EtOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
CH3CN
CH3CN
CH2Cl2
CHCl3
Toluene
i-PrOH
MeOH
t-BuOH
EtOH
RT
50
50
80
Reflux
RT
Reflux
Reflux
Reflux
80
80
Reflux
80
48
12
12
12
12
24
24
24
24
24
9
10
80
62
76
55
No product
14
Race
Race
23
62
72
9
10
11
12
13
14
15
9
13
27
58
5
Reflux
meta-substituted, and para-substituted aromatic aldehydes,
including electron-donating or electron-withdrawing
groups, undergo this one-pot multicomponent process to
afford 2,4,5-trisubstituded imidazoles in good yields
(Table 3). Aliphatic aldehydes afforded the corresponding
imidazoles in moderate yields (Table 3, entries 15 and
16). And the yield of furaldehyde to a corresponding
imidazole was very good. But the results of salicylalde-
hyde (Table 3, entry 5) and o-hydroxybenzaldehyde
(Table 3, entry 8) did not satisfy us. The reason is may
be that they have acidity of hydroxyl group, but catalyst
is alkaline, thus both of them affecting the catalytic
activity, thereby affecting the yields. Various functional
groups were found to be compatible under the optimum
reaction conditions. In general, the reactions were
clean, easy to purify, and tolerate the different functional
groups.
In order to explore the applicability of this method, the
same reaction conditions were applied for the synthesis of
1,2,4,5-tetrasubstituted imidazoles via the one-pot, four-
component condensation of 1,2-diketone (1mmol), alde-
hydes (1mmol), primary amine (1mmol), and ammonium
acetate (1 mmol) as depicted in Scheme 3.
The substrate scope of the reaction was then evaluated
using a variety of structurally diverse aldehydes, primary
amines, and 1,2-diketone. The 1,2,4,5- tetrasubstituted imi-
dazoles were obtained in moderate yields (Table 4).
Scheme 1. Three component condensation for synthesis 2,4,5-trisubstituded imidazoles.
N
Ph
O
Ph
catalyst
Ph
+
+
Ph-CHO
1eq.
NH4OAc
2eq.
NH
O
Ph
Ph
1eq.
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670
F. Xu, W. Nige, Y. Tian, and G. Li
Vol 50
Table 2
Condensation of 1,2-diketone, benzaldehyde, and ammonium acetate using different catalyst in n-buOH.
Entry
Catalyst
Catalyst (%)
Temp.(ꢀC)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
PPh3
DMAP
DMAP
Hexamethylenetramine
Benzotriazole
Diphenylguanidine
Benzimidazole
10
10
5
5
5
80
50
80
80
80
80
80
n-Butanol
n-Butanol
n-Butanol
n-Butanol
n-Butanol
n-Butanol
n-Butanol
24
24
12
12
12
12
12
80
81
76
68
88
69
61
5
5
Scheme 2. Benzotriazole-catalyzed synthesis of 2,4,5-trisubstituded imidazoles.
N
Ph
Ph
Ph
O
5mol% benzotriazole
n-BuOH, 80oC
R
+
+
R-CHO
1eq.
NH4OAc
2eq.
NH
O
Ph
1eq.
Table 3
Synthesis of 2,4,5-trisubstituted imidazoles.
EnEtrnytry
1
Aldehyde
Product
Time (h)
12
Yield (%)
88
2
12
76
3
4
12
12
82
75
5
12
70
6
7
12
12
75
81
(Continued)
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Simple and Efficient Method for the Synthesis of Highly
671
Substituted Imidazoles Catalyzed by Benzotriazole
Table 3
(Continued)
Entry
8
Aldehyde
Product
Time (h)
Yield (%)
63
12
9
12
83
80
83
10
11
12
12
12
12
79
13
14
14
13
83
82
15
16
17
12
12
10
76
75
81
Scheme 3. Benzotriazole-catalyzed synthesis of 1,2,4,5-tetrasubstituded imidazoles.
N
Ph
Ph
Ph
R1
O
5mol% benzotriazole
n-BuOH, 80oC
1
R2NH2
1eq.
NH4OAc
1eq.
+
+
+
R -CHO
N
R2
O
Ph
1eq.
1eq.
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F. Xu, W. Nige, Y. Tian, and G. Li
Vol 50
Table 4
Synthesis of 1,2,4,5-tetrasubstituted imidazoles catalyzed by benzotriazole.
Entry
1
Aldehyde
Amine(1)
Product
Time (h)
13
Yield (%)
60
2
3
15
15
62
64
4
5
15
14
58
56
EXPERIMENTAL
A plausible mechanism for the benzotriazole catalyzed
synthesis of substituted imidazoles (Scheme 4) has been
proposed. In the case of 2,4,5-trisubstituted imidazoles, the
reaction proceeds through diamine intermediate A, which
may form by two different pathways (pathway I or pathway
II). Path I involves the reaction of benzotriazole that has rich
electron pair with aldehyde leading to the formation of inter-
mediate and subsequent condensation with two molecules of
ammonia to form diamine intermediate A. Path II provides
diamine intermediate A via inimium catalyst. Intermediate
A condenses with carbonyl carbons of the 1,2-diketone
followed by dehydration to afford the imino B, which
rearranges to the desired trisubstituted imidazoles.
All solvents and reagents were used as obtained from commercial
sources. 1,2-Diketones were prepared according to standard methods
and their purities were established before utilization by melting point.
1H NMR spectra were recorded at 300 MHz, from CDCl3 and
CD3SOCD3 solutions. Ultra-high resolution MS was obtained on
MaXis UHR-TOP (Bruker Daltonic Corporation, Germany). The
IR spectra were recorded on Fourier transform infrared spectrometer
EQUINX55 (Brucher Corporation, Germany). All runs were con-
ducted at least in duplicate. The substituted imidazoles were identified
by comparison with samples prepared according to known procedures.
A general procedure for the synthesis of 2,4,5-substituted
imidazole derivatives. In
a 50 mL round bottom flask,
benzotriazole (6 mg) and aldehyde (1.0 mmol) were taken in
n-butanol (10mL) to dissolve. Then 1,2-diketone (1.0 mmol) and
ammonium acetate (2.0mmol) were added. After the reaction
mixture was heated at 80ꢀC slowly until completion of the
determinate time, the reaction mixture was cooled to room
temperature and the solvent was removed by rotary evaporator.
The crude residue was recrystallized by petroleum ether to obtain
the pure corresponding substituted imidazole derivatives.
CONCLUSION
In summary, we have identified a one-pot synthesis of
highly functionalized trisubstituted and tetrasubstituted
imidazoles from readily available starting materials utilizing
benzotriazole as the catalyst. This one-pot procedure is very
simple, easy work-up and purification of product.
2,4,5-Triphenyl-1H-imidazole (3–1).
NMR( DMSO-d6): d12.71(s, 1H), 8.09(d, J= 7.4Hz, 2H), 7.23–7.56
Mp 270–272ꢀC. 1H
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Simple and Efficient Method for the Synthesis of Highly
673
Substituted Imidazoles Catalyzed by Benzotriazole
Scheme 4. A plausible mechanisms for the formation of imidazoles. Pathway I—benzotriazole through electron pair. Pathway II—iminium catalysis.
Pathway I
N
NH2
N
N
H
OH2
NH4OAc
-H2O
N
N
N
N
N
H
NH2
N
H
O
NH2
NH2
NH4OAc
CHO
N
N
A
N
H
-2H2O
Ph
Ph
Ph
Ph
Ph
O
O
H
N
N
N
H
N
Ph
B
Pathway II
N
N
N
NH2
NH2
O
2NH3
N
N
N
H
H
H
-
HOAc
-H2O
N
N
N
Ph
O
O
C
H
-2H2O
Ph
Ph
Ph
Ph
H
N
N
N
N
H
Ph
B
(m, 13H); FTIR (KBr, cmÀ1): 3462, 2964, 1599, 1460; HRMS (ESI): m/z
calcd for C21H16N2 [M-H]+ 295.1313, found 295.1310.
7.90(d, J= 8.4 Hz, 2H), 7.23–7.52(m, 10 H), 6.86(d, J=8.2Hz, 2H);
FTIR (KBr, cmÀ1): 3455, 3283, 1701, 1284; HRMS (ESI): m/z calcd
for C21H16N2O [M+H]+ 313.1263, found 313.1266.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (3–2). Mp
226–228ꢀC. 1H NMR (DMSO-d6): d 7.86(d, J = 8.5Hz, 2H),
7.57–7.09(m, 10H), 6.88(d, J = 8.6 Hz, 2H), 3.83(s, 3H); FTIR
(KBr, cmÀ1): 3422, 3027, 2953, 1612, 1492, 1249; HR-MS (ESI):
m/z calcd for C22H18N2O [M+ H]+ 327.1419, found 327.1420.
4,5-Diphenyl-2-p-tolyl-1H-imidazole (3–3). Mp 233–235ꢀC.
1H NMR (DMSO-d6 ): d 12.57 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H),
7.22–7.56(m, 12H), 2.35(s, 3H); FTIR (KBr, cmÀ1): 3442, 3027,
1599, 1493, 1322; HRMS (ESI): m/z calcd for C22H18N2
[M + H]+ 311.1470, found 311.1473.
2-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazole (3–6).
Mp
253–253.5ꢀC. 1H NMR (DMSO-d6): d 12.71(s, 1H), 8.14
(d, J = 8.4 Hz, 2H), 7.91–6.95(m, 12H); FTIR (KBr, cmÀ1):
3428, 3028, 1607, 1492; HRMS (ESI): m/z calcd for
C21H15N2F [M + H]+ 315.1219, found 315.1217.
2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazole (3–7).
Mp
259–261ꢀC. 1H NMR (DMSO-d6): d 12.80(s, 1H), 8.04(d,
J = 8.4 Hz, 2H), 7.69(d, J = 8.4 Hz, 2H), 7.55–7.12(m, 10H);
FTIR (KBr, cmÀ1): 3430, 3029, 1600, 1483; HRMS (ESI): m/z
calcd for C21H15N2Br [M + H]+ 375.0419, found 375.0418.
4-(4,5-Diphenyl-1H-imidazole-2-yl)-phenyl-dimethylamine (3–
4).
Mp 250–252ꢀC. 1H NMR (300MHz, CDCl3): d 7.77
2-(4,5-Diphenyl-1H-imidazol-2-yl)-phenol (3–8).
Mp
(d, J = 8.6 Hz, 2H), 7.53(d, J = 6.1 Hz, 4H), 7.40–7.17(m, 6H),
6.73(d, J =8.6 Hz, 2H), 3.00(s, 6H); FTIR (KBr, cmÀ1): 3473,
3035, 1615, 1508; HRMS (ESI): m/z calcd for C23H21N3
[M + H]+ 340.1735, found 340.1733.
209.5–211ꢀC. 1H NMR (DMSO-d6): d 13.10 (br, s, 1H), 8.05
(d, J = 7.8, 1H), 7.26–7.52(m, 11H), 6.97(m, 2H); FTIR (KBr,
cmÀ1): 3447, 3192, 3057, 1601; HRMS (ESI): m/z calcd for
C21H16N2O [M + H]+ 313.1263, found 313.1262.
4-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (3–5).
Mp 253–
2-(4,5-Diphenyl-1H-imidazol-2-yl)-benzonitrile (3–9).
Mp
256ꢀC. 1H NMR (300 MHz, DMSO-d6): d 12.40(s, 1H), 9.62(s, 1H),
274–276ꢀC. 1H NMR (DMSO-d6):
d
13.10(s, 1H), 8.26
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F. Xu, W. Nige, Y. Tian, and G. Li
Vol 50
(d, J= 8.1 Hz, 2H), 7.95(d, J= 8.1 Hz, 2H), 727–754(m, 10H); FTIR
(KBr, cmÀ1): 3460, 3052, 2226, 1609, 1489; HRMS (ESI): m/z
calcd for C22H15N3 [M + H]+ 322.1266, found 322.1264.
1,2-Bis(4-methoxypheyl)-45-diphenyl-1H-imidazole (4–2). Mp
1
197–199ꢀC. H NMR (CDCl3): d 7.59(s, 2H), 7.37(d, J=8.6Hz,
2H), 7.10–7.39(m, 8H), 6.93(d, J= 8.6 Hz, 2H), 6.76(d, J=7.8Hz,
4H), 3.77(s, 3H), 3.74(s, 3H); FTIR (KBr, cmÀ1): 3012, 2932, 1608,
1514; HRMS (ESI): m/z calcd for C29H24N2O2 [M + H]+ 433.1838,
found 433.1839.
1-(4-Methoxyphenyl)-2,4,5-triphenyl-1H-imidazole (4–3). Mp
167–169ꢀC. 1H NMR (300 MHz, CDCl3): d 7.60(d, J=7.2Hz, 2H),
7.46(d, J= 3.6 Hz, 2H), 7.35–7.06(m, 10H), 6.95(d, J= 8.7 Hz, 2H),
6.73(d, J=8.7Hz, 2H), 3.73(s, 3H); FTIR (KBr, cmÀ1): 3051,
2960, 1601, 1510; HRMS (ESI): m/z calcd for C28H22N2O
[M + H]+ 403.1732, found 403.1734.
1-(4-Methoxyphenyl)-2,4,5-triphenyl-1H-imidazole (4–4). Mp
163–165ꢀC. 1H NMR (CDCl3): d 7.55(d, J= 7.1 Hz, 2H), 7.32
(d, J= 8.5 Hz, 2H), 7.25–7.07(m, 9H), 7.04(d, J= 6.4 Hz, 2H), 6.97
(d, J= 5.9 Hz, 2H), 6.71(d, J= 8.6 Hz, 2H), 3.70(s, 3H); FTIR
(KBr, cmÀ1): 3660, 2956, 1607, 1481; HRMS (ESI): m/z calcd for
C28H22N2O [M+ H]+ 403.1732, found 403.1730.
4-(4,5-Diphenyl-1H-imidazole-2-yl)-phenyl-diethylamine (3–10). Mp
221–223ꢀC. 1H NMR (CDCl3): d 7.72(d, J= 8.5 Hz, 2H), 7.50(d,
J=6.3Hz, 4H), 7.35–7.15(m, 6H), 6.66(d, J=8.4Hz, 2H), 3.40–3.33(m,
4H), 1.17(t, 6H); FTIR (KBr, cmÀ1): 3468, 3029, 2969, 2932, 1616;
HRMS (ESI): m/z calcd for C25H25N3 [M + H]+ 368.2048, found 368.2045.
4-(4,5-Diphenyl-1H-imidazole-2-yl)-phenyl-methyl (3–11). Mp
240.5–242ꢀC. 1H NMR (300 MHz, DMSO-d6): d 12.85(s,1H), 8.24
(d, J= 7.9 Hz, 2H), 8.07(d, J= 7.9 Hz, 2H), 7.83–6.80(m, 10H), 3.88
(s, 3H); FTIR (KBr, cmÀ1): 3348, 3055, 1649, 1609, 1438; HRMS
(ESI): m/z calcd for C23H18N2O2 [M + H]+ 355.1368, found 354.1365.
2-(2,4-Dichloropheny)-4,5-dipenyl-1H-imidazole (3–12). Mp
174.5–175.5ꢀC. 1H NMR (CDCl3): d 10.22(s, 1H), 8.41(d,
J = 8.6Hz, 1H), 7.22–7.56(m, 12H); FTIR (KBr, cmÀ1): 3066,
2928, 1594, 1476, HRMS (ESI): m/z calc. for C21H14N2Cl2
[M + H]+ 365.0534, found 365.0535.
2-(4-Methylphenyl)-1,4,5-triphenylimidazole (4–5).
Mp
1
180–182ꢀC. H NMR (300 MHz, CDCl3): d 7.60 (d, J = 7.0 Hz,
3H), 7.01–7.40(m, 16H), 2.30(s, 3H); FTIR (KBr, cmÀ1): 3042,
1595, 1493; HRMS (ESI): m/z calcd for C28H22N2 [M + H]+
387.1783, found 387.1786.
2-(2,6-Dichloropheny)-4,5-dipenyl-1H-imidazole (3–13). Mp
1
229–230ꢀC. H NMR (CDCl3): d 9.42(s, 1H), 7.66 (d, J=7.0Hz,
2H), 7.17–7.57 (m, 11H); FTIR (KBr, cmÀ1): 3055, 1599, 1447;
1194; HRMS (ESI): m/z calcd for C22H18N2O [M + H]+ 327.1419,
found 327.1416.
2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazole (3–14).
Mp
1
265.5–266.5ꢀC. H NMR (300MHz, DMSO-d6): d 12.71(s, 1H),
8.10(d, J =8.2 Hz, 2H), 7.77–7.09(m, 12H); FTIR (KBr, cmÀ1):
3430, 3055, 1602, 1433; HRMS (ESI): m/z calcd for C21H15N2Cl
[M + H]+ 331.0924, found 331.1927.
Acknowledgment. We are pleased to acknowledge the financial
support from the National Natural Science Foundation of China
(20872085, 21072124).
4,5-Diphenyl-1H-imidazole (3–15).
Mp 230–231.5ꢀC. 1H
NMR (DMSO-d6): d 12.45 (s, 1H), 7.77 (s, 1H), 7.33–7.44(m,
10H); FT–IR (KBr, cmÀ1): 3059, 2990, 1602, 1513; HRMS
(ESI): m/z calcd for C15H12N2 [M + H]+ 221.1000, found
221.1008.
2-Hexyl-4,5-diphenyl-1H-imidazole (3–16). Mp 129–130ꢀC.
1H NMR (CDCl3): d 11.26(s, 1H), 7.44(d, J = 6.2Hz, 4H), 7.22(d,
J = 6.1Hz, 6H), 2.63–2.27(m, 2H), 1.54(dd, J = 15.2, 7.5 Hz, 2H),
1.35–1.00(m, 6H), 0.92–0.64(m, 3H); FTIR (KBr, cmÀ1): 3031,
2953, 2924, 2854, 1602; HRMS (ESI): m/z calcd for C21H24N2
[M + H]+ 305.1935, found 305.1932.
2-Furan-2-yl-4,5-diphenyl-1H-imidazole (3–17). Mp 231–232ꢀC.
1H NMR (CDCl3): d 9.84(s, 1H), 7.47(d, J= 18.7 Hz, 5H), 7.29(s, 6H),
6.95(s, 1H), 6.50(s, 1H); FTIR (KBr, cmÀ1): 3056, 1601, 1525, 1425;
HRMS (ESI): m/z calcd for C19H14N2O [M+H]+ 287.1106, found
REFERENCES AND NOTES
[1] Heers, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. J
Med Chem 1979, 22, 1003.
[2] Hunkeler, W.; Mohler, H.; Pieri, L.; Polc, P.; Bonetti, E. P.;
Cumin, R.; Schaffner, R.; Haefely, W. Nature 1981, 290, 514.
[3] Brimblecomble, R. W.; Duncan, W. A. M.; Durant, G. J.;
Emmett, J. C.; Ganellin, C. R.; Parsons, M. E. J Int Med Res 1975, 3, 86.
[4] ]Tanigawara, Y.; Aoyama, N.; Kita, T.; Shirakawa, K.; Komada,
F.; Kasuga, M.; Okumura, K. Clin Pharmacol Ther 1999, 66, 528.
[5] Wauquier, A.; Van Den Broeck, W. A. E.; Verheyen, J. L.;
Janssen, P. A. J. Eur. J. Pharmacol. 1978, 47, 367.
[6] Philips, A. P.; White, H. L.; Rosen, S. Eur. Pat. Appl. EP 1982,
58890.
[7] Lee, J. C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.;
Kumer, S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Keys, J. R.; Vatter,
S. W. L.; Strickler, J. E.; McLaughlin, M. M.; Siemens, I. R.; Fisher, S. M.;
Livi, G. P.; White, J. R.; Adams, J. L.; Young, P. R. Nature 1994, 372, 739.
[8] De Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.;
Mantalo, N.; Pivnichnny, J. V.; Colwell, L.; Koch, G. E.; Cascieri, M.
A.; Hagmenn, W. K. Bioorg Med Chem Lett 1999, 9, 641.
[9] Schmierer, R.; Mildenberger, H.; Buerstell, H. German Patent
1987, 361464; Chem. Abstr. 1988, 108, 37838.
[10] Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Custem, J. J
Med Chem 1979, 22, 1003.
[11] Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.;
Ursini, A. Bioorg Med Chem Lett 1999, 9, 1023.
[12] Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R.
W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y. H.; Marsh, K.;
Warner, R.; Lee, J. Y.; Zielinsky-Mozong, N.; Frost, D.; Rosenberg, S.
H.; Sham, H. L. J Med Chem 2002, 45, 1697.
[13] (a) Welton, T. Chem Rev 1999, 99, 2071; (b) Wasserscheid,
P.; Keim, W. Angew Chem Int Ed Engl 2000, 39, 3772.
[14] (a) Hermann, W. A.; Kocher, C. Angew Chem Int Ed Engl
1997, 36, 2162; (b) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J.
287.1108.
A general procedure for the synthesis of 1,2,4,5-substituted
imidazole derivatives.
In a 50 mL round bottom flask,
benzotriazole (6 mg) and aldehyde were taken in n-butanol
(10mL) and dissolved. Then 1,2-diketone (1.0mmol), ammonium
acetate (1.0mmol), and primary amine (1.0 mmol) were added,
after which the reaction mixture was heated at 80ꢀC slowly until
the determinate time. The reaction mixture was cooled to room
temperature, and the solvent was removed by rotary evaporator.
The crude residue was purified by column chromatography using
ethyl acetate and petroleum ether (1:7) as eluent to give the
corresponding substituted imidazole derivatives.
1,2,4,5-Tetraphenylimidazole (4–1).
Mp 216–217ꢀC. 1H
NMR (CDCl3): d 7.60(d, J = 7.3 Hz, 2H), 7.43(d, J = 5.1 Hz,
2H), 7.25(s, 12H), 7.14(s, 2H), 7.03(d, J = 6.0 Hz, 2H); FTIR
(KBr, cmÀ1):3057, 1595, 1494; HRMS (ESI): m/z calcd for
C27H20N2 [M + H]+ 373.1626, found 373.1627.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2013
Simple and Efficient Method for the Synthesis of Highly
675
Substituted Imidazoles Catalyzed by Benzotriazole
Org. Chem. 1999, 64, 3804; (c) Bourissou, D.; Guerret, O.; Gabbai, F. P.;
Bertrand, G. Chem Rev 2000, 100, 39.
[15] Gostev, F. E.; Kol’tsova, L. S.; Petrukhin, A. N.; Titov, A. A.;
Shiyonok, A. I.; Zaichenko, N. L.; Marevtsev, V. S.; Sarkisov, O. M. J.
Photochem. Photobiol., A 2003, 156, 15.
Tetrahedron Lett 1996, 37, 835; (c) Gallagher, T. F.; Seibel, G. L.; Kassis,
S.; Laydon, J. T.; Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.;
Fier-Thompson, S. M.; Abt, J. W.; Soreson, M. E.; Smietana, J. M.; Hall,
R. F.; Garigipati, R. S.; Bender, P. C.; Kumar, S.; Young, P. R.; Adams, J.
L. Bioorg Med Chem 1997, 5, 49.
[27] (a) Shaabani, A.; Rahmati, A. J. Mol. Catal. A: Chem. 2006,
249, 246; (b) Shaabani, A.; Rahmati, A.; Farhangi, E.; Badri, Z. Catal.
Commun. 2007, 8, 1149.
[16] Nagawade, R. R.; Shinde, D. B. Acta Chin. Slov. 2007, 54, 642.
[17] Chauveau, E.; Marestin, C.; Schiets, F.; Mercier, R. Green
Chem. 2010, 12, 1018.
[28] Heravi, M. M.; Bakhtiari, K.; Oskooie, H. A.; Taheri, S. J.
Mol. Catal. A: Chem. 2007, 263, 279.
[29] Sharma, G. V. M.; Jyothi, Y.; Lakahmi, P. S. Synth. Commun.
2006, 36, 2991.
[30] Hasaninejad, A.; Zare, A.; Shekouhy, M.; Ameri Rad, J. J
Comb Chem 2010, 12, 844.
[31] Sangshetti, J. N.; Kokare, N. D.; Kotharkara, S. A.; Shinde, D.
B. J. Chem. Sci. 2008, 5, 463.
[18] Kidwai, M.; Mothsra, P.; Bansal, V.; Somvanshi, R. K.;
Ethayathulla, A. S.; Dey, S.; Singh, T. P. J. Mol. Catal. A: Chem. 2007,
265, 177.
[19] Kantevari, S.; Vuppalapati, S. V. N.; Biradar, D. O.; Nagarapu,
L. J. Mol. Catal. A: Chem. 2007, 266, 109.
[20] (a) Heravi, M. M.; Derikvand, F.; Bamoharram, F. F. J. Mol.
Catal. A: Chem. 2007, 263, 112; (b) Nagarapu, L.; Apuri, S.; Kantevari,
S. J. Mol. Catal. A: Chem. 2007, 266, 104.
[32] Sharma, S. D.; Hazarika, P.; Konwar, D. Tetrahedron Lett
2008, 49, 2216.
[33] Nageswar, Y. V. D.; Narayana Murthy, S.; Madhav, B. Tetra-
hedron Lett 2010, 51, 5252.
[21] Karimi, A. R.; Alimohammadi, Z.; Azizian, J.; Mohammadi,
A. A.; Mohammadizadeh, M. R. Catal. Commun. 2006, 7, 728.
[22] Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. Tetrahedron
2009, 65, 10155.
[34] Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem
Rev 1998, 98, 409.
[23] Hervi, M. M.; Derikvand, F.; Haghighi, M. Monasth. Chem.
2008, 139, 31.
[35] Verma, A. K.; Singh, J.; Sankar, V. K.; Chaudhary, R.; Chan-
dra, R. Tetrahedron Lett 2007, 48, 4207.
[24] Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron
Lett 2008, 49, 2575.
[36] Talukdar, S.; Chen, R. J.; Chen, C. T.; Lo, L. C.; Fang, J. M. J
Comb Chem 2001, 3, 341.
[25] Karimi, A. R.; Alimohammadi, Z.; Amini, M. M. Mol Divers
2010. 14, 635.
[37] Talukdar, S.; Chen, C. T.; Fang, J. M. J Org Chem 2000, 65,
3148.
[26] (a) Wang, J.; Mason, R.; Derveer, D. V.; Feng, K.; Bu, X. R. J
Org Chem 2003, 68, 5415; (b) Sarshar, S.; Siev, D.; Mjalli, A. M. M.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet